Document Detail

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression.
Jump to Full Text
MedLine Citation:
PMID:  24473089     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Since its original identification as a leukocyte gelatinase/type V collagenase and tumour type IV collagenase, gelatinase B/matrix metalloproteinase (MMP)-9 is now recognised as playing a central role in many aspects of tumour progression. In this review, we relate current concepts concerning the many ways in which gelatinase B/MMP-9 influences tumour biology. Following a brief outline of the gelatinase B/MMP-9 gene and protein, we analyse the role(s) of gelatinase B/MMP-9 in different phases of the tumorigenic process, and compare the importance of gelatinase B/MMP-9 source in the carcinogenic process. What becomes apparent is the importance of inflammatory cell-derived gelatinase B/MMP-9 in tumour promotion, early progression and triggering of the "angiogenic switch", the integral relationship between inflammatory, stromal and tumour components with respect to gelatinase B/MMP-9 production and activation, and the fundamental role for gelatinase B/MMP-9 in the formation and maintenance of tumour stem cell and metastatic niches. It is also apparent that gelatinase B/MMP-9 plays important tumour suppressing functions, producing endogenous angiogenesis inhibitors, promoting inflammatory anti-tumour activity, and inducing apoptosis. The fundamental roles of gelatinase B/MMP-9 in cancer biology underpins the need for specific therapeutic inhibitors of gelatinase B/MMP-9 function, the use of which must take into account and substitute for tumour-suppressing gelatinase B/MMP-9 activity and also limit inhibition of physiological gelatinase B/MMP-9 function.
Antonietta Rosella Farina; Andrew Reay Mackay
Related Documents :
7593779 - Epidermal cytokines in allergic contact dermatitis.
10764989 - The roles of cytokines in photoaging.
19379509 - Activation of p2x(7)-mediated apoptosis inhibits dmba/tpa-induced formation of skin pap...
15599309 - In vivo recognition by the host adaptive immune system of microencapsulated xenogeneic ...
7937799 - Intradermal gene immunization: the possible role of dna uptake in the induction of cell...
1419749 - Distribution of interleukin 1 receptor antagonist protein (irap), interleukin 1 recepto...
9990529 - Cytokines and the microcirculation in ischemia and reperfusion.
19693659 - The molecular mechanisms of cell death in the course of transient ischemia are differen...
25045209 - Functional roles of syk in macrophage-mediated inflammatory responses.
Publication Detail:
Type:  Journal Article     Date:  2014-01-27
Journal Detail:
Title:  Cancers     Volume:  6     ISSN:  2072-6694     ISO Abbreviation:  Cancers (Basel)     Publication Date:  2014  
Date Detail:
Created Date:  2014-01-29     Completed Date:  2014-01-29     Revised Date:  2014-04-10    
Medline Journal Info:
Nlm Unique ID:  101526829     Medline TA:  Cancers (Basel)     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  240-96     Citation Subset:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Full Text
Journal Information
Journal ID (nlm-ta): Cancers (Basel)
Journal ID (iso-abbrev): Cancers (Basel)
Journal ID (publisher-id): cancers
ISSN: 2072-6694
Publisher: MDPI
Article Information
Download PDF
© 2014 by the authors; licensee MDPI, Basel, Switzerland.
Received Day: 16 Month: 12 Year: 2013
Revision Received Day: 20 Month: 1 Year: 2014
Accepted Day: 21 Month: 1 Year: 2014
Electronic publication date: Day: 27 Month: 1 Year: 2014
collection publication date: Month: 3 Year: 2014
Volume: 6 Issue: 1
First Page: 240 Last Page: 296
PubMed Id: 24473089
ID: 3980597
DOI: 10.3390/cancers6010240
Publisher Id: cancers-06-00240

Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression
Antonietta Rosella Farina
Andrew Reay Mackay*
Department of Applied Clinical and Biotechnological Sciences, University of L’Aquila, Via Vetoio, Coppito 2, L’Aquila 67100, Italy; E-Mail:
* Author to whom correspondence should be addressed; E-Mail:; Tel.: +39-0862-433542; Fax: +39-0862-433523.

1. Introduction

Since the original identification of galetinase B/matrix metalloproteinase (MMP)-9, as a human leukocyte gelatinase [1,2,3,4], its characterisation as a type V collagenase [5], the observation that malignant tumour cells express an identical enzyme that associates with metastatic behaviour and degrades type IV collagen under certain conditions [6,7,8,9,10] and its subsequent cloning from HT-1080 fibrosarcoma cells [11], research into the physiological and pathological functions of gelatinase B/MMP-9, in contrast to almost all other MMPs, has continued to increase at a steady rate [12,13]. Gelatinase B/MMP-9 involvement in malignant tumour progression has now moved on from original concepts of an almost exclusive role in matrix degradation, associated with tumour invasion, to include roles in almost all aspects of tumour biology, ranging from initiation and early progression, to angiogenesis, dissemination, invasion and motility, formation of the cancer stem cell niche, regulation of tumour immunological surveillance, metastatic site preparation and promotion of metastatic growth.

In the present article, following a briefly description of the human gelatinase B/MMP-9 gene, protein and mechanisms that regulate its expression, activation and activity, we review current concepts concerning gelatinase B/MMP-9 involvement in tumour progression, starting with the genetic damage that results in transformation and accompanies tumorigenicity, neoplastic expansion and the accumulation of mutations, increased survival, tumour-associated angiogenesis, adhesive interactions, matrix degradation and the loss of basement membrane, tumour cell invasion, motility, intravasation and extravasation, evasion of immunological surveillance, and regulation of the cancer stem cell and metastatic niches. We also review tumour-associated mechanisms that alter the equilibrium between gelatinase B/MMP-9 and its inhibitors and address novel ways to inhibit gelatinase B/MMP-9 involvement in tumour progression.

2. The Gelatinase B/MMP-9 Gene and mRNA

The human gelatinase B/MMP-9 gene localises to chromosome 20q11.2-q13.1, consists of 7,654 bases, starting from 44,637,547 bp from pter to 44,645,200 bp from pter, and is arranged into 13 exons [14]. The 2.2 kb gelatinase B/MMP-9 promoter resembles that of MMP-1 and MMP-3 rather than the MMP-2 one, and contains a TATA motif at position -29, GC box at position -563, TGF-beta inhibitory element at position -474, AP-1 elements at positions -79 and -209, three Ets binding PEA3 sites between -599 and -531, an NF-κB element at positions -600 and -328, two AP-2 elements and a (CA)n segment [12]. Gelatinase B/MMP-9 is transcribed as a single 2.4 kb mRNA species and alternative splice variants have not been reported [15,16]. The gelatinase B/MMP-9 3'-UTR contains functional bindings sites for miR-491-5p, miR-885-5p [17] and miR-211 [18].

Gelatinase B/MMP-9 SNPs

A single C > T nucleotide polymorphism at position −1562 within the gelatinase B/MMP-9 promoter, originally associated with coronary atherosclerosis [19], deregulates gelatinase B/MMP-9 expression and associates with gastric tumour progression [20], susceptibility to oral squamous cell carcinoma [21,22,23], nasopharyngeal carcinoma [24], squamous cell carcinoma of the lung [25] and oesophageal squamous cell carcinoma [26], and also associates with a higher risk of metastasis in the Asian, but not the European population [27]. Polymorphisms in the length of (CA)n sequence within the gelatinase B/MMP-9 promoter have been reported, with lengths of (CA)21 and (CA)23 shown to increase gelatinase B/MMP-9 transcription [28,29,30]. This region is close to TRE, SP1 and NF-κB cis elements and may alter their function. The (CA)n element binds a specific DNA binding protein, dependent upon CA number [30]. The gelatinase B/MMP-9 polymorphism Rs1056628CC, detected within the Chinese population, is characterised by a change in base 2182 from A to C within the 3'-UTR miR491-5p binding sequence and increases gelatinase B/MMP-9 expression, potentially through altered miR-491-5p binding [31]. Two gelatinase B/MMP-9 coding region single nucleotide polymorphisms rs2250889 (P574R) and rs17576 (R279Q) have been associated with risk of lung cancer and lung cancer metastasis [32], and with reduced overall survival of patients with loco regionally advanced nasopharyngeal carcinoma, characterised by increased tissue gelatinase B/MMP-9 expression [33,34], lymph node metastasis in gastric cancer [35] and risk of gallbladder cancer [36] but these SNPs do not appear to associate with colon cancer susceptibility in a Chinese cohort study [37]. In addition to these reports, gelatinase B/MMP-9 coding region SNPs Arg279Gln and Arg668Gly may represent potential predictors of survival in Chinese patients with non-small cell lung cancer [38].

3. The Gelatinase B/MMP-9 Protein

We direct the reader to the excellent and extensive reviews by Van den Steen and colleagues, and Vandooren and colleagues [12,13], concerning gelatinase B/MMP-9 biochemistry and molecular biology. Briefly, the gelatinase B/MMP-9 protein is a multi-domain metallo-enzyme, with a catalytic site composed of a metal binding domain separated from the active site by three fibronectin repeats that facilitate the degradation of large substrates such as elastin and denatured collagens. Within this region the amino acids Asp309, Asn319, Asp232, Tyr320 and Arg3076 are important for gelatin binding. The catalytic site is maintained inactive by an amino-terminal pro-peptide PRCGXPD, with the cysteine coordinated with the catalytic Zn2+. The COOH terminus of gelatinase B/MMP-9 contains a hemopexin domain that regulates substrate binding, interacts with inhibitors and facilitates cell surface binding. A central O-glycosylated domain provides molecular flexibility, regulates gelatinase B/MMP-9 substrate specificity, gelatinase B/MMP-9-dependent invasion, interaction with TIMP and cell surface localisation. This domain facilitates the movement of gelatinase B/MMP-9 along macromolecular substrates and unwinds collagen initially cleaved by other enzymes, permitting gelatinase B/MMP-9-mediated degradation [12,13].

3.1. Gelatinase B/MMP-9 Catalytic Site

Within the gelatinase B/MMP-9 catalytic domain the amino acid Glu402 and Zn2+ ion are essential for function, amino acids Leu397 and Ala406 are important for general catalytic activity, Asp410 enhances type V collagenolytic activity, Pro415 enhances gelatinolytic activity [39] and Gly substitution of Glu415 renders gelatinase B/MMP-9 collagenolytic [40]. The propeptide domain contains a “cysteine switch” sequence that binds to the catalytic Zn2+ ion, inhibiting catalytic activity. Gelatinase B/MMP-9 activation is achieved by proteolytic removal of this sequence by enzymes that include: trypsin, cathepsin G, kallikrien, elastase, chymase, neutrophil elastase and the MMPs-1, -2, -3, -7, -10, -13 and -26 [12]. Debate exists, however, as to whether plasmin can directly activate gelatinase B/MMP-9 [12,41]. Indirect plasmin-mediated gelatinase B/MMP-9 activation is achieved via MMP-1, MMP-3 and MMP-7 [12]. In addition to proteolytic gelatinase B/MMP-9 activation, agents that modify the interaction between the pro-peptide cysteine and the catalytic site Zn2+ ion, such as ionic detergents, organo-mercurials, oxidising agents, S-nitrosylation and S-glutothiolation can also activate gelatinase B/MMP-9 [12,42,43,44]. The gelatinase B/MMP-9 catalytic domain contains six disulphide bonds that are necessary for intracellular trafficking and gelatinase B/MMP-9 secretion [45]. The gelatinase B/MMP-9 catalytic site also contains cryptic plasmin degradation sites that are exposed by divalent cation chelators and by the bisphosphonate alendronate (Fosamax) and upon degradation irreversibly inhibit gelatinase B/MMP-9 catalytic activity [41].

3.2. Gelatinase B/MMP-9 Hemopexin Domain

The gelatinase B/MMP-9 hemopexin domain exhibits a relatively unique covalent structure in which Cys516 and Cys704 form a disulphide bridge, which is involved in domain function but is not required for gelatinase B/MMP-9 secretion [45,46]. This domain facilitates interactions with substrates, gelatinase B/MMP-9 oligomerisation, binds the carboxyl terminal of TIMP-1, binds cell surface proteins such Ku70/80 and LRP, and upon binding appropriate substances, such as heme, also mediates autocatalytic gelatinase B/MMP-9 activation [47]. Divergent disulphide bridging between the 17-cysteine residues within gelatinase B/MMP-9 regulates structure and function. Disulphide bridging within fibronectin repeats are essential for gelatinase B/MMP-9 secretion. Hemopexin domain function depends upon disulphide bridging and disulphide bridging between the O-glycosylation or hemopexin domains facilitates gelatinase B/MMP-9 dimerization or oligomerisation, promoting CD44 binding, which results in activation of the EGF receptor and subsequent ERK/1/2 mediated cancer cell migration [46,48]. Gelatinase B/MMP-9 hemopexin domain hetero-dimerization with proteins such as TIMP-1 and NGAL protects gelatinase B/MMP-9 against proteolytic degradation.

3.3. Gelatinase B/MMP-9 O-Glycosylation Domain

The O-glycosylated domain of gelatinase B/MMP-9, also known as the type V collagen-like domain, represents a 64 amino acid linker containing 22 proline residues, six glycine residues and approximately 12–14 O-linked glycans [49]. This domain is active in hemopexin domain orientation, which is important for molecular interactions with exogenous proteins, including gelatinase B/MMP-9 substrates [49]. The removal of this domain reduces gelatinase B/MMP-9 specificity for macromolecular substrates, including gelatin [13].

3.4. Truncated Gelatinase B/MMP-9 Isoforms

Several truncated gelatinase B/MMP-9 isoforms have been described that include proteolytically active fragments derived from autocatalysis and exogenous proteolytic degradation. The 65 kDa gelatinase B/MMP-9 catalytically active fragment generated by MMP-3 is deleted of COOH terminal sequence and escapes TIMP-1 inhibition. KLK7 and meprin-α also remove this domain from gelatinase B/MMP-9 [50,51,52]. A novel 82 kDa inactive pro-gelatinase B/MMP-9 form has been described in human leukaemic cells, which also escapes TIMP inhibition [53,54] and a similar sized human pro-gelatinase B/MMP-9 isoform is generated by the action of plasmin [41].

4. Gelatinase B/MMP-9 Substrates

Gelatinase B/MMP-9 was originally characterised as a gelatinase/V collagenase [1,2,3,4,5], and was later attributed type IV collagenolytic activity [6,11]. Although there is controversy surrounding the susceptibility [55] or resistance [8,40,56] of triple helical domains of collagens to degradation by gelatinase B/MMP-9, the capacity of gelatinase B/MMP-9 to degrade native type IV collagen may be limited, therefore, to non-triple helical, less-disulphide cross-linked or pre-digested molecular forms of type IV collagen [8,57,58]. It remains debatable whether activated gelatinases alone degrade type IV collagen within the context of an insoluble basement membrane [8,57,58,59]. Gelatinase B/MMP-9 does, however, degrade basement membrane laminin, disrupting basement membrane structure, tissue architecture [60] and inducing apoptosis [61]. In addition to its capacity to degrade extracellular matrix components, recent reports have characterized an ever-increasing array of substrates susceptible to degradation by gelatinase B/MMP-9, dramatically widening the potential physiological and pathological sphere of gelatinase B/MMP-9 influence. Gelatinase B/MMP-9 exhibits substrate specificity for cytokines, chemokines and growth factors within the extracellular compartment and may also degrade nuclear, mitochondrial and cytoplasmic substrates (Table 1). For a broad spectrum of gelatinase B/MMP-9 substrates, both old and new, we direct reader to the following articles [52,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116,117,118].

5. Gelatinase B/MMP-9 Transcription and Translation

The 2.2 kb human gelatinase B/MMP-9 promoter contains a TATA-like motif at position −29 but no CAAT-like motif. Relative to the transcriptional start site, functional transcription sites include: an SP1 binding GC box located at −563, a retinoblastoma binding element or GT box that also binds SP1 at position −54, and three additional GT boxes. In addition to a TGF-β1 inhibitory element at −474 bp and 4 potential AP-1 binding elements, the functional AP-1 site at position −79 is essential for basal and jun/Fos induced expression in HT-1080 and osteosarcoma cells [119], three functional PEA3/Ets binding sites localise between −599 and −531 are also involved in basal gelatinase B/MMP-9 transcription [119,120]. A functional NF-κB binding site is located at −600 and a second site at −328 bp [121], and potentially functional inhibitory AP-2-like binding sites immediately upstream of the GC-box that interferes with Sp-1 binding [122], an alternating microsatellite CA sequence in close proximity to the AP1 site at position −79 [12] (Figure 1).

Synergism between transcriptional elements characterises basal-, cytokine- and phorbol ester-induced gelatinase B/MMP-9 transcription, with the AP-1 element at position −79 necessary, but not sufficient for transcription, cooperating with NF-κB (−600) and SP1 (−563) elements, respectively [119]. The NF-κB element (−600) is required for gelatinase B/MMP-9 transcription induced during spontaneous epithelial to neuroblast transition and by all-trans-retinoic acid in human neuroblastoma cells [123,124], by TNF-α in HT-1080 fibrosarcoma cells and rabbit fibroblasts [119,125,126], IL1β [127], Bcl2 [128], HIV-1-Tat [129], KiSS1 [130], synergistic combinations of cytokines and growth factors [126,131] and thioredoxin [132], acting in concert with other elements including the AP-1 site at position −79. The Ets element at −541 acting together with the AP-1 element at position −533 regulates gelatinase B/MMP-9 transcription induced by c-Ha- Ras, EGF and fibroblast cell contact [12,120,133]. Both RBE (−54) and AP-1 (−79) elements regulate v-Src induced gelatinase B/MMP-9 transcription in fibrosarcoma cells, c-Ha-Ras induced gelatinase B/MMP-9 transcription in adenocarcinoma cells and c-Ha-ras/v-myc-induced gelatinase B/MMP-9 transcription in rat embryo cells [133]. The RBE element (−54) also functions together with the NF-κB element (−600) in gelatinase B/MMP-9 transcription induced by spontaneous epithelial to neuroblast conversion exhibited by SK-N-SH neuroblastoma cells [123]. In general, gelatinase B/MMP-9 transcription with few exceptions depends upon the concerted interaction between several transcriptional cis elements and cognate transcription factors, with particular important roles highlighted for AP1 (−79) and NF-κB (−600) elements, with NF-κB and SP1 transcription factors specific determinant for gelatinase B/MMP-9 expression. Recently, a functional binding site for the E2 protein expressed by human oncogenic papilloma virus 8 has been characterised at position −1100 of the human MMP-9 promoter and shown to promote MMP-9 transcription [134].

The gelatinase B/MMP-9 protein is constitutively expressed by only a limited number of cell types, such as keratinocytes, macrophages, polymorphonuclear leukocytes and some malignant tumour cell lines, including MDA-MB-231 breast cancer, HT-1080 fibrosarcoma and A2058 melanoma cell lines [12,15] and is readily induced in wide range of normal and tumour cell types by pro-inflammatory cytokines, activators of PKC and growth factors with gelatinase B/MMP-9 expression regulated through inhibitory STAT and SMAD pathways and stimulatory PKC, Ras/MAPK, TRAD/TRAF, MEK/JNK, ASK/MKK and IRAK/TRAF pathways [12,13,15].

Gelatinase B/MMP-9 expression is also regulated at the level of mRNA stability, translation and protein secretion [135,136,137,138,139,140,141].

6. Gelatinase B/MMP-9 Expression, Bioavailability, Activity and Endogenous Inhibitors

Gelatinase B/MMP-9 expression is up-regulated in vitro by pro-inflammatory cytokines and PKC activators in human melanoma, neuroblastoma, teratocarcinoma, lung cancer and fibrosarcoma cells [15,16] and in rabbit fibroblasts [131], by chemokines in prostate cancer cells [142] and by growth factors, such as TGFβ in human breast cancer cells [143], EGF in human prostate [144], squamous cell carcinoma [145] and renal carcinoma cells [146], HGF in colon [147], renal [148], hepatocellular carcinoma [149], mesothelioma [150], lung cancer [151] and pancreatic tumour cells [152], by FGF in rabbit fibroblasts [131], human osteosarcoma cells [153], human bladder cancer cells [154] and human breast cancer cells [155,156], by neuropeptides in prostate cancer cell lines [157] and by haemoglobin in malignant melanoma and bladder cancer cells [158]. Gelatinase B/MMP-9 is also induced in neuroblastoma cells in association with spontaneous epithelial to neuroblast phenotype conversion and following treatment with all-trans-retinoic acid [123,124] and released from IL-8 stimulated neutrophils [159].

Gelatinase B/MMP-9 enzymatic activity is inhibited by the universal systemic protease inhibitor α2-macrogloblin [160], members of the tissue inhibitors of metalloproteinases (TIMPs) family [161,162] and is also antagonized by its own isolated hemopexin domain [41,163]. TIMPs 1–4 are 20–30 kDa glycoprotein MMP inhibitors that depend upon disulphide bridges between 6 cysteine pairs for their inhibitory activity [161,162,164]. TIMP-1 exhibits a unique binding interaction with gelatinase B/MMP-9 and, with the exception of human neutrophils, exhibits a high level of coordinated expression with TIMP-1, is frequently secreted as a TIMP-1/gelatinase B/MMP-9 complex and binds gelatinase B/MMP-9 with high affinity, in contrast to TIMP-2 and TIMP-3 [12,15,41,123,157,162]. The interaction between pro-form gelatinase B/MMP-9 and TIMP-1 involves the C-terminal domains of both proteins and in this form TIMP-1 is available to inhibit other MMPs. Upon gelatinase B/MMP-9 activation, TIMP-1 inhibits gelatinase B/MMP-9 catalytic activity through N-terminal interaction with the gelatinase B/MMP-9 catalytic site, with inhibition facilitated by the gelatinase B/MMP-9 C-terminus, since it does not readily occur in gelatinase B/MMP-9 C-terminus deletion mutants. In contrast to TIMP-1, TIMP-2 inhibition of gelatinase B/MMP-9 depends upon the N-terminal domain, but does not involve C-terminal interaction and is less effective that TIMP-1. TIMP-3 is a matrix-associated inhibitor that interacts with and inhibits gelatinase B/MMP-9 to a lesser extent than either TIMP-1 or TIMP-2 [161,162].

The bioavailability of gelatinase B/MMP-9 is regulated by forming complexes with low-density lipoprotein receptor-related proteins (LRP)-1 and LRP2 via functional endocytosis, promoting intracellular gelatinase B/MMP-9 uptake and leupeptin-sensitive degradation [49,165]. Autocatalytic gelatinase B/MMP-9 degradation is prevented when monomeric gelatinase B/MMP-9 is complexed with Neutrophil gelatinase-associated lipocalin (NGAL) in an interaction that does not result in gelatinase B/MMP-9 inhibition, effectively prolonging enzymatic activity [166,167].

The Gelatinase B/MMP-9/TIMP-1 Protease-Antiprotease Equilibrium

Mechanisms that alter the equilibrium between gelatinase B/MMP-9 and its TIMP-1 inhibitor in favour of protease activity, facilitate gelatinase B/MMP-9 involvement in tumour pathology, and include differential expression, evasion from TIMP inhibition, and TIMP-1 inactivation.

Gelatinase B/MMP-9 and TIMP-1 are frequently co-ordinately expressed in a large number of cell types and secreted as a pro-gelatinase B/MMP-9/TIMP-1 complex [12,15]. The tumor environment is however complex, and composed of tumor, stromal and inflammatory elements that also contribute to the modulation of this important equilibrium. Tumor infiltrating neutrophils release gelatinase B/MMP-9 in TIMP-free form, facilitating tumor-associated differential gelatinase B/MMP-9 and TIMP-1 expression [168,169] Furthermore, the differential up-regulation of gelatinase B/MMP-9 but not TIMP-1 expression has been reported in human ovarian cancer [170], skin cancer [171], squamous cell carcinoma of the hypopharynx [172] and colon and rectal tumours in vivo [173], and has also been demonstrated in malignant melanomas induced in metallothionin/RET transgenic mice [174]. In vitro, differential up-regulation of gelatinase B/MMP-9 but not TIMP-1 expression characterises PC-3 prostate tumor cell/stromal cell co-cultures and endothelial cells co-cultured with fibroblasts [175,176], cervical carcinoma cells in response to CD40L activation [177], human head and neck squamous carcinoma cells in response to c-erbB ligands [178], spontaneous epithelial to neuroblast transformation of human neuroblastoma cells [123], retinoic acid treatment of differentiation resistant human neuroblastoma cells [124], peroxiredoxin expression in metastatic human MDA-MB-231 breast cancer cells [179], thioredoxin expression in human MDA-MB-231 breast cancer cells [132] and bFGF treatment of human retinoblastoma cells [180].

Differential gelatinase B/MMP-9 and TIMP-1 regulation may also involve promoter SNPs and/or 3’-UTR micro RNA binding sites. Indeed, gelatinase B/MMP-9 SNPs that augment gelatinase B/MMP-9 expression have been associated with increased risk of different forms of cancer (See Section Gelatinase B/MMP-9 SNPs on page 241), as have altered levels of miRs that bind miR binding sites within the 3'-UTR region of gelatinase B/MMP-9. The miRs -211, 491-5p and 885-5p target and inhibit gelatinase B/MMP-9 expression and are down regulated in human glioblastoma multiforme, in association with increased gelatinase B/MMP-9 expression [17,18], and miR-19a has been reported to regulate gelatinase B/MMP-9 expression in colon cancer cells [181]. Furthermore, a recent report has shown that miR-17 targets the TIMP-1 protein-coding region and its inhibition enhances TIMP-1 expression and decreases gelatinase B/MMP-9 activity [182]. It is likely, therefore, that altered patterns of miR expression may also facilitate the differential expression of gelatinase B/MMP-9 and TIMP-1 in malignant tumours.

