Document Detail

The role of extracellular vesicles in phenotypic cancer transformation.
Jump to Full Text
MedLine Citation:
PMID:  24133383     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Cancer has traditionally been considered as a disease resulting from gene mutations. New findings in biology are challenging gene-centered explanations of cancer progression and redirecting them to the non-genetic origins of tumorigenicity. It has become clear that intercellular communication plays a crucial role in cancer progression. Among the most intriguing ways of intercellular communication is that via extracellular vesicles (EVs). EVs are membrane structures released from various types of cells. After separation from the mother membrane, EVs become mobile and may travel from the extracellular space to blood and other body fluids.
CONCLUSIONS: Recently it has been shown that tumour cells are particularly prone to vesiculation and that tumour-derived EVs can carry proteins, lipids and nucleic acids causative of cancer progression. The uptake of tumour-derived EVs by noncancerous cells can change their normal phenotype to cancerous. The suppression of vesiculation could slow down tumour growth and the spread of metastases. The purpose of this review is to highlight examples of EV-mediated cancer phenotypic transformation in the light of possible therapeutic applications.
Authors:
Eva Ogorevc; Veronika Kralj-Iglic; Peter Veranic
Related Documents :
20166933 - Recent advances in anti-survivin treatments for cancer.
24833143 - Low serum interleukin-13 levels correlate with poorer prognoses for colorectal cancer p...
23319113 - Alterations in mtdna: a qualitative and quantitative study associated with cervical can...
Publication Detail:
Type:  Journal Article; Review     Date:  2013-07-30
Journal Detail:
Title:  Radiology and oncology     Volume:  47     ISSN:  1318-2099     ISO Abbreviation:  Radiol Oncol     Publication Date:  2013  
Date Detail:
Created Date:  2013-10-17     Completed Date:  2014-06-24     Revised Date:  2014-06-24    
Medline Journal Info:
Nlm Unique ID:  9317213     Medline TA:  Radiol Oncol     Country:  Slovenia    
Other Details:
Languages:  eng     Pagination:  197-205     Citation Subset:  -    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

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

Full Text
Journal Information
Journal ID (nlm-ta): Radiol Oncol
Journal ID (iso-abbrev): Radiol Oncol
Journal ID (publisher-id): RADO
ISSN: 1318-2099
ISSN: 1581-3207
Publisher: Versita, Warsaw
Article Information
Download PDF
Copyright © by Association of Radiology & Oncology
open-access:
Received Day: 22 Month: 2 Year: 2013
Accepted Day: 02 Month: 5 Year: 2013
collection publication date: Month: 9 Year: 2013
Electronic publication date: Day: 30 Month: 7 Year: 2013
Volume: 47 Issue: 3
First Page: 197 Last Page: 205
PubMed Id: 24133383
ID: 3794874
DOI: 10.2478/raon-2013-0037
Publisher Id: rado-47-03-197

The role of extracellular vesicles in phenotypic cancer transformation
Eva Ogorevc1
Veronika Kralj-Iglic2
Peter Veranic3
1 Laboratory of Biophysics, Faculty of Electrical Engineering, University of Ljubljana, Slovenia
2 Faculty of Health Sciences, University of Ljubljana, Slovenia
3 Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
Correspondence: Correspondence to: Prof. Peter Veranič, PhD, Institute of Cell Biology, Faculty of Medicine, University of Ljubljana, Lipičeva 2, Ljubljana, Slovenia. E-mail: peter.veranic@mf.uni-lj.si
Disclosure: No potential conflicts of interest were disclosed.