Extracellular activation of the thioredoxin redox system, up-regulated in malignant tumours, has been shown to inhibit TIMP but not MMP activity in vitro and in models of human neuroblastoma and UV irradiated dermal fibroblasts [164,183]. Furthermore, the myeloperoxidase/H202/hypochlorous acid (HOCl) system of inflammation induces the oxidative inactivation of TIMPs, whilst promoting the activation of MMPs, at concentrations found during inflammation [184,185], providing mechanisms through which the gelatinase B/MMP-9/TIMP equilibrium within tumours can be altered in favour of proteolytic activity even under conditions of high level TIMP expression [186]. TIMP MMP-inhibitory activity, furthermore, can be destroyed by neutrophil elastase, trypsin and α-chymotrypsin, all of which activate gelatinase B/MMP-9 [12,187,188], providing an additional mechanism for irreversible TIMP inhibition combined with gelatinase B/MMP-9 activation within inflammatory tumour environments and also environments such as the pancreas, in which trypsin and trypsin-like enzymes are expressed [189]. Finally, truncated gelatinase B/MMP-9 isoforms generated by enzymatic digestion or present on the cell surface of human leukemic cells have been shown to escape TIMP inhibition (see Section 3.4).

7. Gelatinase B/MMP-9, Tumour Initiation/Promotion and Genetic Instability

Potential pro-oncogenic roles for gelatinase B/MMP-9 have been reported, implicating gelatinase B/MMP-9 in neoplastic transformation, tumour initiation/promotion and genetic instability (Figure 2). Gelatinase B/MMP-9 localises to the nucleus, despite lack of classical nuclear localisation signal [190,191] and nuclear gelatinase activity associates with increased levels of DNA fragmentation [192,193,194]. Indeed, nuclear gelatinase degrades the nuclear matrix protein poly-ADP-ribose-polymerase (PARP), hindering DNA repair [193,195]. Furthermore, gelatinase B/MMP-9 binds the DNA damage heterodimer Ku70/80, providing a potential mechanism for its nuclear translocation [196]. Nuclear gelatinase B/MMP-9 has been reported in human gliomas, astrocytomas and neuroblastomas [197,198].

Gelatinase B/MMP-9 has been reported to protect colorectal cancer cells against microsatellite instability, with reduced gelatinase B/MMP-9 activity associated with increased microsatellite instability. This has been attributed to inhibitory mutations within the promoter of the gelatinase B/MMP-9 activator MMP-3 and is associated with better prognosis [199,200,201]. Microsatellite instability, furthermore, down-regulates gelatinase B/MMP-9 expression by introducing polymorphisms that reduce the number of (CA)n repeats within gelatinase B/MMP-9 regulatory domain to below 22 [28].

A role for inflammatory neutrophil-derived gelatinase B/MMP-9 in intestinal adenoma initiation has been described in heterozygous APC (APC-min) knockout mice, with a 40% reduction in adenoma formation observed upon gelatinase B/MMP-9 knockout [202]. Increased gelatinase B/MMP-9 activity provided by inflammatory neutrophils, furthermore, augments neutrophil recruitment via gelatinase B/MMP-9-mediated degradation and super-activation of IL-8 [106], augmenting neutrophil-mediated genetic instability [106,203]. Gelatinase B/MMP-9 also induces Rac1b alternative splice variant expression, which promotes chromosomal instability by increased reactive oxygen species levels and activating Snail-mediated transcription, resulting in increased oxidative DNA damage [204,205].

Gelatinase B/MMP-9 has also been reported to promote liver tumour initiation by the proteolytic release and activation of matrix-associated TGFβ and VEGF [206], and in human mammary epithelial cells induces cell surface expression of the HER2/Neu oncoprotein, inhibiting apoptosis and shifting normal mammary cells towards a transformed phenotype, in the presence of oestrogen [207].

In contrast, gelatinase B/MMP-9 optimises non-homologous end joining (NHEJ) DNA repair in human glioma cells. Indeed, down-regulation of gelatinase B/MMP-9 expression, combined with either urokinase or cathepsin B, delays DNA repair by lowering KU70/80 recruitment to damaged DNA. This reduces NHEJ DNA repair function, increases the levels of DNA damage and promotes apoptosis [208].

8. Gelatinase B/MMP-9 and Tumour Initiating Cell Proliferation and Expansion

Clonal expansion of transformed cells is also an essential step in tumour progression and is facilitated by inflammation and involves a change in equilibrium between proliferation, apoptosis and angiogenesis [209,210].

In the heterozygous APC knockout mouse model (APC-min), neutrophil-derived gelatinase B/MMP-9 stimulates adenoma initiating cell proliferation, promoting adenoma expansion, and implicating gelatinase B/MMP-9 in the expansion of tumour cell populations that lack full APC function. It is likely that this involves gelatinase B/MMP-9-mediated release and activation of non-matrix cytokines, such as TNFα and IL-1β and matrix-associated growth factors, such as VEGF, TGFβ and FGFs and/or the degradation of growth inhibitors [211,212,213,214]. Indeed, gelatinase B/MMP-9 degrades IGF-BPs augmenting the circulating levels of IGF, promoting astrocytoma growth [215], and increasing circulating VEGF and EGF levels [216], which also promote adenoma cell proliferation in APC-min mice. Furthermore, transcriptional silencing of gelatinase B/MMP-9 inhibits human glioma cells proliferation [208] and Wnt signalling induced by hypoxia stimulating gelatinase B/MMP-9 expression and promotes neural stem cell proliferation [217], suggesting that a hypoxia/Wnt/gelatinase B/MMP-9 axis may also promote proliferation of the cancer stem/progenitor cell component of neural-related tumours.

9. Gelatinase B/MMP-9, Stem Cells and the Cancer Stem Cell Niche

The stem cell niche is a unique, specialised location responsible for maintaining stem cells. Stem cells within the niche are anchored by intracellular and cell matrix adhesive interactions, which regulate stem cell numbers, stem cell self-renewal and potentially asymmetrical stem cell division. Normal stem cells and cancer stem cells exhibit similar behaviour [218,219]. Cancer stem cell niches have been identified in tumours and implicated in tumour heterogeneity, metastatic progression and therapeutic resistance, and are regulated by conditions within the tumour and promoted by tumour associated stress such as hypoxia [220,221]. Gelatinase B/MMP-9 has been implicated in regulating stem cell niche behaviour and within the bone marrow, degrading extracellular matrices within the stem cell niche, resulting in the activation and mobilisation of haemopoetic stem cells. This is facilitated by the conversion of stem cell factor from its membrane bound to free form, promoting c-Kit receptor-mediated stem cell proliferation [90]. Gelatinase B/MMP-9 also releases circulating endothelial precursor stem cells from the bone marrow, contributing to angiogenesis [90]. Interaction between stroma-derived factor (SDF)-1 and the chemokine receptor CXCR4 is essential for stem/progenitor cell function [222] and induces gelatinase B/MMP-9 expression. A similar interaction induces gelatinase B/MMP-9 expression in cancer cells, promoting dissemination and metastasis to bone [222,223,224]. Wnt signalling induces gelatinase B/MMP-9 expression and maintains stem cell niche integrity [225,226]. Wnt signalling is up regulated in cancer, and also stimulates cancer stem cell proliferation, resistance to apoptosis, tumour invasion and metastasis [227,228,229]. Furthermore, Wnt-induced gelatinase B/MMP-9 expression has been implicated in embryonic neural stem cells proliferation in conditions of hypoxia [217], a similar mechanism may, therefore, regulate cancer stem cells proliferation within neural tumours [218].

10. Gelatinase B/MMP-9 and Epithelial to Mesenchymal Transition (EMT)

Epithelial to mesenchymal transition (EMT) represents the conversion of polarized immotile epithelial cells into motile mesenchymal progenitor cells. This mechanism is important in development (type 1), normal wound healing or pathological fibrosis (type 2) and in the metastatic transformation of cancer cells (type 3) [230]. Type 3 EMT is fundamental for tumour progression to metastasis, and is either re-activated in de-differentiated epithelial cancer cells or activated in epithelial cancer stem cells, inducing a more motile and invasive phenotype [228]. It may also be transient, with metastatic cells reverting back to an epithelial phenotype at destination.

Gelatinase B/MMP-9 is an important EMT-related gene, and is not only a consequence but also a cause of EMT (Figure 3). Gelatinase B/MMP-9 cooperates with Snail transcription factor to induce EMT in epidermoid carcinoma cells [231], is involved in medulloblastoma cell EMT [232], is induced by Twist transcription factor an essential inducer of EMT [233,234,235] and by krupple like factor (KLF)-8, a critical component of FAK-regulated breast cancer EMT, which induces gelatinase B/MMP-9 expression in human breast cancer cells, promoting migration, invasion, angiogenesis and metastasis [234,235,236]. EMT in gastric cancer involves a Shh/PI3K/Akt/gelatinase B/MMP-9 pathway, which promotes metastatic dissemination to lymph nodes [237]. In human neuroblastoma cells, spontaneous EMT-like phenotypic conversion from a less invasive epithelial to more invasive neuroblast phenotype, associates with the induction of gelatinase B/MMP-9 expression and increased gelatinase B/MMP-9-mediated invasion [123].

11. Gelatinase B/MMP-9 and Cancer-Related Inflammation

Inflammation is now considered to be a hallmark of tumour progression, and regulates tumour-associated angiogenesis, tumour cell proliferation, invasion and metastasis [209,210]. Gelatinase B/MMP-9 is considered to be a tuner and amplifier of inflammatory and immune functions [106,238] and is up regulated by pro-inflammatory cytokines such as TNFα, IL-1β, IL-6 and TGFβ in a wide variety of human tumour cells, stromal and endothelial cells [12,13,15]. Gelatinase B/MMP-9 activates pro-inflammatory cytokines TNFα and IL-1β, increases the activity of chemokines CXCL1, CXCL4, CXCL7 and CXCL8, releases TGFβ from matrix stores, is released by activated neutrophils in TIMP-1-free form and acts as a nanomolar effector of tumour associated inflammation [12,13]. Neutrophil-derived gelatinase B/MMP-9 also interacts with neutrophil NGAL, which prevent autolytic gelatinase B/MMP-9 processing but does not impair gelatinase B/MMP-9 activity, promoting tumour progression [130,161]. CXCL8 interaction with the chemokine receptor CXCR2 induces gelatinase B/MMP-9 release from neutrophils [239], and activation of the chemokine receptor CXCR4 up-regulates gelatinase B/MMP-9 expression in prostate tumour cells, promoting invasion and metastasis [240]. Furthermore, myeloperoxidase/H2O2/HOCl system activation in neutrophils activates gelatinase B/MMP-9 and inhibits TIMP activity [184,185]. Gelatinase B/MMP-9, therefore, exhibits an integral relationship with tumour-associated inflammation. Indeed, the inhibition of gelatinase B/MMP-9 expression by inhibitors of pro-inflammatory cyclooxygenase-2 reduces tumour cell proliferation, invasion and metastasis [241,242]. In addition to its relationship with neutrophils, gelatinase B/MMP-9 also promotes macrophage and tumour cell invasion by cleaving the TGF-β-induced protein βig-h3, releasing it from the extracellular matrix, whereas non-degraded βig-h3 inhibits cell migration by promoting cell-cell contact and cell-extracellular matrix interactions [243].

In contrast to its tumour-promoting effects, high-level gelatinase B/MMP-9 expression has also been reported to promote tumour regression in a breast cancer model, augmenting neutrophil infiltration and promoting tumour-associated macrophage anti-tumour activity [244].

12. Gelatinase B/MMP-9 and Angiogenesis

The formation of new blood vessels is a highly orchestrated process that depends upon mitogenic and non-mitogenic angiogenic factors and involves matrix remodelling, cell migration, and regulated adhesive interactions between vascular cells and with the matrix. Tumour neovascularisation is fundamental for primary tumour expansion, metastatic progression and metastatic growth, and occurs via processes including sprouting angiogenesis, vasculogenesis, co-option inter-susception and/or vascular mimicry. Unlike normal vessels, blood vessels within tumours are abnormal, immature and inflammatory in nature [245].

Gelatinase B/MMP-9 is a critical pro-angiogenic molecule [246] and triggers the “angiogenic switch” in the quiescent vasculature [247,248] (Figure 4). Both host inflammatory and vascular gelatinase B/MMP-9 has been shown to be crucial for the development of the tumour angiogenic vasculature in models of pancreatic, ovarian and skin cancer [170,211,249]. Neutrophil gelatinase B/MMP-9 regulates pericyte proliferation, apoptosis and recruitment during angiogenesis [170] and mobilises the recruitment of bone marrow-derived angiogenic precursors to the tumour stroma enhancing the tumour angiogenic and vasculargenic process [90,250,251,252]. Gelatinase B/MMP-9 also triggers “the angiogenic switch” by mobilising and activating angiogenic mitogens from matrix stores at the onset of tumour-associated angiogenesis [169,211,251,253]. This process is facilitated by the release of TIMP-1-free gelatinase B/MMP-9 from neutrophils, which acts as an exceptionally potent nanomolar angiogenic factor, releasing both FGF and VEGF from matrices [169,254].

The gelatinase B/MMP-9/VEGF axis not only supports angiogenesis but also promotes hyperactive haematopoiesis, [255,256], which also promotes tumour progression by expanding myeloid-derived suppressors that suppress T-lymphocyte proliferation and activation, promoting tumour evasion of immune surveillance [257,258,259]. Mouse gelatinase B/MMP-9 has been shown to cleave VEGF to a truncated VEGF121 form that promotes irregular neovascularisation by altering interactions with heparan sulphate and other matrix components [118]. This, however, does not appear to extend to human gelatinase B/MMP-9 [80].

In addition to promoting pericyte recruitment, gelatinase B/MMP-9 also promotes the recruitment of pro-angiogenic monocytes and CD34+ endothelial cell progenitors, which express VE-cadherin and VEGFR2, to tumours, markedly influencing angiogenesis [252,260,261,262,263] and induces the release of circulating endothelial precursor stem cells from the bone marrow by degrading c-kit ligand, contributing to both angiogenesis and vasculogenesis [90]. In human neuroblastoma, gelatinase B/MMP-9 recruits bone marrow-derived leukocytes and support cells to tumour vessels, regulating vessel maturation [264] and the VEGF/gelatinase B/MMP-9 axis has been implicated in the robust angiogenic response associated with TrkAIII oncogene promotion of neuroblastoma tumorigenicity [265]. In gelatinase B/MMP-9 knockout mice, impaired vascularisation associates with reduced pericyte-recruitment [266] and vascular pericytes have been shown to express gelatinase B/MMP-9 in human breast tumours [267]. In general, knockout technology has implicated MMP9 in skeletal growth plate vascularisation [268] and in bone marrow derived CD11b+ myelomonocytic cell-mediated vasculogenesis in irradiated tumour tissues, with the absence of gelatinase B/MMP-9 associated with small tumours containing mature vessels [269]. Gelatinase B/MMP-9 has also been implicated in capillary branching during ischemia-induced revascularisation [270].

Although, bone marrow-cell derived gelatinase B/MMP-9 appears to be sufficient for tumour vasculogenesis, it is not essential and can be substituted by gelatinase B/MMP-9 from either stromal, smooth muscle or tumour cell components. Indeed, fibroblast gelatinase B/MMP-9 enhances endothelial cell survival and function [271], gelatinase B/MMP-9 from circulating macrophages promotes angiogenesis in a model of pancreatic cancer [272] and increased tumour cell gelatinase B/MMP-9 promotes angiogenesis in a model of neuroblastoma [265].

Tumour-associated hypoxia is a major stimulus for angiogenesis and hypoxia exhibits an overall tendency to increase vascular gelatinase B/MMP-9 expression [273,274]. Neovascularization induced by hypoxia involves Nox2-derived ROS-mediated gelatinase B/MMP-9 activation [275] and under conditions of hypoxia gelatinase B/MMP-9 modulates endothelial cell behaviour, promoting human microvascular endothelial cell invasive and angiogenic capacity [276]. Inflammatory cytokines TNFα, IL-17 and IL-18 promote gelatinase B/MMP-9 regulated migration of pericyte and vascular smooth muscle cell migration during angiogenesis [277,278,279,280] and gelatinase B/MMP-9 knockout impairs both pericyte and vascular smooth muscle cell migration, decreasing intimal vascular hyperplasia [281,282]. Furthermore, in addition to mobilising bone marrow CD34+ stem cells, gelatinase B/MMP-9 also promotes endothelial cell progenitor proliferation [262,263], degrades basement membrane type IV collagen, exposing cryptic αVβ3 integrin binding sites that promote angiogenesis [283] and releases VEGF from matrices in angiogenic islets, promoting angiogenesis [211,251].

In contrast to autocrine angiogenesis stimulating effects of gelatinase B/MMP-9 [212], gelatinase B/MMP-9 also exhibits capacity to negatively regulate angiogenesis by producing endogenous anti-angiogenic factors such as endostatin, tumstatin and angiostatin [72,112,284,285]. Endostatin, formed by gelatinase B/MMP-9 digestion of the type XVIII collagen α1 chain [72], blocks VEGFR2 and α5β1-mediated angiogenesis, inhibits gelatinase B/MMP-9 activity [286,287,288,289] and reduces metastasis in patients with high-grade transitional cell carcinoma of the bladder [290]. Tumstatin, formed by gelatinase B/MMP-9 digestion of the collagen IV α3 chain, inhibits endothelial cells proliferation and promotes αVβ3-mediated endothelial cell apoptosis [235,239]. Angiostatin, formed by gelatinase B/MMP-9 digestion of plasminogen and plasmin [112,113], acts as a competitive inhibitor of tissue-type plasminogen activator and single chain urokinase-mediated plasminogen activation, inhibits plasmin-mediated laminin degradation, impairs plasminogen association with the tumour cell surface, and inhibits plasmin-dependent tumour invasion and angiogenesis [113,285]. The gelatinase B/MMP-9 hemopexin domain, which can be generated by plasmin-mediated degradation of cryptic sites within the gelatinase B/MMP-9 catalytic domain, also inhibits gelatinase B/MMP-9 activity and angiogenesis [41,163,291].

Other interactions involving gelatinase B/MMP-9 that regulate angiogenesis include: thrombospondin-1 induction of gelatinase B/MMP-9 expression but inhibition of gelatinase B/MMP-9 activation [292], and gelatinase B/MMP-9 interaction with syndecan-1, which promotes syndecan-1 shedding and enhances medulloblastoma cells tube forming capacity. This involves an gelatinase B/MMP-9/syndecan-1/miR-494 regulatory loop, involved in regulating irradiation-induced angiogenesis, in which syndecan and gelatinase B/MMP-9 activity negatively feedback to regulate miR494 expression, which promotes angiogenesis [293]. Interaction between angiogenic endothelial cells and prostate cancer cells has also been reported to activate an IL-6/androgen receptor/TGFβ/gelatinase B/MMP-9 signal pathway that augments prostate cancer invasion in association with angiogenesis [294].

Angiogenic factors stimulate and/or associate with gelatinase B/MMP-9 expression. Ang2 expression correlates with that of gelatinase B/MMP-9 [295]. VEGF induces gelatinase B/MMP-9 expression in vascular cells and some malignant tumour cell types [296,297,298]. Hypoxia induces VEGF-A expression resulting in the recruitment of pro-angiogenic neutrophils that deliver the gelatinase B/MMP-9 and trigger the “angiogenic switch” [299]. Angiogenic fibroblast growth factors induce gelatinase B/MMP-9 expression in tumour and stromal tissues [153,300,301], and agents that inhibit MMP9 expression and/or gelatinase B/MMP-9 activity, such as DMBT [302], propofol [303], secreted protein acidic and rich in cysteine (SPARC) [304], S100A4 [305], xylitol [306], wortmanin [235], BMP4 [307], and aloe emodin [308], down regulate angiogenesis in different models.

Vasculargenic mimicry by tumour cells has been equated to tumour-associated angiogenesis [309]. Gelatinase B/MMP-9 has been also implicated in the vasculargenic mimicry exhibited by Adriamycin-resistant MCF-7 breast cancer cells, promoting tubular network formation through a VEGF receptors VEGFR-2 and VEGFR-3-mediated mechanism, implicating gelatinase B/MMP-9 in tumour-associated vascular mimicry [310].

Gelatinase B/MMP-9 and Lymphangiogenesis

Lymphagiogenesis is also an important component of tumour progression, with lymphatic vessels providing important routes for metastatic dissemination [311,312]. Although gelatinase B/MMP-9 is not required for normal skin lymphangiogenesis [313], tumour induced lymphangiogenesis has been reported to involve a sonic hedgehog/PI3K/Akt/gelatinase B/MMP-9 pathway, leading to lymph node metastases in gastric cancer [237]. Furthermore, neutrophil-derived gelatinase B/MMP-9 has been implicated in inflammation-associated lymphangiogenesis, promoting VEGF-A bioavailability and bioactivity [314] and, together with VEGF-C, has been implicated in lymphangiogenesis and lymph node metastasis in breast cancer [315].

13. Gelatinase B/MMP-9 and Disruption of Tissue Architecture

The loss of tissue architecture is one of the earliest hallmarks of premalignant epithelial cancer and results in tumour proliferation, local invasion and angiogenesis [316]. In malignant breast cancer, tumour cells loose their capacity to form ordered structures and proliferate as disorganised colonies [317]. Raf/MEK/ERK-mediated induction of gelatinase B/MMP-9 expression results in the destruction of breast tissue architecture, during breast cancer initiation, by degrading basement membrane laminin and destroying basement membrane integrity. This results in de-regulated tissue polarity and the loss of growth control (Figure 4). Gelatinase B/MMP-9 inhibition halts this process by preserving basement membrane integrity, which in turn reverses phenotype, arrests growth and re-establishes a differentiated acinar polarity [60].

14. Gelatinase B/MMP-9 Induction of Intracellular Signalling

Gelatinase B/MMP-9 interacts with the cellular surface through either Ku70/80 [196], CD44 [48,318] or via integrins [318]. Gelatinase B/MMP-9 interacts with αL, β5, α4 and β1 subunits through its catalytic site and interacts with CD44, α4, β5 and β1 subunits through the hemopexin domain [319,320]. These interactions stimulate migration, promote survival, increase both proteolytic and non-proteolytic invasion [318,320,321,322] and promote angiogenesis [169]. Signalling events in these interactions include, JNK involvement in gelatinase B/MMP-9-mediated dendritic cell migration, which is blocked by the JNK inhibitor SP600125 [323], and MAPK and IP3K involvement in gelatinase B/MMP-9-induced endothelial cell migration, which is blocked by the MAPK inhibitor PD98059 and by the IP3K inhibitor LY294002. Apoptosis in medulloblastoma, associated with loss of gelatinase B/MMP-9 expression, involves β1 integrin, ERK signalling and NF-κB activation [324,325]. Gelatinase B/MMP-9 interaction with α4β1 and CD44 induces survival signalling in CLL cells, activating lyn kinase, phosphorylating STAT and up-regulating Mcl-1 expression [322]. Interaction between gelatinase B/MMP-9 and CD44 results in EGF receptor activation and signalling through ERK, Akt and FAK, which promotes tumour cell invasion and migration [326], with FAK coordinating adhesion, polarisation, migration, invasion, survival and death [327].

15. Gelatinase B/MMP-9, Tumour Cell Invasion and Motility

Within the tumour context, gelatinase B/MMP-9 was originally identified as a novel type IV collagenolytic protease secreted by metastatic Ras transformed fibroblasts and implicated in basement membrane disruption required for tumour invasion and metastasis [6,7]. Although it remains debatable as to whether gelatinase B/MMP-9 alone can effectively degrade type IV collagen within the context of an insoluble basement membrane matrix, gelatinase B/MMP-9 promotes invasion by disrupting basement membrane structure by degrading basement membrane laminin and type IV collagen, in concert with other enzyme systems [8,57,59,60]. Interaction between tumour cells and stroma at the invasive edge regulates gelatinase B/MMP-9 expression, which combined with gelatinase B/MMP-9 released by tumour-associated neutrophils and macrophages, increases invasiveness [175,328,329,330] (Figure 5).

Tumor cell invasion is, however, a complex process that depends upon alterations in protein expression, interaction between tumour, inflammatory and stromal cells, altered intercellular and extracellular adhesive interactions, and changes in the tumour microenvironment. It is regulated by pro-inflammatory cytokines, chemokines, growth factors, matrix components, integrin and non-integrin receptors, proteases and inhibitors, and depends upon the cellular motile response. Cellular motility is achieved by different mechanisms and can reversibly switch between mesenchymal and amoeboid migration, which promote invasion as either single cells or collective chains, sheets, columns, tubes or clusters [331].

Protease involvement in migration and invasion is relatively restricted to mesenchymal motility, whereas amoeboid motility does not require proteolytic activity but involves a high level of cellular deformability, low affinity substrate binding and cycles of morphological contraction and expansion [331,332]. Mesenchymal migration, on the other hand, requires high affinity binding to integrin and non-integrin receptors. During mesenchymal migration, integrin or non-integrin receptors concentrate to membrane lamellipodia, filopodia, pseudopodia and invadopodia, promoting adapter protein-mediated intracellular interaction with the actin cytoskeleton. This results in the formation of focal contacts and adhesions with extracellular matrix components, the maturation of which activates intracellular focal adhesion kinases (FAKs) that form transient signalling complexes with Src kinases, promoting movement by inducing the turnover of focal contact providing the propulsive force for movement by continually modifying of cell-matrix interactions. These events depend upon proteolytic activity and involve the fibronectin integrin receptors α5β1 or αVβ6, the laminin integrin receptors α6β1 or α6β4, the fibronectin/vitronectin integrin receptor αVβ3 and the fibrillar collagen receptor α2β1 [331].

Gelatinase B/MMP-9 regulates mesenchymal migration, co-localises with integrins at lamellipodia on migrating cells [333] and co-operates with αVβ3 integrin to increase breast cancer cell migration and metastatic capacity [334]. FAK-Src signalling through JNK transcriptionally upregulates gelatinase B/MMP-9 expression, promoting gelatinase B/MMP-9-mediated invasion [335,336,337], and αVβ6 or α5β1 interaction with fibronectin also increases gelatinase B/MMP-9 expression, and gelatinase B/MMP-9-mediated migration and invasion of squamous cell carcinoma and melanoma cells [338,339,340]. Fibronectin also induces gelatinase B/MMP-9 expression in ovarian cancer cells through FAK and ras activation [335] and laminin has been shown to up-regulate gelatinase B/MMP-9 expression in macrophages and in A2058 melanoma cells but not in other malignant tumour cells [341,342]. Gelatinase B/MMP-9 promotes chain migration of neural crest cells [343] and collective migration of epithelial cancer cells, in association with EMT [344].

Gelatinase B/MMP-9 also interacts with the non-integrin receptor CD44, concentrating gelatinase B/MMP-9 to cell extensions, which control the turnover of adhesive interactions and extracellular matrix degradation required for motility, in a coordinated process that also involves ezrin, actin and Krp1 [336]. Gelatinase B/MMP-9 interaction with CD44 also promotes breast cancer cell migration and invasion in association with EGFR activation [48]. An N-cadherin/FGFR/gelatinase B/MMP-9 axis has been implicated in breast cancer cell invasion and metastasis, bypassing E-cadherin invasion and metastasis suppressing signals [155]. Gelatinase B/MMP-9 degradation of protease nexin-1 has also been implicated in a novel pathway through which gelatinase B/MMP-9 regulates tumour cell invasion, impairing the capacity of nexin to bind and down-regulate the activity of uPA [345].

In contrast to these reports, gelatinase B/MMP-9 has also been shown to degrade the β4 component of α6β4 integrin, de-regulating sheet migration of epithelial cells [346]. Furthermore, gelatinase B/MMP-9 interaction with α4β1 integrin and CD44 on the surface of chronic leukemic cells has been shown to inhibit migration in response to chemotactic gradients [318]. Tumour cells, furthermore, can undergo mesenchymal to amoeboid transition (MAT). Gelatinase B/MMP-9 is not required for amoeboid movement through 3D interstitial matrices [332] and MAT has been shown to increase metastatic capacity in association with reduced gelatinase B/MMP-9 expression [347].

Gelatinase B/MMP-9 and Primary Tumour Cell Escape

In order to escape the constraints of the primary tumour, tumor cells invade, move and alter their adhesive interactions. Chemotactic motile responses may direct tumour cells to lymphatic or blood vessels and tumour interaction, with tumour associated macrophages facilitating directional movement within tumours [348]. HGF activation of tumour cell c-met induces gelatinase B/MMP-9 expression, increasing tumor cell motility and scattering [349].

16. Gelatinase B/MMP-9 and Immunological Surveillance

The capacity to evade elimination by immunological/inflammatory mechanisms is an essential feature of tumour progression to metastasis. Gelatinase B/MMP-9 is an important regulator of both innate and tumour immune responses [12]. This is illustrated in gelatinase B/MMP-9 knockout mice, which do not resolve contact hypersensitivity reactions, implicating gelatinase B/MMP-9 in the down regulation of the immune response [350], suggesting an analogous role for gelatinase B/MMP-9 in cancer. In support of this, gelatinase B/MMP-9 expression associates with that of anti-pathogen immune-response-related genes in late stage compared to early stage lung tumours, although it remains to be determined whether any of these represent novel gelatinase B/MMP-9 substrates [351]. Gelatinase B/MMP-9 degrades ICAM-1, down-regulating leukocyte homing [80] and promotes evasion of the immune system by chronic myeloid leukemia cells by solubilizing cell membrane ICAM-1 [352]. Gelatinase B/MMP-9 degrades the IL-2 receptor α, repressing activation and proliferation of tumour infiltrating T-lymphocytes in cervical cancer [85,86]. Gelatinase B/MMP-9 degrades Surfactant protein D (SP-D), an important component of innate immune defence, leading to loss of innate immune function, limiting SP-D involvement in tumour immunology and renders oncology patients more susceptible to infection [353]. Gelatinase B/MMP-9 digests C1q complement component at a site required for interaction with the C1qR02 receptor, repressing C1q/C1qR02 involvement in tumour immunology [109] and may also degrade complement component C1r [65]. C5a induces the expression of the gelatinase B/MMP-9 stimulator IL-1β in monocytes [15,354] and the complement membrane attack complex induces gelatinase B/MMP-9 expression in cells protected against MAC-mediated lysis by CD59 [355], suggesting that activation of the complement system may promote tumour-associated gelatinase B/MMP-9 expression. Gelatinase B/MMP-9 also degrades the β2 subunit of macrophage CD18 integrin receptor, important for macrophage recruitment [91].

A role for gelatinase B/MMP-9 has also been reported in the development of tumour tolerance. This has been attributed to gelatinase B/MMP-9 induction of tolerogenic dendritic cells (tDC), through the release and activation of TGFβ, which increases the number of regulatory T (Treg) lymphocytes that promote tumour tolerance by suppressing CD8+ cytotoxic T cells [356,357,358]. In support of this, inhibition of gelatinase B/MMP-9 expression blocks tDC development and increases tDC and Treg numbers in cancer tissues [356,358,359,360,361]. Furthermore, the VEGF/gelatinase B/MMP-9 axis promotes hyperactive haematopoiesis, expanding myeloid-derived suppressors of T-lymphocyte proliferation and activation, which results in the repression tumour immune surveillance, which promotes tumour progression [255,256,257,258,259].

17. Gelatinase B/MMP-9 Haematogenous and Lymphatic Metastatic Dispersal

Tumour cell intravasation represents an important mechanism for haematogenous metastatic dissemination. The breaching of the vascular wall is considered to represent a rate limiting step for intravasation and consequently for haematogenous metastasis [311].

Gelatinase B/MMP-9 has been implicated in intravasation and subsequent metastasis formation [362] (Figure 6), with a particular role for inflammatory neutrophil-derived gelatinase B/MMP-9 highlighted in the promotion of haematogenous tumour cell dispersion of HT1080 fibrosarcoma and PC3 prostate carcinoma cells in xenograft models [12]. Neutrophil-derived gelatinase B/MMP-9 involvement in tumour-associated intravasation requires neutrophil attraction to the activated endothelial cell surface, neutrophil activation and release of TIMP-1-free gelatinase B/MMP-9. Activation of TIMP-1 free gelatinase B/MMP-9 releases angiogenic factors stored within the extracellular matrix, which promote endothelial sprouting and new vessel formation, and gelatinase B/MMP-9-assisted tumour cell intravasation and dissemination [363]. In support of this, gelatinase B/MMP-9 expression correlates with the intravasation and metastatic dissemination of HT-1080 fibrosarcoma cells, which is inhibited by the gelatinase B/MMP-9 inhibitor marimistat [362]. Furthermore, keratinocyte growth factor induces gelatinase B/MMP-9 expression and venous invasion by pancreatic cancer cells [364].

Gelatinase B/MMP-9 has also been implicated in lymphatic dissemination of colon cancer to lymph nodes. This mechanism involves gelatinase B/MMP-9 and the chemokine receptor CCR7. C-C chemokine interaction with CCR7 promotes gelatinase B/MMP-9 expression and lymphatic dissemination of colon cancer, whereas CCR7 knockdown reduces gelatinase B/MMP-9 expression lymphatic dissemination and lymph node metastases, implicating the CCR7/gelatinase B/MMP-9 axis in lymphatic metastatic dissemination of colon cancer [365]. In gastric cancer, lymphatic dissemination and lymph-node metastasis associate with increased expression of both Twist and gelatinase B/MMP-9 [233].

18. Gelatinase B/MMP-9 and Extravasation

After tumour cells that arrest in the microvasculature of distant organs they either extravasate or grow within vessels [366,367], adding to the debate as to whether extravasation is indeed a critical step in the metastatic process [368,369]. Due to the positive contribution made by inflammatory cells to the metastatic process, inflammatory cell-derived gelatinase B/MMP-9 may promote extravasation, as may tumour cell derived gelatinase B/MMP-9. Alternatively, endothelial cell clusters within metastatic sites may be primed to produce gelatinase B/MMP-9 by circulating VEGF through VEGF receptors [296], which may facilitate tumour cell extravasation across an already compromised vascular BM.

19. Gelatinase B/MMP-9 and the Metastatic Niche

Gelatinase B/MMP-9 appears to be one of the genes required for tumor metastasis [6,9,10,12,369]. Organ specific metastatic tropism characterises the metastatic process and is a complex process that involves interaction between infiltrating cancer cells and the local environment [220]. Within the bone marrow, gelatinase B/MMP-9 regulates the recruitment and mobilization of hematopoietic stem and progenitor cells from the quiescent bone marrow niche to the proliferative niche, suggesting that gelatinase B/MMP-9 may play a similar role in cancer stem behaviour within the bone environment. In this process, gelatinase B/MMP-9 activated within the bone marrow, degrades anchorage proteins enabling haematopoietic stem cell (HSC) migration from the osteoblastic to the vascular niche, which promotes their proliferation [90]. This involves gelatinase B/MMP-9 degradation of soluble kit-ligand mobilizing factor from its membrane-associated moiety and also degradation of osteopontin, which together induce stem cell cycling and reduces anchorage to the osteoblastic niche [370]. Furthermore, osteoclasts activated within bone enhance gelatinase B/MMP-9 proteolytic activity, inducing further degradation of the endosteal-niche components osteopontin and membrane bound-stem cell factor [371]. Since cancer stem and normal stem cells share molecular machinery and cancer stem cells hijack physiological stem cell trafficking mechanisms [218], gelatinase B/MMP-9 is likely to play a similar role in stimulating the proliferation cancer stem cells that locate to the bone metastatic niche.

Within non-bone metastatic niches, increased circulating levels of gelatinase B/MMP-9 have been shown to enhance the frequency of colon cancer metastasis to lung in a mouse model. This also associates with reduced size of metastases resulting from reduced tumour vascularisation associated with increased circulating angiostatin levels [372]. Furthermore, distant primary tumours have been shown to induce gelatinase B/MMP-9 in pre-metastatic lung endothelial cell clusters via VEGF receptor-1 signalling, pre-conditioning lungs to metastatic growth, indicating that distant tumours can aggressively determine specific metastatic sites by activating endothelial cells at secondary sites [296,373], in a process involving gelatinase B/MMP-9 expressed by endothelial cells and tumor-associated macrophages that fertilizes the soil necessary for metastatic growth [374]. Many metastatic tumours also release membrane vesicles that gain access to the circulation. Micro-vesicles shed by renal cancer stem cells contain pro-angiogenic factors, including gelatinase B/MMP-9, and promote the formation of a pre-metastatic niche, which is associated with unfavourable outcome [375]. Circulating hematopoietic CD45 and Col1a positive fibrocytes have also been shown to predispose the lung to B16/F10 metastases by recruiting Ly-6C (+) monocytes, in a chemokine and gelatinase B/MMP-9-dependent manner [376]. Furthermore, stromal derived factor (SDF)-1 interaction with the chemokine receptor CXCR4, which is essential for normal stem/progenitor cell function, promotes carcinogenesis, metastasis [377] and trans-endothelial migration of cancer cells by stimulating gelatinase B/MMP-9 secretion, disrupting basement membrane and inducing vascular permeability, promoting tumour cell extravasation. This mechanism promotes cancer stem cell homing to specific metastatic niches and in particular to the bone metastatic niche [222,378].

20. Gelatinase B/MMP-9, Apoptosis, Survival and the Mitochondria

Gelatinase B/MMP-9 regulates cellular survival and apoptosis [195,379]. Pro apoptotic effects have been described for gelatinase B/MMP-9 in the presence of proneurotrophins [380], in cerebellar neurons and retinal ganglion apoptosis [381,382], in hypertrophic growth plate chondrocytes [268] and in HL60 pro-myelocytic leukaemia cells [383]. Pro-survival effects of gelatinase B/MMP-9 have also been described during angiogenesis, through the release and activation of mitogens from matrix stores [211]. Gelatinase B/MMP-9 localises to mitochondria via Hsp70/Hsp60, and can disrupt mitochondrial structure, function and induce mitochondrial mtDNA damage, leading to diabetic retinal capillary cell apoptosis and gelatinase B/MMP-9 inhibition protects mitochondria from ultra-structural, functional and DNA damage [384,385,386], suggesting that gelatinase B/MMP-9 inhibitors may protect against mitochondrial apoptosis. Within the extracellular environment, gelatinase B/MMP-9 promotes neuronal apoptosis by degrading basement membrane laminin [61]. In contrast, siRNA down regulation of gelatinase B/MMP-9 expression induces apoptosis in human glioblastoma cells in association with Fas death receptor-mediated caspase 3 and caspase 8 cleavage, implicating gelatinase B/MMP-9 in protecting glioblastoma cells against Fas ligand-mediated apoptosis [387]. Methylation of the miR-211 gene up-regulates gelatinase B/MMP-9 expression in glioblastoma stem cells and increases their resistance to radiotherapy and chemotherapy-induced death [18]. The activation of α4β1 and CD44 bound gelatinase B/MMP-9 induces lyn/STAT/MCL-1 signalling and apoptosis in chronic lymphocytic leukemia cells, that depends upon gelatinase B/MMP-9 hemopexin and O-glycosylation domains [318,322] and in human medulloblastoma cells inhibition of gelatinase B/MMP-9 expression promotes apoptosis through β1 integrin and ERK activation [325]. In human mammary epithelial cells gelatinase B/MMP-9 expression reduces apoptosis by up regulating cell surface Her2/Neu expression [207].

21. Lessons from Gelatinase B/MMP-9 Knockout and Transgenics

Gelatinase B/MMP-9 knockout reduces intestinal adenoma formation and progression within the context of the APC-min mouse model, and has identified an important role for gelatinase B/MMP-9 released by inflammatory neutrophils in the formation, proliferation and progression of intestinal adenomas in cells, exhibiting compromised APC oncosoppressor function [202]. In contrast, gelatinase B/MMP-9 elimination in Myc/BclXl and RIP1-Tag2 models of pancreatic neuroendocrine carcinogenesis impairs tumour angiogenesis but promotes tumor invasion in association with a shift in inflammatory cell content to cathepsin expressing CD11b/Gr1 positive cells at the invasive front. Plasticity in tumour inflammatory infiltrates, therefore, can alter tumour-associated protease expression to compensate for gelatinase B/MMP-9 loss, helping to explain the MMP inhibitor-induced tumour progression described in human late stage tumor clinical trials [388]. Tumours, unable to grow in gelatinase B/MMP-9 knockout mice, grow readily following auto-transplantiation of normal mouse bone marrow by a mechanism independent of endothelial cell progenitors but involving CD11b positive myelomonocytic cells. In this model gelatinase B/MMP-9 is required for tumor-associated vasculogenesis [269]. Human pancreatic cancer cell growth, impaired in gelatinase B/MMP-9 knockout mice, is promoted by gelatinase B/MMP-9 produced by parabiosed normal stromal cells, implicating stromal gelatinase B/MMP-9 in tumour progression [272]. Gelatinase B/MMP-9 knockout mice also exhibit substantial inhibition of spontaneous metastasis due to impaired triggering of the “angiogenic switch” [389], and in experimental metastasis models, lung metastasis formation by both melanoma and lung carcinoma cells is reduced [390,391]. The inhibition of skin and ovarian cancer metastasis formation in gelatinase B/MMP-9 knockout mice can be reversed by transplantation of normal bone marrow cells, implicating inflammatory cell gelatinase B/MMP-9 in the metastatic process and adding to the role of gelatinase B/MMP-9 in primary tumour initiation, promotion and expansion [170,390].

In contrast to these reports, transgenic α1 integrin mice exhibit increased gelatinase B/MMP-9 expression and produce high level of circulating angiostatin, which reduces primary and metastatic growth of orthotopic cancers, in association with reduced angiogenesis. This identifies an anti-angiogenic, tumour suppressing function for gelatinase B/MMP-9 [392,393,394].

In mice transgenic for the gelatinase B/MMP-9 inhibitor TIMP-1, paradoxical effects have been described, with high circulating TIMP-1 inhibiting DMBA-induced mammary tumour growth, blocking tumorigenesis at an early stage [395]. In contrast, high circulating TIMP-1 promotes subcutaneous B16 melanoma growth in association with increased angiogenesis, whilst suppressing metastatic lung colonisation [396]. High circulating TIMP-1 levels, furthermore, strongly promote liver fibrosis [397], implicating gelatinase B/MMP-9 in normal liver physiology, adding to its physiological roles in the nervous system, inflammation and immunology [12,13,398].

22. Gelatinase B/MMP-9 Inhibitors and Future Directions

More than 50 broad-spectrum MMP inhibitors have been subjected to clinical trials. However, despite impressive results in non-randomized clinical trials, phase II and III clinical trials in patients with a range of different cancers have not been positive, due to a combination of factors that include a lack of understanding of the complexities of MMP involvement in tumour pathogenesis and progression, the lack of inhibitor specificity, drug intolerance and problems with drug dosage [399,400,401]. This was somewhat expected considering reports that several MMPs, including gelatinase B/MMP-9, display anti-tumor activity [72,112,113,284,285,402,403], different MMPs may be involved in different stages of tumour progression and the most potent endogenous gelatinase B/MMP-9 inhibitor, TIMP-1 may promote scattered micro-metastases in the liver [404]. Therefore, the detailed characterisation of exact roles played by the different MMPs within tumour pathogenesis and progression is required, as is the development of highly specific MMP inhibitors.

The impressive quantity of data concerning gelatinase B/MMP-9 involvement in the different phases of tumor progression, reviewed in this article, highlights particularly important roles for inflammatory leukocyte-derived gelatinase B/MMP-9 in tumour initiation and early progression and a more complex involvement of gelatinase B/MMP-9 from inflammatory, stromal and tumour sources in the continued progression of tumours to metastasis. Furthermore, reports also suggest that under certain conditions gelatinase B/MMP-9 may also protect against tumour progression by promoting the formation of systemic inhibitors of angiogenesis, may promote apoptosis and also facilitate anti-tumor inflammatory and immunological reactions (see Section 11 and Section 16). Furthermore, it is also evident that under conditions of MMP inhibition malignant tumour cells compensate by undergoing mesenchymal to amoeboid transition, facilitating protease-independent progression [405].

Current gelatinase B/MMP-9 inhibitors can be divided into those that inhibit gelatinase B/MMP-9 expression or catalytic activity. NSAIDs and HMG-CoA reductase inhibitors inhibit gelatinase B/MMP-9 transcription [238]. Gelatinase B/MMP-9 inhibitory siRNA inhibits gelatinase B/MMP-9 expression and tumorigenicity in a model of medulloblastoma [325] and miR-491-5p, miR-885-5p and miR-211 inhibit gelatinase B/MMP-9 expression and involvement in models of human glioblastoma [17,18]. Gelatinase B/MMP-9 activity can be blocked by the broad range MMP inhibitors d-penicillamine, hydroxamates, bisphosphonates and tetracyclins, [406]. An active site-specific gelatinase B/MMP-9 inhibitory antibody REGA-3G12 has been reported [407], and bisphosphonates inhibit both gelatinase B/MMP-9 expression and activity [41,255]. Zoledronic acid has been shown to inhibit macrophage gelatinase B/MMP-9 and reduces angiogenesis in a model of papillomavirus-induced cervical cancer [255]. Alendronate inhibits gelatinase B/MMP-9 activity and promotes plasmin-mediated destruction of the gelatinase B/MMP-9 catalytic domain, promoting irreversible gelatinase B/MMP-9 inhibition and producing inhibitory gelatinase B/MMP-9 hemopexin fragments, suggesting a novel rational for Alendronate use in pathology dependent upon gelatinase B/MMP-9 activity and plasminogen activation [41].

However, with the exception of REGA-3G12, there are few specific inhibitors of gelatinase B/MMP-9 catalytic activity, attesting to the close similarity exhibited by MMP catalytic sites. A HFDDDE motif of the gelatinase B/MMP-9 catalytic domain interferes with pro-gelatinase B/MMP-9 binding of β2 integrin, inhibits OCI-AML3 leukemia cells transmigration across a human endothelial cell layers and inhibits gelatinase B/MMP-9-mediated extracellular matrix degradation, suggesting potential use in therapeutic reduction of acute myeloid leukemia cells extra medullary infiltration [408]. The peptides CTTHWGFTLC and GRENYHGCTTHWGHTLC also inhibit gelatinase B/MMP-9 catalytic activity but not gelatinase B/MMP-9 activation and inhibit primary HSC-3 tongue carcinoma growth but not tumor spread in a mouse model [409].

Recent approaches have also focussed on molecules that interfere with gelatinase B/MMP-9 activity mediated by the hemopexin and/or O glycosylation domains. Recombinant or isolated gelatinase B/MMP-9 hemopexin domain inhibits gelatinase B/MMP-9 activity [41,163], hampers colorectal cancer cell adhesion and migration [410], inhibits gelatinase B/MMP-9-induced functions in chronic lymphocytic Leukemia B cells [411], and inhibits angiogenesis in glioblastoma xenografts [291]. A peptide mimic of integrin beta chain that binds the gelatinase B/MMP-9 hemopexin domain inhibits gelatinase B/MMP-9 binding to αVβ5 integrin, prevents progelatinase B/MMP-9 activation, inhibits HT-1080 fibrosarcoma cell invasion in vitro and HSC-3 tongue carcinoma xenograft growth in vivo but does not inhibit gelatinase B/MMP-9 activity [412]. Peptide mimics of the first and fourth blades of the gelatinase B/MMP-9 hemopexin domain block gelatinase B/MMP-9 dimerization and inhibit HT-1080 and MDA-MB-435 tumour cell motility [48]. The compound N-[4-(difluoromethoxy) phenyl]-2-[(4-oxo-6-propyl-1H-pyrimidin-2-yl) sulfanyl]-acetamide also binds to the gelatinase B/MMP-9 hemopexin domain, inhibits gelatinase B/MMP-9 homo-dimerization, blocks gelatinase B/MMP-9 mediated migration and reduces xenograft tumorigenicity and metastasis of MDA-MB-435 human breast cancer cells [46]. Deletion of the O-glycosylation domain inhibits macromolecular substrate specificity of gelatinase B/MMP-9 [413], suggesting that inhibitors of O-glycosylation domain function may also be effective inhibitors of gelatinase B/MMP-9 function. Therefore, molecules that interact, interfere or compete with these two domains hold some promise in the development of specific therapeutic inhibitors of gelatinase B/MMP-9 activity and function. When considering the potential therapeutic use of specific gelatinase B/MMP-9 inhibitors, however, potential anti-tumor activity of gelatinase B/MMP-9 (i.e., production of anti-angiogenic molecules) must be taken into account and attempts made also to limit inhibitor interference with physiological gelatinase B/MMP-9 functions.

23. Conclusions

There is no doubt that gelatinase B/MMP-9 plays a fundamental role in tumour biology, ranging from initiation/promotion to angiogenesis, dissemination, immunological surveillance and metastatic growth. Gelatinase B/MMP-9, however, also exhibits anti-tumor activity and plays important physiological functions. It is therefore essential that specific inhibitors of gelatinase B/MMP-9 proteolytic and non-proteolytic functions are developed in order to determine the potential therapeutic efficacy of inhibiting gelatinase B/MMP-9 function in cancer therapy. The difficulty will be to inhibit the tumour promoting functions of gelatinase B/MMP-9, whilst substituting for anti-tumor gelatinase B/MMP-9 effects and minimising the inhibition of physiological gelatinase B/MMP-9 function.


This work was supported by grants from AIRC, Italian Ministry of University Research and the Maugeri Foundation.

Conflicts of Interest

The authors declare no conflicts of interest.