Introduction

Cancer has been traditionally viewed as a consequence of multistep mutations of genetic material that result in transformation of normal to malignant cells. However, nowadays the mainstream paradigms of cancer development and progression are shifting from strictly genocentric towards epigenetic and other nongenetic interpretations. It is thus relevant to explore the possibility that a normal cell could become malignant without previous genetic mutation. In this article several mechanisms of phenotypic transformation are presented mainly involving transfer of membrane attached receptors for growth factors, RNA molecules or even lipids 1,2,3

It was suggested that intercellular communication plays a crucial role in cancer progression.1 Exchange of information is attained through release of specific soluble (or immobilized) signalling molecules and their interaction with corresponding receptors2, or through direct cell-to-cell communication that includes gap junctions3, cytonems4 and tunnelling nanotubes.5 In addition to these mechanisms, a highly conserved way of intercellular communication has recently been revealed - communication via extracellular vesicles (EVs).

It is considered that EVs are membrane-enclosed compartments, released into the surroundings of practically all cell types, both in vivo and in vitro.6 After separation from the mother membrane, vesicles with various types of cargo become mobile and may travel from the extracellular/intercellular space to blood (Figure 1). Besides in blood-isolates7,8, EVs were also found in isolates from other body fluids, i.e. urine9,10, ascites11,12, synovial fluid8,13, malignant pleural effusions12,14, bronchial lavage fluid15, human semen16, breast milk17, pregnancy-associated sera18, amniotic fluid19, ocular fluids20 and human saliva.21 The vesicles detectable in isolates in vitro and in vivo represent a mixed population of various sizes and origins. To date no consensus regarding their classification and nomenclature was reached to distinguish between different types of vesicles. In this work we do not consider the apoptotic bodies (usually larger than 1 μm) which are released from the cell in the final stage of programmed cell death.

The content of EVs depends on the cell of origin and the mechanism of vesicle generation. They were found to transfer surface-bound receptors and their ligands, proteins, genetic material, infectious particles, prions and probably even organelles between cells.22 A fascinating feature of EVs is that they present multiple epitopes to the recipient cells and therefore on one hand carry signalling molecules for phenotypic transformation and, on the other hand, serve as a cell mechanism to get rid of unwanted constitutents.23

Tumour-derived EVs (Figure 2) represent an important component of the tumour microenvironment22, but can also take part in altering non-cancerous counterparts (cells) thus facilitating tumour growth and invasion11, angiogenesis24, metastasis25, chemoresistance26,27, immune evasion28,29 and escape from cell death.30 An increased number of circulating EVs were found in blood isolates of patients with gastrointestinal cancer.3133 It is, however, important to bear in mind that the EVs found in blood isolates are not necesarilly the native circulating vesicles but can also be formed during sampling and isolation procedures due to exposure of the cells to thermal and mechanical stress.6 Nevertheless, studying EVs isolated from blood and other body fluids of cancer patients is of special interest, not only because cancer cells are particularly prone to vesiculation, but also because of greater vulnerability and fragmentation of blood cells (platelets) in cancer patients, which could be reflected in a higher concentration of EVs in blood-isolates6 which could be used as a valuable diagnostic marker.2

Formation of extracellular vesicles

The exact mechanisms underlying the formation of EVs have not yet been fully elucidated, but it seems that vesiculation can be either an extremely well regulated process, or a random, non-specific event associated with, for example, disintegration of the plasma membrane. It is important to realize that general mechanisms of membrane vesiculation can also play a pivotal role in the progression of disease.

Membrane vesiculation takes place in the last phase of membrane budding when the bud is pinched off from the membrane to become a free vesicle (Figure 3A). Budding and vesiculation are essential features of the nonspecific biophysical properties of the membrane that impose local and/or global curvature on the membrane in phospholipid bilayer vesicles34,35, in erythrocytes36 and in other cells.37,38 The packing and distribution of membrane constituents creates local membrane curvature which is consistent with lateral sorting of membrane constituents.39 During budding, accumulation of molecules that energetically favour large curvature drives the formation of buds and EVs.40 Vesiculation can also be induced by nonlocal events such as an increase or a decrease in the difference between two membrane areas, as described within the bilayer couple concept.4143