1.. Sopata I.,Dancewicz A.M.. Presence of a gelatin-specific proteinase and its latent form in human leukocytesBiochim. Biophys. ActaYear: 197437051052310.1016/0005-2744(74)90112-04216367
2.. Murphy G.,Bretz U.,Baggiolini M.,Reynolds J.J.. The latent collagenase and gelatinase of human polymorphonuclear neutrophil leukocytesBiochem. J.Year: 19801925175256263256
3.. Dewald B.,Bretz U.,Baggiolini M.. Release of gelatinase from a novel secretory compartment of human neutrophilsJ. Clin. Investig.Year: 19827051852510.1172/JCI1106436286726
4.. Hibbs M.A.,Hasty K.A.,Seyer J.M.,Kang A.H.,Mainardi C.L.. Biochemical characterisation of the secreted forms of human neutrophil gelatinaseJ. Biol. Chem.Year: 1985260249325002982822
5.. Hibbs M.A.,Hoidal J.R.,Kang A.H.. Expression of a metalloproteinase that degrades native type V collagen and denatured collagens by cultured human alveolar macrophagesJ. Clin. Investig.Year: 1987801644165010.1172/JCI1132533680518
6.. Ballin M.,Gomez D.E.,Sinha C.C.,Thorgeirsson U.P.. Ras oncogene mediated induction of a 92kDa metalloproteinase; strong correlation with the malignant phenotypeBiochem. Biophys. Res. Commun.Year: 198815483283810.1016/0006-291X(88)90215-X3044367
7.. Ballin M.,Mackay A.R.,Hartzler J.L.,Nason A.,Pelina M.D.,Thorgeirsson U.P.. Ras levels and metalloproteinase activity in normal versus neoplastic rat mammary tissuesClin. Exp. MetastasisYear: 1991917918910.1007/BF017563882032422
8.. Mackay A.R.,Hartzler J.L.,Pelina M.D.,Thorgeirsson U.P.. Studies on the ability of 65-kDa and 92-kDa tumor cell gelatinases to degrade type IV collagenJ. Biol. Chem.Year: 199026521929219342174891
9.. Bernhardt E.J.,Gruber S.B.,Muschel R.J.. Direct evidence linking expression of matrix metalloproteinase 9 (92 kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cellsProc. Natl. Acad. Sci. USAYear: 1994914293429710.1073/pnas.91.10.42938183903
10.. Bernhardt E.J.,Muschel R.J.,Hughes E.N.. Mr 92,000 gelatinase release correlates with the metastatic phenotype in transformed rat embryo cellsCancer Res.Year: 199050387238772162246
11.. Wilhelm S.M.,Collier I.M.,Marmer B.L.,Eisen A.Z.,Grant G.A.,Goldberg G.I.. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase, which is identical to that secreted by normal human macrophagesJ. Biol. Chem.Year: 198926417213172212551898
12.. Van den Steen P.E.,Dubois B.,Nelissen I.,Rudd P.M.,Dwek R.A.,Opdenakker G.. Biochemistry and Molecular biology of gelatinase B or matrix metalloproteinase-9 (gelatinase B/MMP-9)Crit. Rev. Biochem. Mol. Biol.Year: 20023737553610.1080/1040923029077154612540195
13.. Vandooren J.,van den Steen P.E.,Opdenakker G.. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (gelatinase B/MMP-9): The next decadeCrit. Rev. Biochem. Mol. Biol.Year: 20134822227210.3109/10409238.2013.77081923547785
14.. Hutala P.,Tuuttila A.,Chow L.T.,Lohi J.,Keski O.J.,Tryggvason K.. Complete structure of the human gene for 92-kDa type IV collagenase. Divergent regulation of expression of the 92- and 72- kilodalton enzyme genes in HT-180 cellsJ. Biol. Chem.Year: 199126616485164901653238
15.. Mackay A.R.,Ballin M.,Pelina M.D.,Farina A.R.,Nason A.M.,Hartzler J.L.,Thorgeirsson U.P.. Effect of phorbol ester and cytokines on matrix metalloproteinase expression and tissue inhibitor of metalloproteinase expression in tumor and normal cell linesInvasion MetastasisYear: 1992121681841284126
16.. Masure S.,Billiau A.,van Damme J.,Opdenakker G.. Human hepatoma cells produce an 85 kDa gelatinase regulated by phorbol 12-myristate 13-acetateBiochim. Biophys. ActaYear: 1990105431732510.1016/0167-4889(90)90103-K2169896
17.. Yan W.,Zhang W.,Sun L.,Liu L.,You G.,Wang Y.,Kang C.,You Y.,Jiang T.. Identification of gelatinase B/MMP-9 specific microRNA expression profile as potential targets of anti-invasion therapy in glioblastoma multiformeBrain Res.Year: 2011141110811521831363
18.. Asuthkar S.,Velpula K.K.,Chetty C.,Gorantla B.,Rao J.S.. Epigenetic regulation of miRNA-211 by gelatinase B/MMP-9 governs glioma cell apoptosis, chemosensitivity and radiosensitivityOncotargetYear: 201231439145423183822
19.. Zhang B.,Ye S.,Herrmann S.M.,Eriksson P.,de Maat M.,Evans A.,Arveiler D.,Luc G.,Cambien F.,Hamsten A.,et al. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosisCirculationYear: 1999991788179410.1161/01.CIR.99.14.178810199873
20.. Matsumura S.,Oue N.,Nakayama H.,Kitadai Y.,Yoshida K.,Yamaguchi Y.,Imai K.,Nakachi K.,Matsusaki K.,Chayama K.,et al. A single nucleotide polymorphism in the gelatinase B/MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancerJ. Cancer Res. Clin. Oncol.Year: 2005131192510.1007/s00432-004-0621-415565457
21.. Tu H.F.,Wu C.H.,Kao S.Y.,Liu C.J.,Liu T.Y.,Liu M.T.. Functional -1562 C to T polymorphism in matrix metalloproteinase-9 (MMP-9) promoter is associated with the risk for oral squamous cell carcinoma in younger male area usersJ. Oral Pathol. Med.Year: 20073640941410.1111/j.1600-0714.2007.00552.x17617834
22.. Vairaktaris E.,Vassiliou S.,Nkenke E.,Serefoglou Z.,Derka S.,Tsigris C.,Vylliotis A.,Yapijakis C.,Neukam F.W.,Patsouris E.. A metalloproteinase-9 polymorphism which affects expression is associated with increased risk of oral squamous cell carcinomaEur. J. Surg. Oncol.Year: 20083445045510.1016/j.ejso.2007.03.02417498910
23.. Vairaktaris E.,Serefoglou Z.,Avgoustidis D.,Yapijakis C.,Critselis E.,Vylliotis A.,Spyridonidou S.,Derka S.,Vassiliou S.,Nkenke E.,et al. Gene polymorphisms related to angiogenesis, inflammation and thrombosis that influence risk for oral cancerOral Oncol.Year: 20094524725310.1016/j.oraloncology.2008.05.00318674955
24.. Nasr H.B.,Mestiri S.,Chahed K.,Bounaouina N.,Gabbouj S.,Jalbout M.,Chouchane L.. Matrix metalloproteinase-1 (-16076) 1G/2G and -9 (-1562) C/T promoter polymorphisms: Susceptibility and prognostic implications in nasopharyngeal carcinomasClin. Chim. ActaYear: 2007384576310.1016/j.cca.2007.05.01817599818
25.. Rollin J.,Regina S.,Vourc’h P.,Lochman S.,Blechet C.,Reverdiau P.,Gruel Y.. Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancerLung CancerYear: 20075627328010.1016/j.lungcan.2006.11.02117208328
26.. Wu J.,Zhang L.,Luo H.,Zhu Z.,Zhang C.,Hou Y.. Association of matrix metalloproteinase-9 gene polymorphisms with genetic susceptibility to oesophageal squamous cell carcinomaDNA Cell. Biol.Year: 20082755355710.1089/dna.2008.073218680431
27.. Liu D.,Guo H.,Li Y.,Xu X.,Yang K.,Bai Y.. Association between polymorphisms in the promoter regions of matrix metalloproteinases (MMPs) and risk of cancer metastasis: A meta-analysisPLoS OneYear: 20127e3125122348060
28.. Shimajiri S.,Arima N.,Tanimoto A.,Murata Y.,Hamada T.,Wang K.Y.,Sasaguri Y.. Shortened microsatellite d(CA)21 sequence down-regulates promoter activity of matrix metalloproteinase 9 geneFEBS Lett.Year: 1999455707410428474
29.. Maeda S.,Haneda M.,Guo B.,Koya D.,Hayashi K.,Sugimoto T.,Isshiki K.,Yasuda H.,Kashiwagi A.,Kikkawa R.. Dinucleotide repeat polymorphism of matrix metalloproteinase-9 gene is associated with diabetic nephropathyKidney Int.Year: 2001601428143410.1046/j.1523-1755.2001.00945.x11576356
30.. Peters D.G.,Kassam A.,St. Jean P.L.,Yonas H.,Ferrell R.E.. Functional polymorphism in the matrix metalloproteinase-9 promoter as a potential risk factor for intracranial aneurysmStrokeYear: 1999302612261610.1161/01.STR.30.12.261210582986
31.. Yuan M.,Zhan Q.,Duan X.,Song B.,Zeng S.,Chen X.,Yang Q.,Xia J.. A functional polymorphism at miR-491–5p binding site in the 3'-UTR of gelatinase B/MMP-9 gene confers increased risk for atherosclerotic cerebral infarction in a Chinese populationAtherosclerosisYear: 201322644745210.1016/j.atherosclerosis.2012.11.02623257658
32.. Hu Z.,Huo X.,Lu D.,Qian J.,Zhou J.,Chen Y.,Xu L.,Ma H.,Zhu J.,Wei Q.,et al. Functional polymorphisms of matrix metalloproteinase-9 are associated with risk of occurrence and metastasis of lung cancerClin. Cancer Res.Year: 2005115433543910.1158/1078-0432.CCR-05-031116061858
33.. Liu H.,Huang P.Y.,Tang L.Q.,Chen Q.Y.,Zhang H.,Zhang L.,Guo L.,Luo D.H.,Mo H.Y.,Xiang Y.Q.,et al. Functional polymorphisms of matrix metalloproteinase-9 and survival in patients with locoregionally advanced nasopharyngeal carcinoma treated with radiotherapyMed. Oncol.Year: 20133068510.1007/s12032-013-0685-623955812
34.. Liu Z.,Li L.,Yang Z.,Luo W.,Li X.,Yang H.,Yao K.,Wu B.,Feng W.. Increased expression of gelatinase B/MMP-9 is correlated with poor prognosis of nasopharyngeal carcinomaBMC CancerYear: 20101027010.1186/1471-2407-10-27020534121
35.. Tang Y.,Zhu J.,Chen L.,Chen L.,Zhang S.,Lin J.. Associations of matrix metalloproteinase-9 protein polymorphisms with lymph node metastasis but not invasion of gastric cancerClin. Cancer Res.Year: 2008142870287710.1158/1078-0432.CCR-07-404218451255
36.. Sharma K.L.,Misra S.,Kumar A.,Mittal B.. Higher risk of matrix metalloproteinase (MMP-2, 7, 9) and tissue inhibitor of metalloproteinase (TIMP-2) genetic variants in gallbladder cancerLiver Int.Year: 2012321278128610.1111/j.1478-3231.2012.02822.x22621753
37.. Yang Z.H.,Li S.N.,Liu J.X.,Guo Q.X.,Sun X.W.. MMP-9 polymorphisms are related to serum lipids levels but not associated with colorectal cancer susceptibility in Chinese populationMol. Biol. Rep.Year: 2012399399940410.1007/s11033-012-1804-822729913
38.. Jin G.,Miao R.,Hu Z.,Xu L.,Huang X.,Chen Y.,Tian T.,Wei Q.,Boffetta P.,Shen H.. Putative functional polymorphisms of MMP-9 predict survival of NSCLC in a Chinese populationInt. J. CancerYear: 20091242172217810.1002/ijc.2419019132754
39.. O’Farrell T.J.,Pourmotabbed T.. Identification of structural elements important for matrix metalloproteinase type V collagenolytic activity as revealed by chimeric enzymes. Role of fibronectin-like domain and active site of gelatinase BJ. Biol. Chem.Year: 2000275279642797210823838
40.. O’Farrell T.J.,Guo R.,Hasegawa H.,Pourmotabbed T.. Matrix metalloproteinase-1 takes advantage of the induced fit mechanism to cleave the triple-helical type I collagen moleculeBiochemistryYear: 200645154111541810.1021/bi060849d17176063
41.. Farina A.R.,Cappabianca L.,di Ianni N.,Ruggeri P.,Ragone M.,Merolla S.,Gulino A.,Mackay A.R.. Alendronate promotes plasmin-mediated MMP-9 inactivation by exposing cryptic plasmin degradation sites within the MMP-9 catalytic domainFEBS Lett.Year: 20125862366237410.1016/j.febslet.2012.05.04822677171
42.. Triebel S.,Blaser J.,Reinke H.,Knauper V.,Tschesche H.. Mercurial activation of human PMN leukocyte type IV procollagenase (gelatinase)FEBS Lett.Year: 199229828028410.1016/0014-5793(92)80077-T1312026
43.. Okamoto T.,Akaike T.,Sawa T.,Miyamoto Y.,van del Vliet A.,Maeda H.. Activation of matrix metalloproteinases by peroxynitrite-induced protein S-glutothiolation via disulphide S-oxide formationJ. Biol. Chem.Year: 2001276295962960211395496
44.. Gu Z.,Kaul M.,Yan B.,Kridel S.J.,Cui J.,Strongin A.,Smith J.W.,Liddington R.C.,Lipton S.A.S.. nitrosylation of matrix metalloproteinases: Signalling pathway to neuronal cell deathScienceYear: 20022971186119010.1126/science.107363412183632
45.. Kahn M.M.G.,Simizu S.,Suzuli T.,Masuda A.,Kawatani M.,Muroi M.,Dohmae N.,Nad Osada H.. Protein disulphide isomerase-mediated disulphide binds regulate gelatinolytic activity and secretion of matrix metalloproteinase-9Exp. Cell Res.Year: 201231890491110.1016/j.yexcr.2012.02.02122406264
46.. Dufour A.,Sampson N.S.,Li J.,Kuscu C.,Rizzo R.C.,Deleon J.L.,Zhi J.,Jaber N.,Liu E.,Zucker S.,et al. Small-molecule anticancer compounds selectively target the hemopexin domain of matrix metalloproteinase-9Cancer Res.Year: 2011714977498810.1158/0008-5472.CAN-10-455221646471
47.. Geurts N.,Martens E.,van Aelst I.,Proost P.,Opdenakker G.,van den Steen P.E.. Beta-haematin interaction with the hemopexin domain of gelatinase B/MMP-9 provokes autocatalytic processing of the propeptide, thereby priming activation by MMP-3BiochemistryYear: 2008472689269910.1021/bi702260q18237197
48.. Dufour A.,Zucker S.,Sampson N.S.,Kuscu C.,Cao J.. Role of matrix metalloproteinase-9 dimers in cell migration: Design of inhibitory peptidesJ. Biol. Chem.Year: 2010285359443595610.1074/jbc.M109.09176920837483
49.. Van den Steen P.E.,van Aelst I.,Hvidberg V.,Piccard H.,Fiten P.,Jacobsen C.,Moestrup S.K.,Fry S.,Royle L.,Wormald M.R.,et al. The hemopexin and O-glycosylated domains tune gelatinase B/MMP-9 bioavailability via inhibition of binding to cargo receptorsJ. Biol. Chem.Year: 2006281186261863710.1074/jbc.M51230820016672230
50.. Bellini T.,Trentini A.,Manfrinato M.C.,Tamborino C.,Volta C.A.,di Foggia V.,Fainardi E.,Dallocchio F.,Castellazzi M.. Matrix metalloproteinase-9 activity detected in body fluids is the result of two different enzyme formsJ. Biochem.Year: 201215149349910.1093/jb/mvs01422343748
51.. Geurts N.,Becker-Pauly C.,Martens E.,Proost P.,van den Steen P.E.,Stoker W.,Opdenakker G.. Meprins process matrix metalloproteinase-9 (gelatinase B/MMP-9)/gelatinase B and enhance the activation kinetics by MMP-3FEBS Lett.Year: 20125864264426910.1016/j.febslet.2012.10.03323123160
52.. Ramani V.C.,Kaushal G.P.,Haun R.S.. Proteolytic activation of kallikrien-related peptidase 7 produces unique active matrix metalloproteinase-9 lacking the C-terminal domainsBiochim. Biophys. ActaYear: 201118131525153110.1016/j.bbamcr.2011.05.00721616098
53.. Reis C.,Lottspeich F.,Dittmann K.H.,Petrides P.E.. HL60 leukemia cells produce an autocatalytically truncated form of matrix metalloproteinase-9 with impaired sensitivity to inhibition by tissue inhibitors of metalloproteinasesLeukemiaYear: 199610152015268751473
54.. Reis C.,Pitsch T.,Mentele R.,Zahler S.,Egea V.,Nagase H.,Jochum M.. Identification of a novel 82 kDa proMMP-9 species associated with the surface of leukaemic cells: (Auto-) catalytic activation and resistance to inhibition by TIMP-1Biochem. J.Year: 200740554755810.1042/BJ2007019117489740
55.. Bigg H.F.,Rowan A.D.,Barker M.D.,Cawston T.E.. Activity of matrix metalloproteinase-9 against native collagen I and IIFEBS J.Year: 20072741246125510.1111/j.1742-4658.2007.05669.x17298441
56.. Van den Steen P.E.,Proost P.,Brand D.D.,Kang A.H.,van Damme J.,Opdenakker G.. Generation of glycosylated remnant epitopes from human type II collagen by gelatinase BBiochemistryYear: 200443108091081610.1021/bi049366515311942
57.. Eble J.A.,Ries A.,Lichy A.,Mann K.,Stanton H.,Gavrilovic J.,Murphy G.,Kuhn K.. The recognition sites of the integrins α1β1 and α2β1 within collagen IV are protected against gelatinase A attack in the native proteinJ. Biol. Chem.Year: 199627130964309708940084
58.. Shoji A.,Kabeya M.,Sugawara M.. Real-time monitoring of matrix metalloproteinase-9 collagenolytic activity with a surface plasmon resonance biosensorAnal. Biochem.Year: 2011419536010.1016/j.ab.2011.07.03121864497
59.. Mackay A.R.,Corbitt R.H.,Hartzler J.L.,Thorgeirsson U.P.. Basement membrane type IV collagen degradation: Evidence for the involvement of a proteolytic cascade independent of metalloproteinasesCancer Res.Year: 199050599760012144209
60.. Beliveau A.,Mott J.D.,Lo A.,Chen E.I.,Koller A.A.,Yaswen P.,Muschler J.,Bissel M.J.. Raf-induced MMP-9 disrupts tissue architecture of human breast cells in three-dimensional culture and is necessary for tumor growth in vitroGenes Dev.Year: 2010242800281110.1101/gad.199041021159820
61.. Gu Z.,Cui J.,Brown S.,Fridman R.,Mobashery S.,Strongin A.Y.,Lipton S.A.. A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemiaJ. Neurosci.Year: 2005256401640810.1523/JNEUROSCI.1563-05.200516000631
62.. Xu D.,Suenaga N.,Edelman J.,Fridman R.,Muschel R.,Kessler B.M.. Novel MMP-9 substrates in cancer cells revealed by a label-free quantitative proteomics approachMol. Cell. ProteomicsYear: 200872215222810.1074/mcp.M800095-MCP20018596065
63.. Cauwe B.,van den Steen P.E.,Opdenakker G.. The biochemical, biological, and pathological kaleidoscope of cell surface substrates processed by matrix metalloproteinasesCrit. Rev. Biochem. Mol. Biol.Year: 20074211311510.1080/1040923070134001917562450
64.. Cauwe B.,Opdenakker G.. Intracellular substrate cleavage: A novel dimension in the biochemistry, biology and pathology of matrix metalloproteinasesCrit. Rev. Biochem. Mol. Biol.Year: 20104535142310.3109/10409238.2010.50178320812779
65.. Prudova A.,auf dem Keller U.,Butler G.S.,Overall C.M.. Multiplex N-terminome analysis of MMP-2 and MMP-9 substrate degradomes by iTRAQ-TAILS quantitative proteomicsMol. Cell. ProteomicsYear: 2010989491110.1074/mcp.M000050-MCP20120305284
66.. Gioia M.,Monaco S.,van den Steen P.E.,Sbardella D.,Grasso G.,Marini S.,Overall C.M.,Opdenakker G.,Coletta M.. The collagen binding domain of gelatinase A modulates degradation of collagen IV by gelatinase BJ. Mol. Biol.Year: 200938641943410.1016/j.jmb.2008.12.02119109975
67.. Murphy G.,Reynolds J.J.,Bretz U.,Baggiolini M.. Partial purification of collagenase and gelatinase from human polymorphonuclear leucocytes. Analysis of their actions on soluble and insoluble collagensBiochem. J.Year: 19822032092216285893
68.. Morodomi T.,Ogata Y.,Sasaguri Y.,Morimatsu M.,Nagase H.. Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukaemia and HT-1080 fibrosarcoma cellsBiochem. J.Year: 19922856036111379048
69.. Kridel S.J.,Chen E.,Kotra L.P.,Howard E.W.,Mobashery S.,Smith J.W.. Substrate hydrolysis by matrix metalloproteinase-9J. Biol. Chem.Year: 2001276205722057811279151
70.. Stegemann C.,Didangelos A.,Ballarobre-Barriero J.,Langley S.R.,Mandal K.,Jahangiri M.,Mayr M.. Proteomic identification of matrix metalloproteinase substrates in the human vasculatureCirc. Cardiovasc. Genet.Year: 2013610611710.1161/CIRCGENETICS.112.96445223255316
71.. O’Farrell T.J.,Pourmattabbed T.. The fibronectin-like domain is required for the type V and XI collagenolytic activity of gelatinase BArch. Biochem. Biophys.Year: 1998354243010.1006/abbi.1998.06629633594
72.. Ferreras M.,Felbor U.,Lenhard T.,Olsen B.R.,Delaissé J.. Generation and degradation of human endostatin proteins by various proteinasesFEBS Lett.Year: 200048624725110.1016/S0014-5793(00)02249-311119712
73.. Ochieng J.,Fridman R.,Nagia-Makker P.,Kleiner D.E.,Liotta L.A.,Stetler-Stevenson W.G.,Raz A.. Galectin-3 is a novel substrate for human matrix metalloproteinase-2 and 9BiochemistryYear: 199433141091411410.1021/bi00251a0207947821
74.. Zampila R.,Lopez E.F.,Chiao Y.A.,Dai Q.,Escobar G.P.,Hakala K.,Weintraub S.T.,Lindsey M.L.. Proteomic analysis identifies in vivo candidate matrix metalloproteinase-9 substrates in the left ventrical post-myocardial infactionProteomicsYear: 2010102214222310.1002/pmic.20090058720354994
75.. Siri A.,Knauper V.,Veirana N.,Caocci F.,Murphy G.,Zardi L.. Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinasesJ. Biol. Chem.Year: 1995270865086547536739
76.. Katsuda S.,Okada Y.,Okada Y.,Imai K.,Nakanishi I.. Matrix metalloproteinase-9 (92-kd gelatinase/type IV collagenase equals gelatinase B) can degrade arterial elastinAm. J. Pathol.Year: 1994145120812187977651
77.. Lau A.C.,Duong T.T.,Ito S.,Yeung R.S.. Matrix metalloproteinase 9 activity leads to elastin breakdown in an animal model of Kawasaki diseaseArthritis Rheum.Year: 20085885486310.1002/art.2322518311803
78.. Imai K.,Shikata H.,Okada Y.. Degradation of vitronectin by matrix metalloproteinases-1, -2, -3, -7 and 9FEBS Lett.Year: 199536924925110.1016/0014-5793(95)00752-U7544295
79.. Sires U.I.,Griffin G.L.,Broekelmann T.J.,Mecham R.P.,Murphy G.,Chung A.E.,Welgus H.G.,Senior R.M.. Degradation of entactin by matrix metalloproteinasesJ. Biol. Chem.Year: 1993268206920748380588
80.. Hawinkels L.J.A.C.,Ziudwijk K.,Verspaget H.W.,de Jong-Muller E.S.M.,van Duijin W.,Ferreira V.,Fontijn R.D.,David G.,Hommes D.W.,Lamers C.B.H.W.,et al. VEGF release by MMP-9 mediated heparin sulphate cleavage induces colorectal cancer angiogenesisEur. J. CancerYear: 2008441904191310.1016/j.ejca.2008.06.03118691882
81.. Fiore E.,Fusco C.,Romero P.,Stamenkovic I.. Matrix metalloproteinase 9 (MMP-9/gelatinase B) proteolytically cleaves ICAM-1 and participates in tumor cell resistance to natural killer cell-mediated cytotoxicityOncogeneYear: 2002215213522310.1038/sj.onc.120568412149643
82.. Sultan S.,Gosling M.,Nagase H.,Powell J.T.. Shear stress-induced shedding of soluble intercellular adhesion molecule-1 from saphenous vein endotheliumFEBS Lett.Year: 200456416116510.1016/S0014-5793(04)00337-015094060
83.. Andolfo A.,English W.R.,Resnati M.,Murphy G.,Blasi F.,Sidenius N.. Metalloproteinase cleave the urokinase-type plasminogen activator receptor in the D1-D2 linker region and expose epitopes not present in the intact soluble receptorThromb. Haemost.Year: 20028829830612195704
84.. Amano T.,Kwak O.,Fu L.,Marshak A.,Shi Y.B.. The matrix metalloproteinase stromelysin-3 cleaves laminin receptor at two distinct sites between the transmembrane domain and laminin binding sequence within the extracellular domainCell Res.Year: 20051515015910.1038/
85.. Sheu B.C.,Hsu S.M.,Ho H.N.,Lien H.C.,Huang S.C.,Lin R.H.. A novel role of metalloproteinase in cancer-mediated immunosuppressionCancer Res.Year: 20016123724211196168
86.. De Paiva C.S.,Yoon K.-C.,Pangelinan S.B.,Pham S.,Puthenparambi L.M.,Chuang E.Y.,Farley W.J.,Stern M.E.,Li D.-C.,Pflugfelder S.C.. Cleavage of functional IL-2 receptor alpha chain (CD25) from murine corneal and conjunctival epithelial by MMP-9J. Inflamm. Lond.Year: 200963110.1186/1476-9255-6-3119878594
87.. Mohan M.J.,Seaton T.,Mitchell J.,Howe A.,Blackburn K.,Burkhart W.,Moyer M.,Patel I.,Waitt G.M.,Becherer J.D.,et al. The tumor necrosis factor-alpha converting enzyme (TACE): A unique metalloproteinase with highly defined substrate selectivityBiochemistryYear: 2002419462946910.1021/bi026013212135369
88.. Ito A.,Mukaiyama A.,Itoh Y.,Nagase H.,Thogersen I.B.,Enghild J.J.,Sasaguri Y.,Mori Y.. Degradation of interleukin 1 beta by matrix metalloproteinasesJ. Biol. Chem.Year: 19962711465714608663297
89.. Schonbeck U.,Mach F.,Libby P.. Generation of biologically active IL-1 beta by matrix metalloproteinases: A novel caspase-1-independent pathway of IL-1 beta processingJ. Immunol.Year: 1998161334033469759850
90.. Heissig B.,Hattori K.,Dias S.,Friedrich M.,Ferris B.,Hackett N.R.,Crystal R.G.,Besmer P.,Lyden D.,Moore M.A.,et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediate release of kit-ligandCellYear: 200210962563710.1016/S0092-8674(02)00754-712062105
91.. Hollenbeck S.T.,Sakakibara K.,Faries P.L.,Workhu B.,Liu B.,Kent K.C.. Stem cell factor and c-kit are expressed by and may affect vascular SMCs through an autocrine pathwayJ. Surg. Res.Year: 200412028829410.1016/j.jss.2004.01.00515234225
92.. Vaisar T.,Kassim S.Y.,Gomez I.G.,Green P.S.,Hargarten S.,Gough P.J.,Parks W.C.,Wilson C.L.,Raines E.W.,Heinecke J.W.. MMP-9 sheds the beta2 integrin subunit (CD18) from macrophagesMol. Cell. ProteomicsYear: 200981044106010.1074/mcp.M800449-MCP20019116209
93.. Yu Q.,Stamenkovic I.. Localization of matrix metalloproteinase 9 to the cell surface provides a mechanism for CD-44-mediated tumor invasionGenes Dev.Year: 199913354810.1101/gad.13.1.359887098
94.. Lue H.-W.,Yang X.,Wang R.,Qian W.,Xu R.Z.H.,Lyles R.,Osunkoya A.O.,Zhou B.P.,Vessella R.L.,Zayzafoon M.,et al. LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated Erk signallingPLoS OneYear: 20116e2772010.1371/journal.pone.002772022110740
95.. Giebel J. S.,Menicucci G.,McGuire P. G.,Das A.. Matrix metalloproteinases in early diabetic retinopathy and their role in alteration of the blood-retinal barrierLab. Invest.Year: 20058559760710.1038/labinvest.370025115711567
96.. Fitzgerald M.L.,Wang Z.,Park P.W.,Murphy G.,Bernfield M.. Shedding of syndecan-1 and -4 ectodomains is regulated by multiple signalling pathways and mediated by a TIMP-3-sensitive metalloproteinaseJ. Cell. Biol.Year: 200014881182410.1083/jcb.148.4.81110684261
97.. Brule S.,Charnaux N.,Sutton A.,Ledoux D.,Chaigneau T.,Saffar L.,Gattegno L.. The shedding of syndecan-4 and syndecan-1 from HeLa cells and human primary macrophages is accelerated by SDF-1/CXCL12 and mediated by the matrix metalloproteinase-9GlycobiologyYear: 20061648850110.1093/glycob/cwj09816513763
98.. Liu Z.,Zhou X.,Shapiro S.D.,Shipley J.M.,Twining S.S.,Diaz L.A.,Senior R.M.,Werb Z.. The serpin alpha-1 proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivoCellYear: 200010264765510.1016/S0092-8674(00)00087-811007483
99.. Proost P.,van Damme J.,Opdenakker G.. Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic proteinBiochem. Biophys. Res. Commun.Year: 19931921175118110.1006/bbrc.1993.15407685161
100.. Larsen P.H.,Wells J.E.,Stallcup W.B.,Opdenakker G.,Young V.W.. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycanJ. Neurosci.Year: 200323111271113514657171
101.. Agrawal S.,Anderson P.,Durbeej M.,van Rooijen N.,Ivars F.,Opdenakker G.,Sorokin L.M.. Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitisJ. Exp. Med.Year: 20062031007101910.1084/jem.2005134216585265
102.. Backstrom J.R.,Lim G.P.,Cullen M.J.,Tokes Z.A.. Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading amyloid-beta peptide (1–40)J. Neurosci.Year: 199616791079198987819
103.. Yan P.,Hu X.,Song H.,Yin K.,Bateman R.J.,Cirrito J.R.,Xiao Q.,Hsu F.F.,Turk J.W.,Xu J.,Hsu C.Y.,Holtzman D.M.,Lee J.M.. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situJ. Biol. Chem.Year: 2006281245662457410.1074/jbc.M60244020016787929
104.. Tortorella M.D.,Arner E.C.,Hills R.,Gormley J.,Fok K.,Pegg L.,Munie G.,Malfait A.-M.. ADAMTS-4 (aggreganase-1): N-terminal activation mechanismsArch. Biochem. Biophys.Year: 2005444344410.1016/
105.. Greenlee K.J.,Corry D.B.,Engler D.A.,Matsunami R.K.,Tessier P.,Cook R.G.,Werb Z.,Kheradmand F.. Proteomic identification of in vivo substrates from matrix metalloproteinase 2 and 9 reveals a mechanism for resolution of inflammationJ. Immunol.Year: 20061777312732117082650
106.. Van den Steen P.E.,Proost P.,Wuyts A.,van Damme J.,Opdenakker G.. Neutrophil gelatinase B potentiates interleukin-8 tenfold by aminoterminal processing, whereas it degrades CTAP-III, PF-4 and GRO-alpha and leaves RANTES and MCP-2 intactBloodYear: 20002753433534343
107.. Van den Steen P.E.,Wuyts A.,Husson S.J.,Proost P.,van Damme J.,Opdenakker G.. Gelatinase B/MMP-9 and neutrophil collagenase/MMP-8 process the chemokines human GCP-2/CXCL6, ENA-78/CXCL5 and mouse GCP-2/LIX and modulate their physiological activitiesEur. J. Biochem.Year: 20032703739374910.1046/j.1432-1033.2003.03760.x12950257
108.. Cox J.H.,Dean R.A.,Roberts C.R.,Overall C.M.. Matrix metalloproteinase processing of CXCL11/I-TAC results in loss of chemoattractant activity and altered glycosaminoglycan bindingJ. Biol. Chem.Year: 2008283193891939910.1074/jbc.M80026620018411283
109.. Jin F.,Zhai Q.,Qui L.,Meng H.,Zou D.,Wang Y.,Li Q.,Yu Z.,Han J.,Li Q.,et al. Degradation of BM SDF-1 by MMP-9: The role in G-CSF-induced hematopoietic stem/progenitor cell mobilizationBone Marrow Transplant.Year: 20084258158810.1038/bmt.2008.22218679363
110.. Ruiz S.,Henschen-Edman A.H.,Nagase H.,Tenner A.J.. Digestion of C1q collagen like domains by MMPs-1, -2, -3, and -9 further defines the sequence involved in the stimulation of neutrophil superoxide productionJ. Leukoc. Biol.Year: 19996641642210496311
111.. Butler G.S.,Dean R.A.,Tam E.M.,Overall C.M.. Pharmacoproteomics of a metalloproteinase hydroxamates inhibitor in breast cancer cells: Dynamics of membrane type 1 matrix metalloproteinase-mediated protein sheddingMol. Cell. Biol.Year: 2008284896491410.1128/MCB.01775-0718505826
112.. Patterson B.C.,Sang Q.A.. Angiostatin-converting enzyme activities of human matrilysin (MMP-7) and gelatinase B/type IV collagenase (MMP-9)J. Biol. Chem.Year: 1997272288232882510.1074/jbc.272.46.288239360944
113.. Farina A.R.,Tacconelli A.,Cappabianca L.,Gulino A.,Mackay A.R.. Inhibition of human MDA-MB-231 breast cancer invasion by matrix metalloproteinase 3 involves degradation of plasminogenEur. J. Biochem.Year: 20022694476448310.1046/j.1432-1033.2002.03142.x12230559
114.. Bruno M.A.,Cuello C.A.. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascadeProc. Natl. Acad. Sci. USAYear: 20061036735674010.1073/pnas.051064510316618925
115.. Nelissen I.,Martens E.,van den Steen P.E.,Proost P.,Ronsse I.,Opdenakker G.. Gelatinase B/Matrix metalloproteinase-9 cleaves interferon-b and is a target for immunotherapyBrainYear: 20031261371138110.1093/brain/awg12912764058
116.. Takino T.,Koshikawa N.,Miyamori H.,Tanaka M.,Sasaki T.,Okada Y.,Seiki M.,Sato H.. Cleavage of metastasis suppressor gene product KiSS-1 protein/metastin by matrix metalloproteinasesOncogeneYear: 20034617462612879005
117.. Nubling G.,Levin J.,Brader B.,Isreal L.,Bitzel K.,Lorenzi S.,Giese A.. Limited cleavage of tau with matrix metalloproteinase gelatinase B/MMP-9, but not MMP-3, enhances tau oligomer formationExp. Neurol.Year: 201223747047610.1016/j.expneurol.2012.07.01822890115
118.. Lee S.,Jilani S.M.,Nikolova G.V.,Carpizo D.,Iruela-Arispe M.L.. Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumorJ. Cell. Biol.Year: 200516968169110.1083/jcb.20040911515911882
119.. Sato H.,Kita M.,Seiki M.. v-Src activates the expression of 92-kDa type IV collagenase gene through the AP-1 site and the GT box homologous to retinoblastoma control elements. A mechanism regulating gene expression independent of that by inflammatory cytokinesJ. Biol. Chem.Year: 199326823460234688226872
120.. Gum R.,Lengyel E.,Juarez J.,Chen J.H.,Seiki M.,Boyd D.. Stimulation of 92-kDa gelatinase B promoter activity by ras is mitogen-activated protein kinase 1-independent and requires multiple transcription factor binding sites including closely speced PEA3/ets and AP-1 sequencesJ. Biol. Chem.Year: 1996271106721068010.1074/jbc.271.18.106728631874
121.. Han Y.P.,Tuan T.L.,Hughes M.,Wu H.,Garner W.L.. Transforming growth factor-beta-and tumor necrosis factor-alpha-mediated induction and activation of MMP-9 in human skinJ. Biol. Chem.Year: 2001276223412235011297541
122.. Schwarzt B.,Melnikova V.O.,Tellez C.,Mourad-Zeidan A.,Blehm K.,Zhao Y.-J.,McCarty M.,Adam L.,Bar-Eli M.. Loss of AP-2a results in deregulation of E-caherin and MMP-9 and an increase in tumorigenicity of colon cancer cells in vivoOncogeneYear: 2007264049405810.1038/sj.onc.121019317224907
123.. Farina A.R.,Tacconelli A.,Vacca A.,Maroder M.,Gulino A.,Mackay A.R.. Transcriptional up-regulation of matrix metalloproteinase-9 expression during spontaneous epithelial to neuroblast phenotype conversion by SH-N-SH neuroblastoma cells, involved in enhanced invasivity, depends upon GT-box and nuclear factor kappaB elementsCell Growth Differ.Year: 19991035336710359016
124.. Farina A.R.,Masciulli M.-P.,Tacconelli A.,Cappabianca L.,de Santis G.,Gulino A.,Mackay A.R.. All-trans-retinoic acid induces nuclear factor κB activation and matrix metalloproteinase-9 expression and enhances basement membrane invasivity of differentiation-resistant human SK-N-BE 9N neuroblastoma cellsCell Growth Differ.Year: 20021334335412193473
125.. Hozumi A.,Nishimura Y.,Nishiuma T.,Kotani Y.,Yokoyama M.. Induction of MMP-9 in normal human bronchial epithelial cells by TNF-alpha via NF-kappa B-mediated pathwayAm. J. Physiol. Lung Cell Mol. Physiol.Year: 2001281L1444L145211704541
126.. Bond M.,Chase A.J.,Baker A.H.,Newby A.C.. Inhibition of transcription factor NF-kappaB reduces matrix metalloproteinase-1, -3 and -9 production by vascular smooth muscle cellsCardiovasc. Res.Year: 20015055656511376631
127.. Yokoo T.,Kitamura M.. Dual regulation of Il-1 beta-mediated matrix metalloproteinase-9 expression in mesangial cells by NF-kappaB and AP-1Am. J. Physiol.Year: 1996270F123F1308769830
128.. Ricca A.,Biroccio A.,Del Bufalo D.,Mackay A.R.,Santoni A.,Cipitelli M.. Bcl-2 over-expression enhances NF-kappaB activity and induces mmp-9 transcription in human MCF7 (ADR) breast-cancer cellsInt. J. CancerYear: 20008618819610.1002/(SICI)1097-0215(20000415)86:2<188::AID-IJC7>3.0.CO;2-W10738245
129.. Kumar A.,Dhawan S.,Mukhopadhyay A.,Arrarwal B.B.. Human immunodeficiency virus-1-tat induces matrix metalloproteinase-9 in monocytes through protein tyrosine phosphatase-mediated activation of nuclear transcription factor NF-kappaBFEBS Lett.Year: 199946214014410.1016/S0014-5793(99)01487-810580107
130.. Yan L.,Borregaard N.,Kjeldsen L.,Moses M.A.. The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGALJ. Biol. Chem.Year: 2001276372583726510.1074/jbc.M10608920011486009
131.. Bond M.,Fabunmi R.P.,Baker A.H.,Newby A.C.. Synergistic upregulation of metalloproteinase-9 by growth factors and inflammatory cytokines: An absolute requirement for transcription factor NF-kappa BFEBS Lett.Year: 1998435293410.1016/S0014-5793(98)01034-59755853
132.. Farina A.R.,Cappabianca L.,DeSantis G.,di Ianni N.,Ruggeri P.,Ragone M.,Merolla S.,Tonissen K.F.,Gulino A.,Mackay A.R.. Thioredoxin stimulates MMP-9 expression, de-regulates the MMP-9/TIMP-1 equilibrium and promotes MMP-9 dependent invasion by human MDA-MB-231 breast cancer cellsFEBS Lett.Year: 20115853328333610.1016/j.febslet.2011.09.02321963718
133.. Himelstein B.P.,Lee E.J.,Sato H.,Seike M.,Muschel R.J.. Transcriptional activation of the matrix metalloproteinase-9 gene in an H-ras and v-myc transformed rat embryo cell linesOncogeneYear: 199714199519989150367
134.. Akgul B.,Garcia-Escudero R.,Ekechi C.,Steger G.,Navsaria H.,Pfister H.,Storey A.. he E2 protein of human papillomavirus type 8 increases the expression of matrix metalloproteinase-9 in human keratinocytes and organotypic skin culturesMed. Microbiol. Immunol.Year: 201120012713510.1007/s00430-011-0183-421274725
135.. Akool el-S.,Kleinert H.,Hamada F.M.,Abdelwahab M.H.,Forstermann U.,Pfeilschifter J.,Eberhardt W.. Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuRMol. Cell. Biol.Year: 2003234901491610.1128/MCB.23.14.4901-4916.200312832476
136.. Eberhardt W.,Akool el-S.,Rebhan J.,Frank S.,Beck K.F.,Franzen R.,Hamada F.M.,Pfeilschifter J.. Inhibition of cytokine-induced matrix metalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is indirect and due to a NO-mediated reduction of mRNA stabilityJ. Biol. Chem.Year: 2012277335183352812093797
137.. Jiang Y.,Muschel R.J.. Regulation of matrix metalloproteinase-9 (MMP-9) by translational efficiency in murine prostate carcinoma cellsCancer Res.Year: 2002621910191411912173
138.. Morini M.,Mottolese M.,Ferrari N.,Ghiorzo F.,Buglioni S.,Mortarini R.,Noonan D.M.,Natali P.G.,Albini A.. The alpha 3 beta 1 integrin is associated with mammary carcinoma cell metastasis, invasion and gelatinase B (MMP-9) activityInt. J. CancerYear: 20008733634210.1002/1097-0215(20000801)87:3<336::AID-IJC5>3.0.CO;2-310897037
139.. Sehgal I.,Thompson T.C.. Novel regulation of type IV collagenase (matrix metalloproteinase-9 and -2) activities by transforming growth factor-beta1 in human prostate cancer cellsMol. Biol. CellYear: 19991040741610.1091/mbc.10.2.4079950685
140.. Thant A.A.,Nawa A.,Nikkawa F.,Ichigotani Y.,Zhang Y.,Sein T.T.,Amin A.R.,Hamaguchi M.. Fibronectin activates matrix metalloproteinase-9 secretion via the MEK-1-MAPK and the PI3K-Akt pathways in ovarian cancer cellsClin. Exp. MetastasisYear: 20001842342810.1023/A:101092173095211467775
141.. Iyer V.,Pumiglia K.,DiPersio C.M.. Alpha3beta1 integrin regulates MMP-9 mRNA stability in immortalized keratinocytes: A novel mechanism of integrin-mediated MMP gene expressionJ. Cell Sci.Year: 20051181185119510.1242/jcs.0170815728252
142.. Zhang S.,Qi L.,Li M.,Zhang D.,Xu S.,Wang N.,Sun B.J.. Chemokine CXCL12 and its receptor CXCR4 expression are associated with perineural invasion of prostate cancerJ. Exp. Clin. Cancer Res.Year: 2008276210.1186/1756-9966-27-6218983683
143.. Farina A.R.,Coppa A.,Tiberio A.,Tacconelli A.,Turco A.,Colletta G.,Gulino A.,Mackay A.R.. Transforming growth factor-beta1 enhances the invasiveness of human MDA-MB-231 breast cancer cells by up-regulating urokinase activityInt. J. CancerYear: 19987572173010.1002/(SICI)1097-0215(19980302)75:5<721::AID-IJC10>3.0.CO;2-99495240
144.. Festuccia C.,Bologna M.,Vicentini C.,Tacconelli A.,Miano R.,Violini S.,Mackay A.R.. Increased matrix metalloproteinase-9 secretion in short term tissue cultures of prostatic tumor cellsInt. J. CancerYear: 19966938639310.1002/(SICI)1097-0215(19961021)69:5<386::AID-IJC6>3.0.CO;2-18900372
145.. Shima I.,Sasaguri Y.,Kusukawa J.,Nakano R.,Yamana H.,Fujita H.,Kagegawa T.,Morimatsu M.. Production of matrix metalloproteinase 9 (92 kDa gelatinase) by human oesophageal squamous cell carcinoma in response to epidermal growth factorBr. J. CancerYear: 19936772172710.1038/bjc.1993.1328471429
146.. Price T.J.,Wilson H.M.,Haites N.E.. Epidermal growth factor (EGF) increases the in vitro invasion, motility and adhesion interactions of the primary renal carcinoma cell line, A704Eur. J. CancerYear: 199632A1977198210.1016/0959-8049(96)00207-98943684
147.. Uchiyama A.,Essner R.,Dol F.,Nguyen T.,Ramming K.P.,Nakamura T.,Morton D.L.,Hoon D.S.. Interleukin 4 inhibits hepatocyte growth factor-induced invasion and migration of colon carcinomasJ. Cell Biochem.Year: 19966244345310.1002/(SICI)1097-4644(19960915)62:4<443::AID-JCB2>3.0.CO;2-M8891890
148.. Horie S.,Aruga S.,Kawamata H.,Okui N.,Kakizoe T.,Kitamura T.. Biological role of HGF/MET pathway in renal cell carcinomaJ. Urol.Year: 199916199099710.1016/S0022-5347(01)61834-210022739
149.. Jiang Y.,Xu W.,Lu J.,He F.,Yang X.. Invasiveness of hepatocellular carcinoma cell lines: Contribution of hepatocyte growth factor, c-met, and transcription factor Est-1Biochem. Biophys. Res. Commun.Year: 20012861123113010.1006/bbrc.2001.552111527416
150.. Harvey P.,Clark I.M.,Jaurand M.C.,Warn R.M.,Edwards D.R.. Hepatocyte growth factor/scatter factor enhances the invasion of mesothelioma cell lines and the expression of matrix metalloproteinasesBr. J. CancerYear: 2000831147115310.1054/bjoc.2000.144511027427
151.. To Y.,Dohi M.,Matsumoto K.,Tanaka R.,Sato A.,Nakagome K.,Nakamura T.,Yamamoto K.. A two-way interaction between hepatocyte growth factor and interleukin-6 in tissue invasion of lung cancer cell lineAm. J. Resp. Cell. Mol. Biol.Year: 20022722022610.1165/ajrcmb.27.2.4804
152.. Lee K.H.,Hyun M.S.,Kim J.R.. Growth factor-dependent activation of the MAPK pathway in human pancreatic cancer: MEK/ERK and p38 MAP kinase interaction in uPA synthesisClin. Exp. MetastasisYear: 20032049950510.1023/A:102582481602114598883
153.. Kurogi T.,Nabeshima K.,Kataoka H.,Okada Y.,Koono M.. Stimulation of gelatinase B and tissue inhibitor of metalloproteinase (TIMP) production in co-culture of human osteosarcoma cells and human fibroblasts: Gelatinase B production was stimulated via up-regulation of fibroblast growth factor (FGF) receptorInt. J. CancerYear: 199666829010.1002/(SICI)1097-0215(19960328)66:1<82::AID-IJC15>3.0.CO;2-D8608972
154.. Miyake H.,Yoshimura K.,Hara I.,Eto H.,Arakawa S.,Kamidono S.. Basic fibroblast growth factor regulates matrix metalloproteinases production and in vitro invasiveness in human bladder cancer cell linesJ. Urol.Year: 19971572351235510.1016/S0022-5347(01)64779-79146669
155.. Hazan R.B.,Phillips G.R.,Qiao R.F.,Norton L.,Aaronson S.A.. Exogenous expression of N-Cadherin in breast cancer cells induces cell migration, invasion and metastasisJ. Cell Biol.Year: 200014877979010.1083/jcb.148.4.77910684258
156.. Suyama K.,Shapiro I.,Guttman M.,Hazan R.B.. A signalling pathway leading to metastasis is controlled by N-cadherin and the FGF receptorCancer CellYear: 2002230131412398894
157.. Sehgal G.,Hua J.,Bernhard E.J.,Sehgal I.,Thompson T.C.,Muschel R.J.. Requirement for matrix metalloproteinase-9 (gelatinase B) expression in metastasis by murine prostate carcinomaAm. J. Pathol.Year: 19981525915969466586
158.. Siddiqui F.A.,Siddiqui T.F.,Francis J.L.. Haemoglobin induces the production and release of matrix metalloproteinase-9 from human malignant cellsBlood Coagul. FibrinolysisYear: 20031444945510.1097/00001721-200307000-0000412851530
159.. Masure S.,Proost P.,van Damme J.,Opdenakker G.. Purification and identification of 91-kDa neutrophil gelatinase. Release by the activating peptide interleukin-8Eur. J. Biochem.Year: 199119839139810.1111/j.1432-1033.1991.tb16027.x1645657
160.. Rehman A.A.,Ahsan H.,Kahn F.H.. α-2-Macroglobulin: A physiological guardianJ. Cell. Physiol.Year: 20132281665167510.1002/jcp.2426623086799
161.. Gomez D.E.,Alonso D.F.,Yoshiji H.,Thorgeirsson U.P.. Tissue inhibitors of metalloproteinases: Structure, regulation and biological functionsEur. J. Cell Biol.Year: 1997741111229352216
162.. Murphy G.. Tissue inhibitors of metalloproteinasesGenome Biol.Year: 20111223310.1186/gb-2011-12-11-23322078297
163.. Roeb E.,Schleinkofer K.,Kernebeck T.,Potsch S.,Jensen B.,Behrmann I.,Matern S.,Grotzinger J.. The matrix metalloproteinase-9 (mmp-9) hemopexin domain is a novel gelatin-binding domain and acts as an antagonistJ. Biol. Chem.Year: 2002277503265033210.1074/jbc.M20744620012384502
164.. Farina A.R.,Tacconelli A.,Cappabianca L.,Masciulli M.P.,Holmgren A.,Beckett G.J.,Gulino A.,Mackay A.R.. Thioredoxin alters the matrix metalloproteinase/tissue inhibitors of metalloproteinase balance and stimulates human SK-N-SH neuroblastoma cell invasionEur. J. Biochem.Year: 200126840541310.1046/j.1432-1033.2001.01892.x11168376
165.. Hahn-Dantona E.,Ruiz J.F.,Bornstein P.,Strickland D.K.. The low-density lipoprotein receptor-related protein modulates levels of matrix metalloproteinase 9 (MMP-9) by mediating its cellular catabolismJ. Biol. Chem.Year: 2001276154981550311279011
166.. Triebel S.,Blaser J.,Reinke H.,Tschesche H.. A 25 kDa alpha 2-microglobulin-related protein is a component of the 125 kDa form of human gelatinaseFEBS Lett.Year: 199231438638810.1016/0014-5793(92)81511-J1281792
167.. Chakraborty S.,Kaur S.,Guha S.,Batra S.K.. The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancerBiochim. Biophys. ActaYear: 2012182612916922513004
168.. Ardi V.C.,Kupriyanova T.A.,Deryugina E.L.,Quigley J.P.. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesisProc. Natl. Acad. Sci. USAYear: 2007104202622026710.1073/pnas.070643810418077379
169.. Ardi V.C.,van den Steen P.E.,Opdenakker G.,Schweighofer B.,Deryugina E.I.,Quigley J.P.. Neutrophil MMP-9 proenzyme, unencumbered by TIMP-1, undergoes efficient activation in vivo and catalytically induces angiogenesis via a basic fibroblast growth factor (FGF-2)/FGFR-2 pathwayJ. Biol. Chem.Year: 2009284258542586619608737
170.. Huang S.,van Arsdall M.,Tedjarati S.,McCarty M.,Wu W.,Langley R.,Fidler I.J.. Contributions of stromal metalloproteinase-9 to angiogenesis and growth of human ovarian carcinoma in miceJ. Natl. Cancer Inst.Year: 2002941134114210.1093/jnci/94.15.113412165638
171.. O’Grady A.,Dunne C.,O’Kelly P.,Murphy G.M.,Leader M.,Kay E.. Differential expression of matrix metalloproteinase (MMP)-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 in non-melanoma skin cancer: Implications for tumour progressionHistopathologyYear: 20085179380418042068
172.. Heissenberg M.C.,Gorogh T.,Lippert B.M.,Werner J.A.. Metalloproteinases and their inhibitors in squamous cell carcinoma of the hypopharynx: Indicators of individual tumor aggressivenessOtolaryngol. Pol.Year: 1998525215269884585
173.. Roeb E.,Dietrich C.G.,Winograd R.,Arndt M.,Breuer B.,Fass J.,Schumpelick V.,Matern S.. Activity and cellular origin of gelatinases in patients with colon and rectal carcinoma differential activity of matrix metalloproteinase-9CancerYear: 2001922680269110.1002/1097-0142(20011115)92:10<2680::AID-CNCR1622>3.0.CO;2-711745204
174.. Asai M.,Kato M.,Asai N.,Iwashita T.,Murakami H.,Kawai K.,Nakashima I.,Takahashi M.. Differential regulation of MMP-9 and TIMP-2 expression in malignant melanoma developed in metallothionin/RET transgenic miceJpn. J. Cancer Res.Year: 199990869210.1111/j.1349-7006.1999.tb00670.x10076570
175.. Dong Z.,Nemeth J.A.,Cher M.L.,Palmer K.C.,Bright R.C.,Fridman R.. Differential regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1) and TIMP-2 expression in co-cultures of prostate cancer and stromal cellsInt. J. CancerYear: 20019350751510.1002/ijc.135811477554
176.. Schonherr E.,Schaefer L.,O’Connel B.C.,Kresse H.. Matrix metalloproteinase expression by endothelial cells in collagen lattices changes during co-culture with fibroblasts and upon induction of decorin expressionJ. Cell Physiol.Year: 2001187374710.1002/1097-4652(2001)9999:9999<::AID-JCP1048>3.0.CO;2-W11241347
177.. Smola-Hess S.,Schnitzler R.,Hadaschik D.,Smola H.,Mauch C.,Krieg T.,Pfister H.. CD40L induces matrix metalloproteinase-9 but not tissue inhibitor of metalloproteinase-1 in cervical carcinoma cells: Imbalance between NF-kappaB and STAT3 activationExp. Cell Res.Year: 200126720521510.1006/excr.2001.525611426939
178.. O-charoenrat P.,Rhys-Evans P.,Court W.J.,Box G.M.,Eccles S.A.. Differential modulation of proliferation, matrix metalloproteinase expression and invasion of human head and neck squamous carcinoma cells by c-erbB ligandsClin. Exp. MetastasisYear: 19991763163910.1023/A:100675101686010845563
179.. Chang X.Z.,Li D.Q.,Hou Y.F.,Wu J.,Lu J.S.,Di G.H.,Jin W.,Ou Z.L.,Shen Z.Z.,Shao Z.M.. Identification of the functional role of peroxiredoxin 6 in the progression of breast cancerBreast Cancer Res.Year: 20079R7610.1186/bcr178917980029
180.. Kim J.H.,Kim J.H.,Cho C.S.,Jun H.O.,Kim D.H.,Yu Y.S.,Kim K.-W.. Differential roles of matrix metalloproteinase-9 and -2, depending on proliferation or differentiation of retinoblastoma cellsInvest. Opthalmol. Vis. Sci.Year: 2010511783178810.1167/iovs.09-3990
181.. Yu G.,Wang X.,Wu T.,Zhu J.,Huang S.,Wan Y.,Tang J.. MicroRNA-19a targets tissue factor to inhibit colon cancer cells migration and invasionMol. Cell. Biochem.Year: 201338023924710.1007/s11010-013-1679-623666757
182.. Li S.,Guo J.,Wu J.,Sun Z.,Han M.,Shan S.W.,Deng Z.,Yang B.B.,Weisel R.D.,Li R.K.. miR-17 targets tissue inhibitor of metalloproteinase-1 and 2 to modulate cardiac matrix remodellingFASEB J.Year: 2013274254426510.1096/fj.13-23168823825222
183.. Oh J.H.,Chung A.S.,Steinbrenner H.,Sies H.,Brenneisen P.. Thioredoxin secreted upon ultraviolet A irradiation modulates the activities of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 in human dermal fibroblastsArch. Biochem. Biophys.Year: 200442321822610.1016/
184.. Shabani F.,McNeil J.,Tippett L.. The oxidative inactivation of tissue inhibitor of metalloproteinase-1 (TIMP-1) by hypochlorous acid (HOCl), is suppressed by anti-rheumatic drugsFree Radic. Res.Year: 19982811512310.3109/107157698090657979645388
185.. Wang Y.,Rosen H.,Madtes D.K.,Shao B.,Martin T.R.,Heinecke J.W.,Fu X.. Myeloperoxidase inactivates TIMP-1 by oxidising its N-terminal Cystein residueJ. Biol. Chem.Year: 2007282318263183410.1074/jbc.M70489420017726014
186.. Thompson E.W.,Mackay A.R.. Review of: Opposing effects for specific TIMPs in breast cancerBreast Cancer OnlineYear: 20058e5
187.. Okada Y.,Watanabe S.,Nakanishi I.,Kishi J.,Hayakawa T.,Watorek W.,Travis J.,Nagase H.. Inactivation of tissue inhibitor of metalloproteinases by neutrophil elastase and other serine proteinasesFEBS Lett.Year: 198822915716010.1016/0014-5793(88)80817-23162216
188.. Ferry G.,Lonchampt M.,Pennel L.,de Nanteil G.,Canet E.,Tucker G.C.. Activation of MMP-9 by neutrophil elastase in an in vivo model of acute lung injuryFEBS Lett.Year: 199740211111510.1016/S0014-5793(96)01508-69037177
189.. Itkonen O.. Human trypsinogens in the pancreas and in cancerScand. J. Clin. Lab. Invest.Year: 20107013614310.3109/0036551100361531720163205
190.. Tsai J.R.,Wang H.M.,Liu P.L.,Chen Y.H.,Yang M.C.,Chou S.H.,Cheng Y.J.,Yin W.H.,Hwang J.J.,Chong I.W.. High expression of heme oxygenase-1 is associated with tumor invasiveness and poor clinical outcome in non-small cell lung cancer patientsCell. Oncol.Year: 20123546147110.1007/s13402-012-0105-5
191.. Yeghiazaryan M.,Zybura-Broda K.,Cabaj A.,Wlodarczyk J.,Slaeinska U.,Rylski M.,Wilczynski G.M.. Fine-structural distribution of MMP-2 and MMP-9 activities in the rat skeletal muscle upon training: A study of high resolution in situ zymographyHistochem. Cell Biol.Year: 2012138758710.1007/s00418-012-0940-522419075
192.. Yang Y.,Candelario-Jalil E.,Thompson J.F.,Cuadrado E.,Estrada E.Y.,Rosell A.,Montaner J.,Rosenberg G.A.. Increased intranuclear metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemiaJ. Neurochem.Year: 201011213414910.1111/j.1471-4159.2009.06433.x19840223
193.. Kwan J.A.,Schulze C.J.,Wang W.,Leon H.,Sariahmetoglu M.,Sung M.,Sawicka J.,Simms D.E.,Sawicki G.,Schulz R.. Matrix metalloproteinase-2 (MMP-2) is present in the nucleus of cardiac myocytes and is capable of cleaving poly (ADP-ribose) polymerase (PARP) in vitroFASEB J.Year: 20041869069214766804
194.. Hill J.W.,Poddar R.,Thompson J.F.,Rosenberg G.A.,Yang Y.. Intranuclear matrix metalloproteinases promote DNA damage and apoptosis induced by oxygen-glucose deprivation in neuronsNeuroscienceYear: 20121827729022710064
195.. Mannello F.,Luchetti F.,Falcieri E.,Papa S.. Multiple roles of matrix metalloproteinases during apoptosisApoptosisYear: 200510192415711919
196.. Monferran S.,Paupert J.,Dauvillier S.,Salles B.,Muller C.. The membrane form of the DNA repair protein Ku interacts at the cell surface with metalloproteinase 9EMBO J.Year: 2004233758376810.1038/sj.emboj.760040315385961
197.. Sans-Fons G.M.,Sole S.,Sanfeliu C.,Planas A.M.. Matrix metalloproteinase-9 and cell division in neuroblastoma cells and bone marrow macrophagesAm. J. Pathol.Year: 20101772870288510.2353/ajpath.2010.09005020971732
198.. Zhao W.J.,Zhang W.,Li G.L.,Cui Y.,Shi Z.F.,Yuan F.. Differential expression of MMP-9 and AQP4 in human glioma samplesFolia Neuropathol.Year: 20125017618622773464