There is a codependence between membrane shape and structure; moreover, membrane curvature is determined by the shapes of membrane constituents and their interactions.44 Sphingolipids, for example, are located mainly in the outer leaflet of the plasma membrane bilayer, while glycerophospholipids such as phosphatidylserine and phosphatidylethanolamine can under normal circumstances be found only in the inner leaflet.45,46 Cholesterol is believed to occur in similar proportions in both leaflets.47 This balance is maintained by several enzymes: scramblase, flippase and translocase.48 Disruption of membrane asymmetry and consequent bending of the membrane can occur spontaneously or by an energy-requiring process. Further, the composition and configuration of membrane layer areas are affected by pathophysiological processes such as cell activation, hypoxia, irradiation, oxidative injury, exposure to complement proteins and exposure to shear stress.22 Relocation of phosphatidylserine and phosphatidylethanolamine from the inner to the outer leaflet of the plasma membrane is associated with membrane budding and formation of EVs.49 EVs are formed in the last stage of the budding process, and thus their surfaces expose large amounts of phosphatidylserine50 which can be used for the capture of EVs by phosphatidylserine receptors, such as Annexin V.51

Additionally EVs seem to be enriched in proteins and lipids associated with membrane rafts.50,52 Consistent with this, much experimental and theoretical evidence indicates the importance of membrane rafts in the process of membrane budding and vesiculation.48 Membrane rafts are small (10–200 nm) relatively heterogeneous dynamic structures with an increased concentration of cholesterol and sphingolipids.53,54 Potential roles of membrane rafts in membrane transport were proposed: they may serve as platforms for the inclusion of sorting receptors and cargo molecules, as sites for organizing the membrane cytoskeleton, or as sites for organizing vesicle docking and fusion processes.55

Other pathways leading to curvature and subsequent budding of membranes include an increase of intracellular Ca2+ inhibiting translocase, activating scramblase and resulting in loss of membrane asymmetry48, the reorganization of the cytoskeleton48,56, and the presence of protein and lipid driving forces since adding a protein or lipid to just one monolayer might cause asymmetry of monolayer areas and thereby increase the intrinsic curvature of the whole bilayer.57

Membrane budding can be followed by membrane fission, which is still a subject of some debate, but several ideas supporting the pivotal role of endophilin I and dynamin in this process have been suggested.58,59

EVs can also be formed in processes distinct from those already mentioned. EVs smaller than 100 nm, usually called exosomes, are formed by exocytosis after the assembly of several endosomes into a multivesicular body, exiting the endosomal pathway and fusion with the plasma membrane (Figure 3B).50,60,61 Peculiarly large EVs (1 –10 mm) can be formed as a result of nonapoptotic blebbing (Figure 3C).62 This relatively rapid process of EV-formation is caused by actomyosin contractions near the cortical cytoskeleton. The force required for subsequent bleb retraction is generated by actin filaments.62

Interaction of extracellular vesicles with target cells

It is indicated that EVs interact with the membranes of recipient cells. The precise mechanisms of uptake of EVs are still poorly understood, yet it is becoming increasingly evident that their uptake can induce activation of specific signal transduction cascades and thereby influence the physiological or pathological state of recipient cells.23,63

Several types of interactions were proposed involving adhesion of vesicle molecules to cellular surface receptors (receptor-mediated uptake), endocytosis (phagocytosis) and fusion with the plasma membrane.23,64

Potential receptor candidates for interaction with EV-membranes are, notably, receptors for phosphatidylserine. One such receptor is the T-cell immunoglobulin and mucin-domain-containing molecule (TIM) that was described as mediating vesicle uptake.65 Segura et al.66 showed that EVs from mature dendritic cells are enriched in inter-cellular adhesion molecule 1 (ICAM-1), suggesting its role in either helping in capture of EVs by recipient antigen-presenting cells or in favouring T-cell binding of the recipient antigen-presenting cells bearing EVs at their surface (Figure 4A).