199.. Moran A.,Iniesta P.,de Juan C.,Gonzales-Quevedo R.,Sanchez-Pernaute A.,Diaz-Rubio E.,Ramon y Cajal S.,Torres A.,Balibrea J.L.,Benito M.. Stromelysin-1 promoter mutations impair gelatinase B activation in high microsatellite instability sporadic colorectal tumorsCancer Res.Year: 2002623855386012097300
200.. Moran A.,Iniesta P.,de Juan C.,Garcia-Aranda C.,Benito M.. Impairment of stromelysin-1 transcriptional activity by promoter mutations in high microsatellite instability colorectal tumorsCancer Res.Year: 2005653811381410.1158/0008-5472.CAN-04-444215867378
201.. Thiefin G.,Dupont A.,Guillou P.J.,Vitry F.,Bouche O.,Yaziji N.,Lagarde S.,Maquart F.X.,Palot J.P.,Hornebeck W.,et al. Beneficial influence of microsatellite instability on gelatinase-tissue inhibitors of metalloproteinase balance in colorectal cancerAnticancer Res.Year: 20072758358817348445
202.. Sinnamon M.J.,Carter K.J.,Fingleton B.,Matrisian L.M.. Matrix metalloproteinase-9 contributes to intestinal tumourigenesis in the adenomatous polyposis coli multiple intestinal neoplasia mouseInt. J. Exp. Pathol.Year: 20088946647510.1111/j.1365-2613.2008.00621.x19134056
203.. Opdenakker G.,van den Steen P.E.,Dubois B.,Nielssen I.,van Coillie E.,Masure S.,Proost P.,van Damme J.. Gelatinase B functions as regulator and effector in leukocyte biologyJ. Leukoc. Biol.Year: 20016985185911404367
204.. Radisky D.C.,Levy D.D.,Litllepage L.E.,Liu H.,Nelson C.M.,Fata J.E.,Leake D.,Godden E.L.,Albertson D.G.,Nieto M.A.,et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instabilityNatureYear: 200543612312710.1038/nature0368816001073
205.. Samper E.,Nicholls D.G.,Melov S.. Mitochondrial oxidative stress causes chromosomal instability of mouse embryonic fibroblastsAging CellYear: 2003227728510.1046/j.1474-9728.2003.00062.x14570235
206.. Thieringer F.R.,Maass T.,Anthon B.,Meyer E.,Schirmacher P.,Longerich T.,Galle P.R.,Kanzler S.,Teufel A.. Liver-specific overexpression of matrix metalloproteinase 9 (MMP-9) in transgenic mice accelerates development of hepatocellular cancerMol. Carcinog.Year: 20125143944810.1002/mc.2080921681821
207.. Fatunmbi M.,Shelton J.,Aronica S.M.. gelatinase B/MMP-9 increases HER2/neu expression and alters apoptosis levels in human mammary epithelia cellsBreast Cancer Res. Treat.Year: 201213551953010.1007/s10549-012-2191-522878890
208.. Ponnala S.,Veeravalli K.K.,Chetty C.,Dinh D.H.,Rao J.S.. Regulation of DNA repair mechanism in human glioma xenograft cells both in vitro and in vivo in nude micePLoS OneYear: 20116e2619122022560
209.. Hanahan D.,Weinberg R.A.. Hallmarks of cancer: The next generationCellYear: 201114464667410.1016/j.cell.2011.02.01321376230
210.. Colotta F.,Allavena P.,Sica A.,Garlanda C.,Mantovani A.. Cancer-related inflammation, the seventh hallmark of cancer: Links to genetic instabilityCarcinogenesisYear: 2009301073108110.1093/carcin/bgp12719468060
211.. Bergers G.,Brekken R.,McMahon G.,Vu T.H.,Itoh T.,Tamaki K.,Tanzawa K.,Thorpe P.,Itohara S.,Werb Z.,et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesisNat. Cell. Biol.Year: 2000273774410.1038/3503637411025665
212.. Belotti D.,Paganoni P.,Manetti L.,Garofalo A.,Marchini S.,Taraboletti G.,Giavazzi R.. Matrix metalloproteinases (MMP-9 and MMP-2) induce the release of vascular endothelial growth factor (VEGF) by ovarian carcinoma cells: Implications for ascites formationCancer Res.Year: 2003635224522914500349
213.. Mott J.D.,Werb Z.. Regulation of matrix biology by matrix metalloproteinasesCurr. Opin. Cell Biol.Year: 20041655856410.1016/
214.. Brauer P.R.. MMPs—Role in cardiovascular development and diseaseFront Biosci.Year: 20061144747810.2741/181016146744
215.. Rorive S.,Berton A.,D’haene N.,Takacs C.N.,Debeir O.,Decaestecker C.,Salmon I.. Matrix metalloproteinase-9 interplays with the IGFBP2-IGFII complex to promote cell growth and motility in astrocytomasGliaYear: 2008561679169010.1002/glia.2071918563800
216.. Alferez D.,Wilkinson R.W.,Watkins J.,Poulsom R.,Mandir N.,Wedge S.R.,Pyrah I.T.,Smith N.R.,Jackson L.,Ryan A.J.,et al. Dual inhibition of VEGFR and EGFR signalling reduces the incidence and size of intestinal adenomas in Apc(min/+) miceMol. Cancer Ther.Year: 2008759059810.1158/1535-7163.MCT-07-043318347145
217.. Ingraham C.A.,Park G.C.,Makarenkova H.P.,Crossin K.L.. Matrix metalloproteinase (MMP)-9 induced by Wnt signalling increases the proliferation and migration of embryonic neural stem cells at low O2 levelsJ. Biol. Chem.Year: 2011286176491765721460212
218.. Aguilar-Gallardo C.,Simon C.. Cells, stem cells and cancer stem cellsSemin. Reprod. Med.Year: 20133151310.1055/s-0032-133179223329631
219.. Beck B.,Blanpain C.. Unravelling cancer stem cell potentialNat. Rev. CancerYear: 20131372773810.1038/nrc359724060864
220.. Santamaria-Martinez A.,Huelsken J.. The niche under siege: Novel targets for metastasis therapyJ. Intern. Med.Year: 201327412713610.1111/joim.1202423253195
221.. Seidel S.,Garvalov B.K.,Wirta W.,von Stechow L.,Schanzer A.,Meletis K.,Wolter M.,Sommerlad D.,Henze A.T.,Nister M.,et al. A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alphaBrainYear: 201013398399510.1093/brain/awq04220375133
222.. Wang J.,Loberg R.,Taichman R.S.. The pivotal role of CXCL12 (SDF-1)/CXCR4 axis in bone metastasisCancer Met. Rev.Year: 200625573587
223.. Wels J.,Kaplan R.N.,Rafii S.,Lyden D.. Migratory neighbors and distant invaders: Tumor-associated niche cellsGenes Dev.Year: 20082255957410.1101/gad.163690818316475
224.. Chiang A.C.,Massague J.. Molecular basis of metastasisN. Engl. J. Med.Year: 20083592814282310.1056/NEJMra080523919109576
225.. Van Amerongen R.,Nusse R.. Towards an integrated view of Wnt signalling in developmentDevelopmentYear: 20091363205321410.1242/dev.03391019736321
226.. Thiery J.P.. Epithelial-mesenchymal transitions in tumour progressionNat. Rev. CancerYear: 2002244245410.1038/nrc82212189386
227.. Reya T.,Morrison S.J.,Clarke M.F.,Weissman I.L.. Stem cells, cancer, and cancer stem cellsNatureYear: 201141410511111689955
228.. Brabletz T.,Hlubek F.,Spaderna S.,Schmalhofer O.,Hiendlmeyer E.,Jung A.,Kirchner T.. Invasion and metastasis in colorectal cancer: Epithelial-mesenchymal transition, mesenchymal-epithelial transition, stem cells and beta cateninCells Tissues OrgansYear: 2005179566510.1159/00008450915942193
229.. Pardal R.,Clarke M.F.,Morrison S.J.. Applying principles of stem-cell biology to cancerNat. Rev. CancerYear: 2003389590210.1038/nrc123214737120
230.. Margetts P.J.. Twist: A new player in the epithelial-mesenchymal transition of the peritoneal mesothelial cellsNephrol. Dial. Transplant.Year: 2012273978398110.1093/ndt/gfs17222798507
231.. Lin C.Y.,Tsai P.H.,Kandaswami C.C.,Lee P.P.,Huang C.J.,Lee M.T.. Matrix metalloproteinase-9 cooperates with transcription factor snail to induce epithelial-mesenchymal transitionCancer Sci.Year: 201110281582710.1111/j.1349-7006.2011.01861.x21219539
232.. Asuthkar S.,Nalla A.K.,Gondi G.S.,Dinh D.H.,Gujrati M.,Mohanam S.,Rao J.S.. Gadd45a sensitizes medulloblastoma cells to irradiation and suppresses MMP-9-mediated EMTNeuro. Oncol.Year: 2011131059107310.1093/neuonc/nor10921813510
233.. Gao X.H.,Yang X.Q.,Wang B.C.,Liu S.P.,Wang F.B.. Overexpression of twist and matrix metalloproteinase-9 with metastasis and prognosis in gastric cancerAsian Pac. J. Cancer Prev.Year: 2013145055506024175775
234.. Zhao J.,Guan J.L.. Signal transduction by focal adhesion kinase in cancerCancer Metastasis Rev.Year: 200928354910.1007/s10555-008-9165-419169797
235.. Li J.,Li F.,Wang H.,Wang X.,Jiang Y.,Li D.. Wortmannin reduces metastasis and angiogenesis of human breast cancer cells via nuclear factor-kappaB-dependent matrix metalloproteinase-9 and interleukin-8 pathwaysJ. Int. Med. Res.Year: 20124086787610.1177/14732300120400030522906259
236.. Zhao J.,Guan J.L.. Focal adhesion kinase and its signalling pathways in cell migration and angiogenesisAdv. Drug Deliv. Rev.Year: 20116361061510.1016/j.addr.2010.11.00121118706
237.. Yoo Y.A.,Kang M.H.,Lee H.J.,Kim B.H.,Park J.K.,Kim H.K.,Kim J.S.,Oh S.C.. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancerCancer Res.Year: 2011717061707010.1158/0008-5472.CAN-11-133821975935
238.. Opdenakker G.,van den Steen P.E.,van Damme J.. Gelatinase B: A tuner and amplifier of immune functionsTrends Immunol.Year: 20012257157910.1016/S1471-4906(01)02023-311574282
239.. Chakrabarti S.,Patel K.D.. Regulation of matrix metalloproteinase release from IL-8-stimulated human neutrophilsJ. Leukoc. Biol.Year: 20057827928810.1189/jlb.100461215831558
240.. Chinni S.R.,Sivalogan S.,Dong Z.,Filho J.C.,Deng X.,Bonfil R.D.,Cher M.L.. CXCL12/CXCR4 signaling activates Akt and MMP-9 expression in prostate cancer cells: The role of bone microenvironment-associated CXCL12ProstateYear: 200666324810.1002/pros.2031816114056
241.. Kwak Y.E.,Jeon N.K.,Kim J.,Lee E.J.. The cyclooxygenase-2 selective inhibitor celecoxib suppresses proliferation and invasiveness in the human oral squamous carcinomaAnn. NY Acad. Sci.Year: 200710959911210.1196/annals.1397.01417404023
242.. Ishizaki T.,Katsumata K.,Tsuchida A.,Wada T.,Mori Y.,Hisada M.,Kawakita H.,Aoki T.. Etodolac, a selective cyclooxygenase-2 inhibitor, inhibits liver metastasis of colorectal cancer cells via the suppression of gelatinase B/MMP-9 activityInt. J. Mol. Med.Year: 20061735736216391837
243.. Kim Y.H.,Kwon H.J.,Kim D.S.. Matrix metalloproteinase 9 (MMP-9)-dependent processing of Big-h3 protein regulates cell migration, invasion, and adhesionJ. Biol. Chem.Year: 2012287389573896910.1074/jbc.M112.35786323019342
244.. Leifer K.S.,Svensson S.,Abrahamsson A.,Bendrick C.,Robertson J.,Gauldie J.,Olsson A.-K.,Dabrosin C.. Inflammation induced by MMP-9 enhances tumor regression of experimental breast cancerJ. Immunol.Year: 20131904420443010.4049/jimmunol.120261023509357
245.. Farnsworth R.H.,Lackmann M.,Achen M.G.,Stacker S.A.. Vascular remodelling in cancerOncogeneYear: 201310.1038/onc.2013.304
246.. Van Hinsbergh V.W.,Engelse M.A.,Quax P.H.. Pericellular proteases in angiogenesis and vasculogenesisAterioscler. Thromb. Vasc. Biol.Year: 20062671672810.1161/01.ATV.0000209518.58252.17
247.. Joyce J.A.. Therapeutic targeting of the tumor microenvironmentCancer CellYear: 2005751352010.1016/j.ccr.2005.05.02415950901
248.. Bergers G.,Benjamin L.E.. Tumorigenesis and the angiogenic switchNat. Rev. CancerYear: 2003340141010.1038/nrc109312778130
249.. Coussens L.M.,Tinkle C.L.,Hanahan D.,Web Z.. MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesisCellYear: 200010348149010.1016/S0092-8674(00)00139-211081634
250.. Heissig B.,Werb Z.,Rafii S.,Hattori K.. Role of c-kit/Kit ligand signalling in regulating vasculogenesisThromb. Haemost.Year: 20039057057614515175
251.. Mira E.,Lacalle R.A.,Buesa J.M.,de Buitrago G.G.,Jimenez-Baranda S.,Gòmez-Moutòn C.,Mrtinaz A.C.,Manes S.. Secreted MMP-9 promotes angiogenesis more efficiently than constitutive active MMP-9 bound to the tumour cell surfaceJ. Cell Sci.Year: 20041171847185710.1242/jcs.0103515075244
252.. Gao D.,Nolan D.,McDonnell K.,Vahdat L.,Benezra R.,Attorki N.,Mittal V.. Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progressionBiochim. Biophys. ActaYear: 20091796334019460418
253.. Giraudo E.,Inoue M.,Hanahan D.. An amino-bisphosphonate targets MMP-9-expressing macrophages and angiogenesis to impair cervical angiogenesisJ. Clin. Investig.Year: 200411462363315343380
254.. Nosawa H.,Chiu C.,Hanahan D.. Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesisProc. Natl. Acad. Sci. USAYear: 2006103124931249810.1073/pnas.060180710316891410
255.. Melani C.,Sangaletti S.,Barazzetta F.M.,Werb Z.,Colombo M.P.. Amino-bisphosphonate-mediated MMP-9 inhibition breaks the tumor-bone marrow axis responsible for myeloid-derived suppressor cell expansion and macrophage infiltration in tumor stromaCancer Res.Year: 200767114381144610.1158/0008-5472.CAN-07-188218056472
256.. Hagemann T.,Robinson S.C.,Schultz M.,Trumper L.,Balkwill F.R.,Binder C.. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteinasesCarcinogenesisYear: 2004251543154910.1093/carcin/bgh14615044327
257.. Morales J.K.,Kmeiciak M.,Knutson K.L.,Bear H.D.,Manjili M.H.. GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1-bone marrow progenitor cells into myeloid-derived suppressor cellsBreast Cancer Res. Treat.Year: 2010123394919898981
258.. Marigo I.,Dolcetti L.,Serafini P.,Zanovello P.,Bronte V.. Tumor-induced tolerance and immune suppression by myeloid derived suppressor cellsImmunol. Rev.Year: 200822216217910.1111/j.1600-065X.2008.00602.x18364001
259.. Gabrilovich D.I.,Nagaraj S.. Myeloid-derived suppressor cells as regulators of the immune systemNat. Rev. Immunol.Year: 2009916217410.1038/nri250619197294
260.. Urbich C.,Dimmeler S.. Endothelial progenitor cells: Characterisation and role in vascular biologyCirc. Res.Year: 20049534335310.1161/01.RES.0000137877.89448.7815321944
261.. Rafii S.,Lyden D.. Therapeutic stem and progenitor cell transplantation for organ vascularization and regenerationNat. Med.Year: 2003970271210.1038/nm0603-70212778169
262.. Inoue T.,Taguchi I.,Abe S.,Toyoda S.,Nakajima K.,Sakuma M.,Node K.. Activation of matrix metalloproteinase-9 is associated with mobilization of bone marrow-derived cells after coronary stent implantationInt. J. Cardiol.Year: 201115233233610.1016/j.ijcard.2010.07.02820800911
263.. Inoue T.,Sata M.,Hikichi Y.,Sohma R.,Fukuda D.,Uchida T.,Shimizu M.,Komoda H.,Node K.. Mobilization of CD34-positive bone marrow-derived cells after coronary stent implantation: Impact on restenosisCirculationYear: 200711555356110.1161/CIRCULATIONAHA.106.62171417261663
264.. Jodele S.,Chantrain C.F.,Blavier L.,Lutzko C.,Crooks G.M.,Shimada H.,Coussens L.M.,DeClerck Y.A.. The contribution of bone marrow-derived cells to the tumor vasculature in neuroblastoma is matrix metalloproteinase-9 dependentCancer Res.Year: 2005653200320815833851
265.. Tacconelli A.,Farina A.R.,Cappabianca L.,de Santis G.,Tessitore A.,Vetuschi A.,Sferra R.,Rucci N.,Argenti B.,Screpanti I.,et al. TrkA alternative splicing: A regulated tumor-promoting switch in human neuroblastomaCancer CellYear: 2004634736010.1016/j.ccr.2004.09.01115488758
266.. Chantrain C.F.,Shimada H.,Jodele S.,Groshen S.,Ye W.,Shalinsky D.R.,Werb Z.,Coussens L.M.,DeClerck Y.A.. Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitmentCancer Res.Year: 2004641675168610.1158/0008-5472.CAN-03-016014996727
267.. Nielsen B.S.,Sehested M.,Kjeldsen L.,Borregaard N.,Rygaard J.,Dano K.. Expression of matrix metalloproteinase-9 in vascular pericytes in human breast cancerLab. Invest.Year: 1997773453559354769
268.. Vu T.H.,Shipley J.M.,Bergers G.,Berger J.E.,Helms J.A.,Hanahan D.,Shapiro S.D.,Senior R.M.,Werb Z.. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytesCellYear: 19989341142210.1016/S0092-8674(00)81169-19590175
269.. Ahn G.O.,Brown J.M.. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: Role of bone marrow-derived myelomonocytic cellsCancer CellYear: 200813195205
270.. Johnson C.,Sung H.J.,Lessner S.M.,Fini M.E.,Galis Z.S.. Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: Potential role in capillary branchingCirc. Res.Year: 20049426226810.1161/01.RES.0000111527.42357.6214670843
271.. Shekhar M.P.,Werdell J.,Santner S.J.,Pauley R.J.,Tait L.. Breast stroma plays a dominant regulatory role in breast epithelial growth and differentiation: Implications for tumor development and progressionCancer Res.Year: 2001611320132611245428
272.. Nakamura T.,Kuwai T.,Kim J.S.,Fan D.,Kim S.J.,Fidler I.J.. Stromal metalloproteinase-9 is essential to angiogenesis and progressive growth of orthotopic human pancreatic cancer in parabiont nude miceNeoplasiaYear: 2007997998610.1593/neo.0774218030366
273.. He J.Z.,Quan A.,Xu Y.,Teoh H.,Wang G.,Fish J.E.,Steer B.M.,Itohara S.,Marsden P.A.,Davidge S.T.,et al. Induction of matrix metalloproteinase-2 enhances systemic arterial contraction after hypoxiaAm. J. Physiol.Year: 2007292684693
274.. Nakano D.,Hyashi T.,Tazawa N.,Yamashita C.,Inamoto S.,Okuda N.,Mori T.,Sohmiya K.,Kitaura Y.,Okada Y.,et al. Chronic hypoxia accelerates the progression of atherosclerosis in apoliprotein E-knockout miceHypertens. Res.Year: 20052883784510.1291/hypres.28.83716471178
275.. Zalba G.,Fortuno A.,Orbe J.,San Jose G.,Moreno M.U.,Belzunce M.,Rodriguez J.A.,Beloqui O.,Paramo J.A.,Diez J.. Phagocytic NADPH oxidase-dependent superoxide production stimulates metalloproteinase-9: Implications for human atherosclerosisArterioscler. Thromb. Vasc. Biol.Year: 20072758759310.1161/01.ATV.0000256467.25384.c617194891
276.. Jadhav U.,Chigurupati S.,Lakka S.S.,Mohanam S.. Inhibition of matrix metalloproteinase-9 reduces in vitro invasion and angiogenesis in human microvascular endothelial cellsInt. J. Oncol.Year: 2004251407141415492832
277.. Tallant C.,Marrero A.,Gomis-Ruth F.X.. Matrix metalloproteinases: Fold and function of their catalytic domainsBiochim. Biophys. ActaYear: 20101803202810.1016/j.bbamcr.2009.04.00319374923
278.. Li H.,Liang J.,Castrillon D.H.,DePinho R.A.,Olson E.N.,Liu Z.P.. FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene expressionMol. Cell. Biol.Year: 2007272676268610.1128/MCB.01748-0617242183
279.. Chandrasekar B.,Mummidi S.,Mahimainathan L.,Patel D.N.,Bailey S.R.,Imam S.Z.,Greene W.C.,Valente A.J.. Interleukin-18-induced human coronary artery smooth muscle cell migration is dependent on NF-kappaB and AP-1-mediated matrix metalloproteinase-9 expression and is inhibited by atorvastatinJ. Biol. Chem.Year: 2006281150991510910.1074/jbc.M60020020016554298
280.. Cheng G.,Wei L.,Xiurong W.,Xiangzhen L.,Shiguang Z.,Songbin F.. IL-17 stimulates migration of carotid artery smooth muscle cells in an MMP-9 dependent manner via p38 MAPK and ERK1/2-dependent NF-KappaB and AP-1 activationCell. Mol. Neurobiol.Year: 2009291161116810.1007/s10571-009-9409-z19404732
281.. Galis Z.S.,Johnson C.,Godin D.,Magid R.,Shipley J.M.,Senior R.M.,Ivan E.. Targeted disruption of the matrix metalloproteinase-9 gene impairs smooth muscle cell migration and geometrical arterial remodellingCirc. Res.Year: 20029185285910.1161/01.RES.0000041036.86977.1412411401
282.. Jenkins G.M.,Crow M.T.,Bilato C.,Gluzband Y.,Ryu W.S.,Li Z.,Stetler-Stevenson W.,Nater C.,Froehlich J.P.,Lakatta E.G.,et al. Increased expression of membrane type matrix metalloproteinase and preferential localization of matrix metalloproteinase-2 to the neointima of balloon-injured rat carotid arteriesCirculationYear: 199897829010.1161/01.CIR.97.1.829443435
283.. Xu J.,Rodriguez D.,Petitclerc E.,Kim J.J.,Hangai M.,Moon Y.S.,Davis G.E.,Brooks P.C.. Proteolytic exposure of a cryptic site within collagen type IV is required for angiogenesis and tumor growth in vivoJ. Cell Biol.Year: 20011541069108010.1083/jcb.20010311111535623
284.. Hamano Y.,Zeisberg M.,Sugimoto H.,Lively J.C.,Maeshima Y.,Yang C.,Hynes R.O.,Werb Z.,Sudhakar A.,Kalluri R.. Physiological levels of tumstatin, a fragment of collagen IV alpha3 chain, are generated by MMP-9 proteolysis and suppress angiogenesis via alphaV beta3 integrinCancer CellYear: 2003358960110.1016/S1535-6108(03)00133-812842087
285.. Wahl M.L.,Kenan D.J.,Gonzalez-Gronow M.,Pizzo S.V.. Angiostatin’s molecular mechanism: Aspects of specificity and regulation elucidatedJ. Cell. Biochem.Year: 20059624226110.1002/jcb.2048016094651
286.. Kalhuri R.. Basement membranes: Structure, assembly and role in tumor angiogenesisNat. Rev. CancerYear: 2003342243310.1038/nrc109412778132
287.. Sudhakar A.,Sugimoto H.,Yang C.,Lively J.,Zeisberg M.,Kalluri R.. Human tumstatin and human endostatin exhibit distinct anti-angiogenic activities mediated by alpha V beta 3 and alpha 5 beta 1 integrinsProc. Natl. Acad. Sci. USAYear: 20031004766477112682293
288.. Kim Y.M.,Jang J.W.,Lee O.H.,Yeon J.,Choi E.Y.,Kim K.W.,Lee S.T.,Kwon Y.G.. Endostatin inhibits endothelial and tumor cellular invasion by blocking the activation and catalytic activity of matrix metalloproteinaseCancer Res.Year: 2000605410541311034081
289.. Nyberg P.,Heikkila P.,Sorsa T.,Luostarinen J.,Heljasvaara R.,Stenman U.H.,Pihlajaniemi T.,Salo T.. Endostatin inhibits human tongue carcinoma cell invasion and intravasation and blocks the activation of matrix metalloproteinase-2, -9, and -13J. Biol. Chem.Year: 2003278224042241110.1074/jbc.M21032520012690120
290.. Guan K.P.,Ye H.Y.,Yan Z.,Wang Y.,Huo S.K.. Serum levels of endostatin and matrix metalloproteinase-9 associated with high stage and grade primary transitional cell carcinoma of the bladderUrologyYear: 20036171972310.1016/S0090-4295(02)02429-912670552
291.. Ezhilarasan R.,Jadhav U.,Mohaman I.,Rao J.S.,Gujrati M.,Mohaman S.. The hemopexin domain of MMP-9 inhibits angiogenesis and retards the growth of intracranial glioblastoma xenograft in nude miceInt. J. CancerYear: 200912430631510.1002/ijc.2395118942717
292.. Qian X.,Wang T.N.,Rothman V.L.,Nicosia R.F.,Tuszynski G.P.. Thrombospondin-1 modulates angiogenesis in vitro by up-regulation of matrix metalloproteinase-9 in epithelial cellsExp. Cell Res.Year: 199723540341210.1006/excr.1997.36819299165
293.. Asuthkar S.,Velpula K.K.,Nalla A.K.,Gogineni V.R.,Gondi C.S.,Rao J.S.. Irradiation-induced angiogenesis is associated with an MMP-9-miR-494-syndecan-1 regulatory loop on medulloblastoma cellsOncogeneYear: 201310.1038/onc.2013.151
294.. Wang X.,Lee S.O.,Xia S.,Jiang Q.,Luo J.,Li L.,Yeh S.,Chang C.. Endothelial cells enhance prostate cancer metastasis via IL-6-androgen receptor-TGF-β-MMP-9 signalsMol. Cancer Ther.Year: 2013121026103710.1158/1535-7163.MCT-12-089523536722
295.. Loukovaara S.,Robciuc A.,Holopainen J.M.,Lehti K.,Pessi T.,Liinamaa J.,Kukkonen K.T.,Jauhiainen M.,Koli K.,Keski-Oja J.,et al. Ang-2 upregulation correlates with increased levels of MMP-9, VEGF, EPO and TGFβ in diabetic eyes undergoing vitrectomyActa Opthalmol.Year: 20139153153910.1111/j.1755-3768.2012.02473.x
296.. Hiratsuka S.,Nakamura K.,Iwai S.,Murakami M.,Itoh T.,Kijima H.,Shipley J.M.,Senior R.M.,Shibuya M.. MMP9 induction by vascular endothelial cell growth factor receptor-1 is involved in lung specific metastasisCancer CellYear: 2002228930012398893
297.. Wang H.,Keiser J.A.. Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: Role of flt-1Circ. Res.Year: 19988383284010.1161/01.RES.83.8.8329776730
298.. Ghosh S.,Basu M.,Roy S.S.. ETS-1 protein regulates vascular endothelial cell growth factor-induced matrix metalloproteinase-9 and matrix metalloproteinase-13 expression in human ovarian carcinoma cell line SKOV-3J. Biol. Chem.Year: 2012287150011501510.1074/jbc.M111.28403422270366
299.. Christoffersson G.,Vagesjo E.,Vandooren J.,Liden M.,Massena S.,Reinert R.B.,Brissova M.,Powers A.C.,Opdenakker G.,Phillipson M.. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissueBloodYear: 20121204653466210.1182/blood-2012-04-42104022966168
300.. Lungu G.,Covaleda L.,Mendes O.,Martini-Stoica H.,Stoica G.. FGF-1-induced matrix metalloproteinase-9 expression in breast cancer cells is mediated by increased activities of NF-kappaB and activating protein-1Mol. Carcinogen.Year: 20084742443510.1002/mc.20398
301.. Mohan R.,Sivak J.,Ashton P.,Russo L.A.,Pham B.Q.,Kasahara N.,Raizman M.B.,Fini E.M.. Curcuminoids inhibit the angiogenic response stimulated by fibroblast growth factor-2, including expression of matrix metalloproteinase gelatinase BJ. Biol. Chem.Year: 2000275104051041210744729
302.. Tang L.,Ma X.,Tian Q.,Cheng Y.,Yao H.,Liu Z.,Qu X.,Han X.. Inhibition of angiogenesis and invasion by DMBT is mediated by down regulation of VEGF and MMP-9 through Akt pathway in MDA-MB-231 breast cancer cellsFood Chem. Toxicol.Year: 20135620421310.1016/j.fct.2013.02.03223454149
303.. Xu Y.B.,Du Q.H.,Zhang M.Y.,Yun P.,He C.Y.. Propofol suppresses proliferation, invasion and angiogenesis by down regulating ERK/VEGF/MMP-9 signaling in Eca-109 esophageal squamous cell carcinoma cellsEur. Rev. Med. Pharmacol. Sci.Year: 2013172486249424089228
304.. Gorantla B.,Bhoopathi P.,Chetty C.,Gogineni V.R.,Sailaja G.S.,Gondi C.S.,Rao J.S.. Notch signalling regulates tumor-induced angiogenesis in SPARC overexpressed neuroblastomaAngiogenesisYear: 2013168510010.1007/s10456-012-9301-122956186
305.. Jia W.,Gao X.J.,Zhang Z.X.,Zhang G.. S100A4 silencing suppresses proliferation, angiogenesis and invasion of thyroid cancer cells through down regulation of MMP-9 and VEGFEur. Rev. Med. Pharm. Sci.Year: 20131714951508
306.. Yi E.Y.,Kim Y.J.. Xylitol inhibits in vitro and in vivo angiogenesis by suppressing the NF-κB and Akt signalling pathwaysInt. J. Oncol.Year: 20134331532023615861
307.. Xu J.,Zhu D.,Sonoda S.,He S.,Spee C.,Ryan S.J.,Hinton D.R.. Over-expression of BMP4 inhibits choroidal neovascularization by modulating VEGF and MMP-9AngiogenesisYear: 20121521322710.1007/s10456-012-9254-422392094
308.. Suboj P.,Babykutty S.,Valiyaparambil Gopi D.R.,Nair R.S.,Srinivas P.,Gopala S.. Aloe emodin inhibits colon cancer cell migration/angiogenesis by down regulating MMP-2/9, RhoB and VEGF via reduced DNA binding activity of NF-κBEur. J. Pharm. Sci.Year: 20124558159110.1016/j.ejps.2011.12.01222227305
309.. Hendrix M.J.C.,Seftor E.A.,Meltzer P.S.,Gardner L.M.G.,Hess A.R.,Kirschmann D.A.,Schatteman G.C.,Seftor R.E.B.. Expression and function of VE-cadherin in aggressive human melanoma cells: Role invasculogenic mimicryProc. Natl. Acad. Sci. USAYear: 2001988018802310.1073/pnas.13120979811416160
310.. Karoum A.,Mirshahi P.,Faussat A.-M.,Therwath A.,Mirshahi M.,Hatmi M.. Tubular network formation by adriamycin-resistant MCF-7 breast cancer cells is closely linked to MMP-9 and VEGFR-2/VEGFR-3 over-expressionMol. Cell. Pharmacol.Year: 201268517
311.. Wong S.Y.,Hynes R.O.. Lymphatic or hematogenous dissemination: How does a metastatic tumor cell decide?Cell CycleYear: 2006581281710.4161/cc.5.8.264616627996
312.. Christiansen A.,Detmar M.. Lymphangiogenesis and cancerGenes CancerYear: 201121146115810.1177/194760191142302822866206
313.. Rutkowski J.M.,Boardman K.C.,Swarz M.A.. Characterisation of lymphangiogenesis in a model of adult skin regenerationAm. J. Physiol. Heart Circ. Physiol.Year: 20062911402141010.1152/ajpheart.00038.2006
314.. Tan K.W.,Chong S.Z.,Wong F.H.,Evrard M.,Tan S.M.,Keeble J.,Kemeny M.D.,Ng L.G.,Abastado J.P.,Angeli V.. Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-DBloodYear: 20131223666367710.1182/blood-2012-11-46653224113869
315.. Zheng S.Q.,Huang R.Q.,Zhang Y.J.. Role of matrix metalloproteinases (MMP)-2 and -9 and vascular endothelial growth factor C in lymph node metastasis of breast cancerZhonghua Bing Li Xue Za ZhiYear: 20103924024420654122
316.. Elston C.W.,Ellis I.O.. Pathological prognostic factors in breast cancer. 1. The value of histological grade in breast cancer: Experience from a large study with long-term follow-upHistopathologyYear: 20024115416110.1046/j.1365-2559.2002.14892.x12405947
317.. Peterson O.W.,Ronnov-Jessen L.,Howlett A.R.,Bissel M.J.. Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cellsProc. Natl. Acad. Sci. USAYear: 1992899064906810.1073/pnas.89.19.90641384042
318.. Redondo-Munoz J.,Ugarte-Berzal E.,Garcia-Marco J.A.,del Cerro M.H.,van den Steen P.E.,Opdenakker G.,Terol M.J.,Garcia-Pardo A.. Alpha4Beta1 integrin and 190-kDa CD44v constitute a cell surface docking complex fro gelatinase B/MMP-9 in chronic leukemia but not in normal B cellsBloodYear: 200811216917810.1182/blood-2007-08-10924918326820
319.. Brooks P.C.,Silletti S.,von Schalscha T.L.,Friedlander M.,Cheresh D.. Disruption of angiogenesis by Pex, a non catalytic fragment with integrin binding activityCellYear: 199892683693
320.. Dufour A.,Sampson N.S.,Zucker S.,Cao J.. Role of the hemopexin domain of matrix metalloproteinases in cell migrationJ. Cell Physiol.Year: 200821764365110.1002/jcp.2153518636552
321.. Paupert J.,Mansat-De Mas V.,Demur C.,Salles B.,Muller C.. Cell-surface MMP-9 regulates the invasive capacity of leukemia blast cells with Monocytic featuresCell CycleYear: 200871047105310.4161/cc.7.8.564518414048
322.. Redondo-Munoz J.,Ugarte-Berzal E.,Terol M.J.,van den Steen P.E.,Hernandez del Cerro M.,Roderfeld M.,Roeb E.,Opdenakker G.,Garcia-Marco J.A.,Garcia-Pardo A.. Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia B cell survival through its hemopexin domainCancer CellYear: 20101716017210.1016/j.ccr.2009.12.04420159608
323.. Hu X.,Paik P.K.,Chen J.,Yarilina A.,Kockeritz L.,Lu T.T.,Woodgett J.R.,Ivashkiv L.B.. IFN-gamma suppresses IL-10 production and synergizes with TLR2 by regulating GSK3 and CREB/AP-1 proteinsImmunityYear: 20062456357410.1016/j.immuni.2006.02.01416713974
324.. Rao J.S.,Bhoopathi P.,Chetty C.,Gujrati M.,Lakka S.S.. MMP-9 short interfering RNA induced senescence resulting in inhibition of medulloblastoma growth via p16 (INK4a) and mitogen-activated protein kinase pathwayCancer Res.Year: 2007674956496410.1158/0008-5472.CAN-07-038017510426
325.. Bhoopathi. P.,Chetty C.,Kunigal. S.,Vanamala S.K.,Rao J.S.,Lakka S.S.. Blockage of tumour growth due to matrix metalloproteinase-9 inhibition is mediated by sequential activation of β1-integrin, ERK, and NF-κBJ. Biol. Chem.Year: 20082831545155217991734
326.. Wheeler D.L.,Dunn E.F.,Harari P.M.. Understanding resistance to EGFR inhibitors-impact on future treatment strategiesNat. Rev. Clin. Oncol.Year: 2010749350710.1038/nrclinonc.2010.9720551942
327.. Frame M.C.,Patel H.,Serrels B.,Lietha D.,Eck M.J.. The FERM domain: Organizing the structure and function of FAKNat. Rev. Mol. Cell. Biol.Year: 20101180281410.1038/nrm299620966971
328.. Stuelten C.H.,DaCosta Byfield S.,Arany P.R.,Karpova T.S.,Stetler-Stevenson W.G.,Roberts A.B.. Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-alpha and TGF-betaJ. Cell Sci.Year: 20051182143215310.1242/jcs.0233415855236
329.. Mook O.R.,Frederiks W.M.,van Noorden C.J.. The role of gelatinases in colorectal cancer progression and metastasisBiochim. Biophys. ActaYear: 20041705698915588763
330.. Jandova J.,Janda J.,Sligh J.E.. Changes in mitochondrial DNA alter expression of nuclear encoded genes associated with tumorigenesisExp. Cell. Res.Year: 20123182215222510.1016/j.yexcr.2012.06.00622705584
331.. Friedl P.,Wolf K.. Tumour-cell invasion and migration: Diversity and escape mechanismsNat. Rev. CancerYear: 2003336237410.1038/nrc107512724734
332.. Sabeh F.,Shimizu-Hirota R.,Weiss S.J.. Protease-dependent versus -ndependent cancer cell invasion programs: Three-dimensional amoeboid movement revisitedJ. Cell Biol.Year: 2009185111910.1083/jcb.20080719519332889
333.. Legrand C.,Gilles C.,Zahm J.M.,Polette M.,Buisson A.C.,Kaplan H.,Birembaut P.,Tournier J.M.. Airway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodellingJ. Cell Biol.Year: 199914651752910.1083/jcb.146.2.51710427102
334.. Rolli M.,Fransvea E.,Pilch J.,Saven A.,Felding-Habermann B.. Activated integrin aplphavbeta3 cooperates with metalloproteinase MMP-9 in regulating migration of metastatic breast cancer cellsProc. Natl. Acad. Sci. USAYear: 20031009482948712874388
335.. Shibata K.,Kikkawa F.,Nawa A.,Thant A.A.,Naruse K.,Mizutani S.,Hamaguchi M.. Both focal adhesion kinase and c-Ras are required for the enhanced matrix metalloproteinase 9 secretion by fibronectin in ovarian cancer cellsCancer Res.Year: 1998589009039500447
336.. Ozanne B.W.,McGarry L.,Spence H.J.,Johnston I.,Winnie J.,Meagher L.,Stapleton G.. Transcriptional regulation of cell invasion: AP-1 regulation of a multigenic invasion programmeEur. J. CancerYear: 2000361640164810.1016/S0959-8049(00)00175-110959050
337.. Shin E.Y.,Ma E.K.,Kim C.K.,Kwak S.J.,Kim E.G.. Src/ERK but not phospholipase D is involved in keratinocyte growth factor-stimulated secretion of matrix metalloproteinase-9 and urokinase-type plasminogen activator in SNU-16 human stomach cancer cellsJ. Cancer Res. Clin. Oncol.Year: 200212859660210.1007/s00432-002-0388-412458339
338.. Thomas G.J.,Poomsawat S.,Lewis M.P.,Hart I.R.,Speight P.M.,Marshall J.F.. Alpha v beta 6 integrin upregulates matrix metalloproteinase 9 and promotes migration of normal oral keratinocytesJ. Invest. Dermatol.Year: 20011189890411407978
339.. Thomas G.J.,Lewis M.P.,Hart I.R.,Marshall J.F.,Speight P.M.. AlphaVbeta6 integrin promotes invasion of squamous carcinoma cells through up-regulation of matrix metalloproteinase-9Int. J. CancerYear: 20019264165010.1002/1097-0215(20010601)92:5<641::AID-IJC1243>3.0.CO;2-P11340566
340.. Sil H.,Sen T.,Chatterjee A.. Fibronectin-integrin (alpha5beta1) modulates migration and invasion of murine melanoma cell line B16F10 by involving MMP-9Oncol. Res.Year: 20111933534810.3727/096504011X1307969713292521936403
341.. Mackay A.R.,Gomez D.E.,Nason A.M.,Thorgeirsson U.P.. Sudies on the effects of laminin, E-8 fragment of laminin and synthetic laminin peptides PA22–2 and YIGRS on matrix metalloproteinase and tissue inhibitor of metalloproteinase expressionLab. Invest.Year: 1994708008068015284
342.. Kahn K.M.,Falcone D.J.. Role of laminin in matrix induction of macrophage urokinase-type plasminogen activator and 92-kDa metalloproteinase expressionJ. Biol. Chem.Year: 19972728270827510.1074/jbc.272.13.82709079647
343.. Anderson R.B.. Matrix metalloproteinase-2 is involved in the migration and network formation of enteric neural crest-derived cellsInt. J. Dev. Biol.Year: 201054636910.1387/ijdb.082667ra19247964
344.. Fortier A.M.,Asselin E.,Cadrin M.. Keratin 8 and 18 loss in epithelial cancer cells increases collective cell migration and cisplatin sensitivity through claudin up-regulationJ. Biol. Chem.Year: 2013288115551157110.1074/jbc.M112.42892023449973
345.. Xu D.,McKee C.M.,Cai Y.,Ding Y.,Kessler B.M.,Muschel R.J.. Matrix metalloproteinase-9 regulates tumor cell invasion through cleavage of protease nexin-1Cancer Res.Year: 2010706988699810.1158/0008-5472.CAN-10-024220736374
346.. Pal-Ghosh S.,Blanco T.,Tadvalkar G.,Pajoohesh-Ganji A.,Parthasarathy A.,Zieske J.D.,Stepp M.A.. MMP-9 cleavage of the β4 integrin ectodomain leads to recurrent epithelial erosions in miceJ. Cell Sci.Year: 20111242666267510.1242/jcs.08548021750188
347.. Taddei M.L.,Parri M.,Angelucci A.,Bianchini F.,Marconi C.,Giannoni E.,Raugei G.,Bologna M.,Calorini L.,Chiarugi P.. EphA2 induces metastatic growth regulating amoeboid motility and clonogenic potential in prostate carcinoma cellsMol. Cancer Res.Year: 2011914910.1158/1541-7786.MCR-10-029821205836
348.. Wyckoff J.,Wang W.,Lin E.Y.,Wang Y.,Pixley F.,Stanley E.R.,Graf T.,Pollard J.W.,Segall J.,Condeelis J.. A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumorsCancer Res.Year: 2004647022702910.1158/0008-5472.CAN-04-144915466195
349.. Gherardi E.,Birchmeier W.,Birchmeier C.,vande Woude G.. Tageting MET in cancer: Rational and progressNat. Rev. CancerYear: 2012128910310.1038/nrc320522270953
350.. Wang M.,Qin X.,Mudgett J.S.,Ferguson T.A.,Senior R.M.,Welgus H.G.. Matrix metalloproteinase deficiencies affect contact hypersensitivity: Stromelysin-1 deficiency prevents the response and gelatinase B deficiency prolongs the responseProc. Natl. Acad. Sci. USAYear: 1999966885688910359808
351.. Creighton C.,Hanash S.. Expression of matrix metalloproteinase 9 (MMP-9/gelatinase B) in adenocarcinomas strongly correlated with expression of immune response genesIn Silico Biol.Year: 2003330131112954092
352.. Zhu X.S.,Shi W.,An G.Y.,Zhang H.M.,Song Y.G.,Li Y.B.. Matrix metalloproteinase-9 was involved in the immune-modulatory defect of mesenchymal stem cell from chronic myeloid leukemia patientsChin. Med. J.Year: 2011124242321933581
353.. Bratcher P.E.,Weathington N.M.,Nick H.J.,Jackson P.L.,Snelgrove R.J.,Gaggar A.. Gelatinase B/MMP-9 cleaves SP-D and abrogates its innate immune functions in vitroPLoS OneYear: 20127e4188122860023
354.. Geiger T.,Rordorf C.,Galakatos N.,Seligmann B.,Henn R.,Lazdins J.,Vosbeck K.. Recombinant human C5a induces transcription but not translation of interleukin-1 beta mRNA in human monocytesRes. Immunol.Year: 199214311712310.1016/0923-2494(92)80088-31565840
355.. Wu G.,Chen T.,Shahsafaei A.,Hu W.,Bronson R.T.,Shi G.P.,Halperin J.A.,Aktas H.,Qin X.. Complement regulator CD59 protects against angiotensin II-induced abdominal aortic aneurisms in miceCirculationYear: 20101211338134610.1161/CIRCULATIONAHA.108.84458920212283
356.. Voskoboinik I.,Dunstone M.A.,Baran K.,Whisstock J.C.,Trapani J.A.. Perforin: Structure function and role in human immunopathologyImmunol. Rev.Year: 2010235355420536554
357.. Nishikawa H.,Sakaguchi S.. Regulatory T cells in tumor immunityInt. J. CancerYear: 201012775976720518016
358.. Wang J.,Ke X.Y.. The four types of Tregs in malignant lymphomasJ. Hematol. Oncol.Year: 201145010.1186/1756-8722-4-5022151904
359.. Tan W.,Zhang W.,Strasner A.,Grivennikov S.,Cheng J.Q.,Hoffman R.M.,Karin M.. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL.RANK signallingNatureYear: 201147054855310.1038/nature0970721326202
360.. Shah W.,Yan X.,Jing L.,Zhou Y.,Chen H.,Wang Y.. A reversed CD4/CD8 ratio of tumor-infiltrating lymphocytes and a high percentage of CD4(+)FOXP3(+) regulatory T cells are significantly associated with clinical outcome in squamous cell carcinoma of the cervixCell. Mol. Immunol.Year: 20118596621200385
361.. Piersma S.J.,Welters M.J.,van den Burg S.H.. Tumor-specific regulatory T cells in cancer patientsHum. Immunol.Year: 20086924124910.1016/j.humimm.2008.02.00518486758
362.. Kim J.,Yu W.,Kovalski K.,Ossowski L.. Requirement for specific proteases in cancer cell intravasation as revealed by a novel semi-quantitative PCR-based assayCellYear: 19989435336210.1016/S0092-8674(00)81478-69708737
363.. Bekes E.M.,Schweighofer B.,Kupriyanova T.A.,Zajac E.,Ardi V.C.,Quigley J.P.,Deryugina E.L.. Tumor-recruited neutrophils and neutrophil TIMP-free MMP-9 regulate co-ordinately the levels of tumor angiogenesis and efficiency of malignant cell intravasationAm. J. Pathol.Year: 20111791455147010.1016/j.ajpath.2011.05.03121741942
364.. Cho K.,Matsuda Y.,Ueda J.,Uchida E.,Naito Z.,Ishiwata T.. Keratinocyte growth factor induces matrix metalloproteinase-9 expression and correlates with venous invasion in pancreatic cancerInt. J. Oncol.Year: 2012401040104822159401
365.. Li J.,Sun R.,Tao K.,Wang G.. The CCL21/CCR7 pathway plays a key role in human colon cancer metastasis through regulation of matrix metalloproteinase-9Dig. Liver Dis.Year: 201143404710.1016/j.dld.2010.05.01320609636
366.. Sugino T.,Kusakabe T.,Hoshi N.,Yamaguchi T.,Kawaguchi T.,Goodison S.,Sekimata M.,Homma Y.,Suzuki T.. An invasion-independent pathway of blood-borne metastasis: A new murine mammary tumor modelAm. J. Pathol.Year: 20021601973198010.1016/S0002-9440(10)61147-912057902
367.. Mook O.R.,van Marle J.,Vreeling-Sindelarova H.,Jonges R.,Frederiks W.M.,van Noorden C.J.. Visualization of early events in tumor formation of eGFP-transfected rat colon cancer cells in liverHepatologyYear: 20033829530412883473
368.. Chambers A.F.,Groom A.C.,MacDonald I.C.. Dissemination of cancer cells in metastatic sitesNat. Rev. CancerYear: 2002256357210.1038/nrc86512154349
369.. Rundhaug J.E.. Matrix metalloproteinases and angiogenesisJ. Cell Mol. Med.Year: 2005926728510.1111/j.1582-4934.2005.tb00355.x15963249
370.. Kopp H.G.,Ramos C.A.,Rafii S.. Contribution of endothelial progenitors and proangiogenic haematopoietic cells to vascularization of tumors and ischemic tissueCurr. Opin. Hematol.Year: 20061317518110.1097/01.moh.0000219664.26528.da16567962
371.. Kollet O.,Dar A.,Shivtiel S.,Kalinkovich A.,Lapid K.,Sztainberg Y.,Tesio M.,Samstein R.M.,Goichberg P.,Spiegel A.,et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cellsNat. Med.Year: 20061265766410.1038/nm141716715089
372.. Chen X.,Su Y.,Fingleton B.,Acuff H.,Matrisian L.M.,Zent R.,Pozzi A.. An orthotopic model of lung cancer to analyse primary and metastatic NSCL growth in integrin alpha1-null miceClin. Exp. MetastasisYear: 20052218519310.1007/s10585-005-7453-816086239
373.. Kaplan R.N.,Psaila B.,Lyden D.. Niche-to-niche migration of bone-marrow-derived cellTrends Mol. Med.Year: 200713728110.1016/j.molmed.2006.12.00317197241
374.. Van Kempen L.C.L.,Coussens L.M.. MMP-9 potentiates pulmonary metastasis formationCancer CellYear: 2002225125210.1016/S1535-6108(02)00157-512398887
375.. Grange C.,Tapparo M.,Collino F.,Vitillo L.,Damasco C.,Deregibus M.C.,Tetta C.,Bussolati B.,Camussi G.. Microvesicles released from human renal cancer stem cells stimulate angiogenesis and formation of lung pre-metastatic nicheCancer Res.Year: 2011715346535610.1158/0008-5472.CAN-11-024121670082
376.. Van Deventer H.W.,Palmieri D.A.,Wu Q.P.,McCook E.C.,Serody J.S.. Circulating fibrocytes prepare the lung for cancer metastasis by recruiting Ly-6C+ monocytes via CCL2J. Immunol.Year: 20131904861486710.4049/jimmunol.120285723536638
377.. Kucia M.,Reca R.,Miekus K.,Wanzeck J.,Wojakowski W.,Janowska-Wieczorek A.,Ratajczak J.,Ratajczak M.Z.. Trafficking of normal stem cells and cancer stem cells involve similar mechanisms: Pivotal role for the SDF-1/CXCR4 axisStem CellsYear: 20052387989410.1634/stemcells.2004-034215888687
378.. Kaplan R.N.,Rifil S.,Lyden D.. Preparing the “soil”: The pre-metastatic nicheCancer Res.Year: 200666110891109310.1158/0008-5472.CAN-06-240717145848
379.. Mannello F.,Tonti G.A.,Bagnara G.P.,Papa S.. Role and function of matrix metalloproteinases in the differentiation and biological characterisation of mesenchymal stem cellsStem CellsYear: 20052447548116150919
380.. Lee R.,Kermani P.,Teng K.K.,Hempstead B.L.. Regulation of cell survival by secreted proneurotrophinsScienceYear: 20012941945194810.1126/science.106505711729324
381.. Vaillant C.,Meissirel C.,Mutin M.,Belin F.,Lund L.R.,Thomasset N.. MMP-9 deficiency affects axonal outgrowth, migration, and apoptosis in the developing cerebellumMol. Cell. Neurosci.Year: 20032439540810.1016/S1044-7431(03)00196-914572461
382.. Chintala S.K.,Zhang X.,Austin J.S.,Fini M.E.. Deficiency in matrix metalloproteinase gelatinase B (MMP-9) protects against retinal ganglion cell death after optic nerve ligationJ. Biol. Chem.Year: 2002277474614746810.1074/jbc.M20482420012354772
383.. Gazzanelli G.,Luchetti F.,Burattini S.,Mannello F.,Falcieri E.,Papa S.. Matrix metalloproteinases expression in HL-60 promyelocytic leukaemia cell during apoptosisApoptosisYear: 2000516517210.1023/A:100968883153111232244
384.. Moshal. K.S.,Tipparaju S.M.,Vacek T.P.,Kumar M.,Singh M.,Franke I.E.,Patibandla P.K.,Tyagi N.,Rai J.,Metreveli N.,et al. Mitochondrial matrix metalloproteinase activation decreases myocyte contractility in hyperhomocysteinemiaAm. J. Physiol. Heart Circ. Physiol.Year: 2008295H890H89710.1152/ajpheart.00099.200818567713
385.. Kowluru R.A.,Mohammad G.,dos Santos J.M.,Zhong Q.. Abrogation of gelatinase B/MMP-9 gene protects against the development of retinopathy in diabetic mice by preventing mitochondrial damageDiabetesYear: 2011603023303310.2337/db11-081621933988
386.. Overchin A.V.,Tyagi N.,Rodriguez W.E.,Hyden M.R.,Moshal K.S.,Tyagi S.C.. Role of matrix metalloproteinase-9 in endothelial apoptosis in chronic heart failure in miceJ. Appl. Physiol.Year: 2005992398240510.1152/japplphysiol.00442.200516081621
387.. Chetty C.,Lakka S.S.,Bhoopathi P.,Gondi C.S.,Veeravalli K.K.,Fassett D.,Klopfenstein J.D.,Dinh D.H.,Gujrati M.,Rao J.S.. Urokinase plasminogen activator and /or matrix metalloproteinase-9 inhibition induces apoptosis signalling through lipid rafts in glioblastoma xenograft cellsMol. Cancer Ther.Year: 201092605261710.1158/1535-7163.MCT-10-024520716639
388.. Shchors K.,Nozawa H.,Xu J.,Rostker F.,Swigart-Brown L.,Evan G.,Hanahan D.. Increased invasiveness of MMP-9-deficient tumors in two mouse models of neuroendocrine tumorigenesisOncogeneYear: 20133250251310.1038/onc.2012.6022391572
389.. Deryugina E.L.,Quigley J.P.. Matrix metalloproteinases and tumor metastasisCancer Metastasis Rev.Year: 20062593410.1007/s10555-006-7886-916680569
390.. Acuff H.B.,Carter K.J.,Fingleton B.,Gorden D.L.,Matrisian L.M.. Matrix metalloproteinase-9 from bone marrow-derived cells contributes to survival but not growth of tumor cells in lung microenvironmentCancer Res.Year: 20066625926610.1158/0008-5472.CAN-05-250216397239
391.. Itoh T.,Tanioka M.,Matsuda H.,Nishimoto H.,Yoshioka T.,Suzuki R.,Uehira M.. Experimental metastasis is suppressed in MMP-9-deficient miceClin. Exp. MetastasisYear: 19991717718110.1023/A:100660372375910411111
392.. Pozzi A.,Moberg P.E.,Miles L.A.,Wagner S.,Soloway P.,Gardner H.A.. Elevated matrix metalloproteinase and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularizationProc. Natl. Acad. Sci. USAYear: 2000972202220710681423
393.. Pozzi A.,LeVine W.F.,Gardner H.A.. Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesisOncogeneYear: 20022127228110.1038/sj.onc.120504511803470
394.. Chen X.,Su Y.,Fingleton B.,Acuff H.,Matrisian L.M.,Zent R.,Pozzi A.. Increased plasma MMP9 in integrin alpha1-null mice enhances lung metastasis of colon carcinoma cellsInt. J. CancerYear: 2005116526110.1002/ijc.2099715756690
395.. Buck T.B.,Yoshiji H.,Harris S.R.,Bunce O.R.,Thorgeirsson U.P.. The effects of sustained elevated levels of circulating tissue inhibitor of metalloproteinase-1 on the development of breast cancer in miceAnn. NY Acad. Sci. USAYear: 199987873273510.1111/j.1749-6632.1999.tb07775.x
396.. De Lornzo M.S.,Ripoll G.V.,Yoshiji H.,Yamazaki M.,Thorgeirsson U.P.,Alonso D.F.,Gomez D.E.. Altered tumor angiogenesis and metastasis of B16 melanoma in transgenic mice overexpressing tissue inhibitor of metalloproteinase-1In VivoYear: 200317455012655789
397.. Yoshiji H.,Kuriyama S.,Miyamoto Y.,Thorgeirsson U.P.,Gomez D.E.,Kawata M.,Yoshii J.,Ikenaka Y.,Noguchi R.,Tsujinoue H.,et al. Tissue inhibitor of metalloproteinase-1 promotes liver fibrosis development in a transgenic mouse modelHepatologyYear: 2000321248125410.1053/jhep.2000.2052111093731
398.. Dziembowska M.,Wlodarczyk J.. MMP9: Novel function in synaptic plasticityInt. J. Biochem. Cell Biol.Year: 20124470971310.1016/j.biocel.2012.01.02322326910
399.. Zucker S.,Cao J.,Chen W.-T.. Critical appraisal of the use of matrix metalloproteinase inhibitors in cancer treatmentOncogeneYear: 2001196642665010.1038/sj.onc.120409711426650
400.. Pavlaki M.,Zucker S.. Matrix metalloproteinase inhibitors (MMPIs): The beginning of phase I or the termination of phase III clinical trialsCancer Metastasis Rev.Year: 20032217720310.1023/A:102304743186912784996
401.. Overall C.M.,Kleifeld O.. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapyNat. Rev. CancerYear: 2006622723910.1038/nrc182116498445
402.. McCawley L.J.,Wright J.,LaFleur B.J.,Crawford H.C.,Matrisian L.M.. Keratinocyte expression of MMP-3 enhances differentiation and prevents tumor establishmentAm. J. Pathol.Year: 20081731528152910.2353/ajpath.2008.08013218832569
403.. McCawley L.J.,Crawford H.C.,King L.E. Jr.,Mudgett J.,Matrisian L.M.. A protective role for matrix metalloproteinase-3 in squamous cell carcinomaCancer Res.Year: 2004646965697215466188
404.. Kopitz C.,Gerg M.,Bandapalli O.R.,Ister D.,Pennington C.J.,Hauser S.,Flecgsig C.,Krell H.W.,Antolovic D.,Brew K.,et al. Tissue inhibitor of metalloproteinases-1 promotes liver metastasis by inducing hepatocyte growth factor signallingCancer Res.Year: 2007678615862310.1158/0008-5472.CAN-07-023217875701
405.. Wolf K.,Mazo I.,Leung H.,Engelke K.,von Andrian U.H.,Deryugina E.L.,Strongin A.Y.,Brocker E.B.,Friedl P.. Compensation mechanism in tumor cell migration: Mesenchymal-amoeboid transition after blocking of peri-cellular proteolysisJ. Cell Biol.Year: 200316026727710.1083/jcb.20020900612527751
406.. Hu J.,van den Steen P.E.,Sang Q.X.,Opdenakker G.. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseasesNat. Rev. Drug Discov.Year: 2007648049810.1038/nrd230817541420
407.. Martens E.,Leyssen A.,van Aelst I.,Fiten P.,Piccard H.,Hu J.,Descamps F.J.,van den Steen P.E.,Proost P.,van Damme J.,et al. A monoclonal antibody inhibits gelatinase B/MMP-9 by selective binding to part of the catalytic domain and not to the fibronectin or zinc binding domainsBiochim. Biophys. ActaYear: 2007177017818610.1016/j.bbagen.2006.10.01217137715
408.. Stefanidakis M.,Karjalainen K.,Jaalouk D.E.,Gahmberg C.G.,O’Brien S.,Pasqualini R.,Arap W.,Koivunen E.. Role of leukemia cell invadosome in extramedullary infiltrationBloodYear: 20091143008301710.1182/blood-2008-04-14864319636064
409.. Suojanen J.,Vilen S.-T.,Nyberg P.,Heikkila P.,Penate-Medina O.,Saris P.E.J.,Hagstrom J.,Ranta T.-M.,Salo T.,Sorsa T.,et al. Selective gelatinase inhibitor peptide is effective in targeting tongue carcinoma cell tumors in vivoAnticancer Res.Year: 2011313659366422110184
410.. Burg-Roderfeld M.,Roderfeld M.,Wagner S.,Henkel C.,Grotzinger J.,Roeb E.. MMP-9-hemopexin domain hampers adhesion and migration of colorectal cancer cellsInt. J. Oncol.Year: 20073098599217332939
411.. Urgate-Berzal E.,Bailon E.,Amigo-Jiminez I.,Vituri C.L.,Hernandez del Cerro M.,Terol M.J.,Albar J.P.,Rivas G.,Barcia-Marco J.A.,Garcia-Pardo A.. A 17-residue sequence from the matrix metalloproteinase-9 (MMP-9) hemopexin domain binds α4β1 integrin and inhibits MMP-9-induced functions in chronic Lymphocytic Leukaemia B cellsJ. Biol. Chem.Year: 2012287276012761310.1074/jbc.M112.35467022730324
412.. Bjorklund M.,Heikkila P.,Koivunen E.. Peptide inhibition of catalytic and non-catalytic activities of matrix metalloproteinase-9 blocks tumor cell migration and invasionJ. Biol. Chem.Year: 2004279295892959710.1074/jbc.M40160120015123665
413.. Vandooren J.,Geurts N.,Opdenakker G.. Gelatin degradation assay reveals MMP-9 inhibitors and function of O-glycosylated domainWorld J. Biol. Chem.Year: 201126142421537473