The phenomenon of fusion of vesicles with the plasma membrane could be explained by lipid-mediated interactions. Teissier and Pécheur described how lipid rafts, particularly sphingolipids, play a key role in the conformational changes of fusion proteins. These changes lead to interaction of the fusion peptide with the target membrane in viral interactions.68 Parolini et al. showed that exosomes preferentially fuse with the membranes of tumour cells and that in these interactions the microenvironmental pH acts as a key factor by modulating the lipid compostition of the cell and exosome membranes (Figure 4B).69

It seems that phagocytosis is the most effective way of EV-uptake; moreover it has been reported that phagocytic cells have a greater ability for the uptake of EVs than non-phagocytic cells.67 Besides phagocytosis clathrin-dependent endocytosis and macropinocytosis were proposed as mechanisms for the uptake of EVs by the ovarian carcinoma cell line (Figure 4C).70

Despite all the above discoveries, it is still a question whether the vesicle cargo can be transfered to the recipient cell without the interaction with the membranes. Taraboletti et al. showed that acidic pH can induce breakdown of EVs, leading to pericellular release of their cargo and subsequent paracrine activity (Figure 4D).71 Furthermore, it has been stated that the breakdown of EVs upon shedding could represent an important signalling mechanism.72

Extracellular vesicles as vehicles in phenotypic malignant transformations

When EVs are taken up by recipient cells, they can change the cells’ state, either transitionally or in the long term (Figure 5). Transformation of recipient cells due to EV-transfered cargo was shown to be most efficient if the cell was already to some degree pretransformed or immortalized (stem cells).73 It is still unclear whether EVs may be able to exert long-term genomic changes, such as induction of mutations, but it has been brought to light not only that some oncogenes become incorporated into EV-cargo, but also that they can stimulate EV-formation.74 Consenquently, EVs can act as vehicles in malignant transformations of normal cells through the transfer of membrane proteins (receptors and receptor-coupled proteins), cytosol proteins, nucleic acids (RNA and DNA) and lipids.3

Extracellular vesicle-mediated protein transfer

Al Nedawi et al. showed that tumour specific growth receptor EGFRvIII can be transferred between glioma cells by EVs, leading to transfer of oncogenic activity, such as activation of transforming signalling pathways (MAPK and Akt), changes in expression of EGFRvIII-regulating genes (VEGF, Bcl-xL, p27), morphological transformation and increase in anchorage-independent growth capacity.75

Similar findings were reported in a study by Skog et al., where they detect tumour-specific EGFRvIII in serum EVs of glioblastoma patients.24 Moreover, they demonstrated that EVs are enriched in angiogenic proteins (interleukin-6, interleukin-8, VEGF) and that they stimulate tubule formation by endothelial cells.24

A mechanism that controls metastatic progression through the EV-mediated transfer of another receptor, tyrosine kinase MET, has recently been described. EVs with oncoprotein MET from highly metastatic melanomas increased the metastatic behaviour of primary tumours by permanently educating and mobilizing bone marrow progenitors.76

Another example of EV-mediated protein delivery in tumour progession has been described by Sidhu et al.77 The authors showed that extracellular matrix metalloproteinase inducer (EMMPRIN or CD147) is released from the surface of lung carcinoma cells via EVs which rapidly break down to release bioactive EMMPRIN, that stimulates matrix metalloproteinase expression in fibroblasts, thereby facilitating tumour invasion and metastasis.77

Many other proteins have been identified in EVs shed from cancer cells, including among others vascular endothelial growth factor (VEGF)71, tetraspanins64, heat-shock protein 90α78, Mart-1/MelanA, carcinoembryogenic antigen79 and HER2.79,80