[Figure ID: cancers-06-00240-f001]
Figure 1 

Localisation of functional transcriptional elements within the human MMP-9 promoter, displaying the positions, relative to the MMP-9 translational start site, for E2 protein (E2 BS), nuclear factor-kappa binding (NF-κB), specific protein-1 (Sp1), E26 transformation specific (ETS), CA repeat, activator protein-1 (AP1), GTbox and Tata box binding sites.

[Figure ID: cancers-06-00240-f002]
Figure 2 

Representation of the role of inflammatory polymorphonuclear leukocyte (PMN)-derived tissue inhibitor of metalloproteinase (TIMP)-free gelatinase B/MMP-9 in tumour initiation and promotion of genetic instability through degradation of extracellular matrices (ECM) release and activation of cytokines, chemokines and growth factors.

[Figure ID: cancers-06-00240-f003]
Figure 3 

Representation of the role played by inflammatory polymorphonuclear leukocyte (PMN), stromal and tumour cell-derived gelatinase B/MMP-9 in epithelial-mesenchymal transition (EMT) and formation of the stem cell niche through degradation of extracellular matrices (ECM) release and activation of cytokines and growth factors.

[Figure ID: cancers-06-00240-f004]
Figure 4 

Representation of the roles played by inflammatory polymorphonuclear leukocyte (PMN)-derived tissue inhibitor of metalloproteinase (TIMP)-free gelatinase B/MMP-9, gelatinase B/MMP-9 of stromal and tumour origin, oncogenes and hypoxia in activating the tumour angiogenic switch required for tumour progression.

[Figure ID: cancers-06-00240-f005]
Figure 5 

Representation of the roles played by inflammatory polymorphonuclear leukocyte (PMN)-derived tissue inhibitor of metalloproteinase (TIMP)-free gelatinase B/MMP-9, gelatinase B/MMP-9 of stromal and tumour origin, in the loss of tissue architecture and local invasion associated with tumour progression.

[Figure ID: cancers-06-00240-f006]
Figure 6 

Representation of the roles played by inflammatory polymorphonuclear leukocyte (PMN)-derived tissue inhibitor of metalloproteinase (TIMP)-free gelatinase B/MMP-9, and gelatinase B/MMP-9 of stromal and tumour origin, in epithelial-mesenchymal transition (EMT) and subsequent integrin and non-integrin mediated mesenchymal motility and invasion and immature tumour blood vessels.

[TableWrap ID: cancers-06-00240-t001] pii: cancers-06-00240-t001_Table 1.
Table 1 

Update of Gelatinase B/MMP-9 substrates. Substrates (sub) and MMP-9 origins are provided: human (hu), mouse (mu), bovine (bo) and rabbit (ra).

Class Substrate Substrate/MMP-9 source [Refs]
ECM Substrates Collagen type I (bo/mu sub/hu MMP-9) [55]
Collagen type II (hu sub/MMP-9) [56]
Collagen III (bo sub/hu MMP-9) [55]
Collagen IV (hu/mu sub/MMP-9) [8,57,58,66,67,68,69,70]
Collagen V (hu sub/MMP-9) [4,8,68]
Collagen VI (hu sub/MMP-9) [70]
Collagen α1 and α2 (VI) (hu sub/MMP-9) [62]
Collagen α1 (XI) (hu sub/MMP-9) [71]
Collagen α1 (XVIII) (hu sub/MMP-9) [70,72]
Procollgen lysine-2-oxygluterate-5 dioxygenase-1 (hu sub/MMP-9) [62]
Periostin (hu sub/MMP-9) [70]
Galectin-1 (hu sub/MMP-9) [62,65]
Galectin 3 (hu sub/MMP-9) [73]
Fibronectin (hu sub/MMP-9) [68,70,74]
Laminin (mu sub/hu MMP-9) [60,62,68]
Tenascin C (hu sub/MMP-9) [70,74,75]
Tenascin X (hu sub/MMP-9) [70]
Thrombospondin-2 (hu sub/MMP-9) [65]
Insulin growth factor binding protein 4 (hu sub/MMP-9) [65]
Cystatin C (hu sub/MMP-9) [65]
Elastin (Bo/mu sub/hu/mu MMP-9) [76,77]
Vitronectin (hu sub/MMP-9) [78]
Entactin (mu sub/hu MMP-9) [79]
Heparan sulphate (hu sub/MMP-9) [80]
Cell surface substrates ICAM-1 (hu sub/MMP-9) [81,82]
uPAR (hu sub/MMP-9) [83]
Laminin receptor (Xenopus sub/hu MMP-9) [84]
IL2Rα (hu sub/MMP-9) [85,86]
proTNFα (hu sub/MMP-9) [87]
IL-1β (hu sub/MMP-9) [88,89]
Kit ligand (mu/hu sub/MMP-9) [90,91]
β2 integrin subunit (mu sub/MMP-9) [92]
proTGFβ (mu sub/MMP-9) [93]
HB-EGF (hu sub/MMP-9) [94]
Occludin tight junction protein (bo sub/huMMP-9) [95]
Syndecan 1 and 4 (mu sub/MMP-9) [96,97]
Serpin α-1 proteinase inhibitor (mu sub/MMP-9) [98]
myelin basic protein (hu sub/MMP-9) [99]
NG2 Proteoglycan (hu sub/MMP-9) [100]
β-distroglycan (mouse substrate/MMP-9 ?) [101]
Soluble beta amyloid protein (hu sub/MMP-9) [102,103]
Fibrilar beta amyloid protein (mu sub/MMP-9 ?) [103]
ADAMTS-4 (aggrecanase-1) (hu sub/MMP-9) [104]
Candidate cell surface substrates Angiopoetin 1 receptor Tie2 (hu sub/MMP-9) [62]
Neuropilin 1 (hu sub/MMP-9) [62]
Integrin α3 (hu sub/MMP-9) [62]
Clatherin heavy chain CLH17 (hu sub/MMP-9) [62]
CD166/ALCAM (hu sub/MMP-9) [62]
Saposin A (hu sub/MMP-9) [62]
Semaphorin 7A (hu sub/MMP-9) [62]
CC Chemokines CCL7 (mu sub/MMP-9) [105]
CCL11 (Eotaxin) (mu sub/MMP-9) [105]
CCL17 (TARC) (mu sub/MMP-9) [105]
CXC Chemokines CXCL1/NAP-3 (hu sub/MMP-9) [106]
CXCL4/PF4 (hu sub/MMP-9) [106]
CXCL8/IL-8 (hu sub/MMP-9) [106]
CXCL7/CTAP-III (hu sub/MMP-9) [106]
CXCL9/ MIG (hu sub/MMP-9) [107]
CXCL10/IP-10 (hu sub/MMP-9) [107]
CXCL6/GCP-2 (hu/mu sub/hu MMP-9) [107]
CXCL5/ENA78 (hu sub/MMP-9) [107]
CXCL11/ITAC (hu sub/MMP-9) [108]
CXCL12/SDF-1 (hu sub/MMP-9) [109]
Other Substrates Leukaemia inhibitory factor (LIF) (hu sub/MMP-9) [62]
Protease nexin-1 (hu sub/MMP-9) [62]
Granulins precursor acrogranin (hu sub/MMP-9) [62]
Hsp90 (hu sub/MMP-9) [62]
uPA precursor (hu sub/MMP-9) [62]
tPA precursor (hu sub/MMP-9) [62]
C1q (hu sub/MMP-9) [110]
C1r-A (mu sub/hu MMP-9) [65]
Pyruvate kinase isoenzymes M1/M2 (ra sub/hu MMP-9) [65]
Collagenase 3 (MMP-13) (hu sub/MMP-9) [62]
Dickkopf-1 (hu sub/MMP-9) [111]
Dickkopf-3 tumour suppressor (hu sub/MMP-9) [65]
DJ-1 oncogene (hu sub/MMP-9) [111]
Follistain-like 3 (hu sub/MMP-9) [111]
Neuron specific enolase (hu sub/MMP-9) [111]
Nieman-Pick C2 (hu sub/MMP-9) [111]
Proglanulins (hu sub/MMP-9) [111]
Ym 1 (mu sub/MMP-9) [105]
S100A8 proinflammatory protein (mu sub/MMP-9) [105]
S100A9 proinflammatory protein (mu sub/MMP-9) [105]
Plasminogen (hu sub/MMP-9) [112,113]
Mature NGF (mu sub/MMP-9) [114]
Interferon-β (hu sub/MMP-9) [115]
KISS-1 metastasis suppressor (hu sub/MMP-9) [116]
Tau (hu sub/MMP-9) [117]
VEGF (mu sub/MMP-9 not hu MMP-9) [80,118]

Article Categories:
  • Review

Keywords: gelatinase B/MMP-9, tumour progression, angiogenesis, metastasis, inflammation, epithelial-mesenchymal transition, invasion, motility, immune surveillance, gelatinase B/MMP-9 inhibitors.

Previous Document:  Glioblastoma multiforme: a look inside its heterogeneous nature.
Next Document:  Chronic Inflammation: Synergistic Interactions of Recruiting Macrophages (TAMs) and Eosinophils (Eos...