Extracellular vesicle-mediated horizontal transfer of (epi)genetic information

Recently it has come to light that messenger RNA (mRNA) and various forms of non-coding RNA, such as microRNA (miRNA), act as key players in information transfer between cells.81 miRNAs are small noncoding RNA gene products believed to negatively regulate other genes’ expression. Furthermore, there is evidence that miRNA species might act as tumour suppressors and oncogenes.82,83 As RNA molecules are unstable in plasma or blood84,85, they should be in some way protected from degradation during systemic transport. Membrane vesicles appear to be ideal candidates for this kind of protection. In fact, it seems that almost all systemically transfered RNA is stored compactly within EVs and is thereby protected from external RNAse.24,81 Additionally, more permanent modulation of recipient cells may be achieved through uptake of EVs containing nucleic acids. Interestingly, a microarray comparison of mRNA populations in EVs and their donor cells showed that specific mRNA species were detected exclusively in EVs, suggesting a specific packaging mechanism that encapsulates these mRNAs into EVs.24,86 Several groups have described the key role of EV-mediated mRNA transfer in tumour progression in various types of cancer, such as colorectal adenocarcinoma87,88, pancreatic adeno-carcinoma88, lung carcinoma88 and glioblastoma.24 The presence of specific miRNA species has been reported in EVs derived either from carcinoma cell-lines or from serum of cancer patients. A study showed that hepatocellular carcinoma cell-derived EVs mediate miRNA transfer and thereby enhance recipient cell growth.89 Ohshima et al. reported that metastatic gastric cancer cell line releases EVs enriched in let-7-miRNAs, known to negatively regulate Ras genes, leading to maintenance of their oncogenesis.90 Another study showed that EVs from the serum of ovarian cancer patients contain specific miRNA signatures and suggested that circulating EVs could potentially be used as surrogate diagnostic markers.91

EVs have been found to transfer DNA between cells, but it is important to keep in mind that EV fractions can also consist of apoptotic bodies, known to contain DNA fragments, possibly contributing to genetic changes and tumour progression.92 A group recently showed that brain tumour cells release EVs that contain single stranded DNA (ssDNA), including both cDNA and genomic DNA.93 The transported DNA contained amplified sequences of the c-Myc oncogene that could be available for horizonzal gene transfer and malignant transformation.93

Mitochondrial dysfunction and especially dys-functions caused by mutations of mtDNA have been implicated with a wide range of age-related pathologies, including cancer.94 It was reported that EVs from glioblastoma and astrocyte cells contain mitochondrial DNA which can be transferred between cells.95

A large part of the mammalian genome is derived from ancient transposable elements, such as DNA-transposons and retrotransposons. While DNA-transposons amplify without any RNA intermediate, retrotransposons need reverse transcriptase to retrotranscribe them before integration into the genome.96 The expression of retrotransposons is increased in tumour cells through hypomethylation of the genome97; further it has been reported that retrotransposon insertion into the genome triggers mutations in tumorigenesis.98 Balaj et al. incubated EVs derived from human medulloblastoma cells and enriched in retrotransposon RNAs, especially HERV-K, with HUVEC cells.93 After incubation the content of HERV-K in the HUVEC cells was increased up to 60-fold, suggesting the active role of EVs in transfering retrotrasposon sequences to normal surrounding cells.93

Extracellular vesicle-mediated lipid delivery

Sphingomyelin is a major membrane phospholipid, mostly localized in the outer leaflet of the mammalian plasma membrane.99 A significantly increased level of sphingomyelin in the highly metastatic adenocarcinoma cell line was reported in comparison to the lower metastatic variant of adenocarcinoma, suggesting the role of sphingomyelin not only as an important membrane component, but also as a key player in tumour metastasis.100

Kim et al. showed the importance of sphingomyelin transfer in cancer progression.101 Namely, they indicated that sphingomyelin is a major active component in angiogenesis. They also found an increased amount of sphingomyelin in EVs derived from tumour cells compared to that from the plasma membrane.101

Suppression of oncogenic transformation by extracellular vesicles

It has been shown that heparin, usually used for the treatment of thromboembolisms102, also has a beneficial effect in suppressing tumour progression in some types of cancer.103,104 Interestingly, both effects of heparin can be explained by suppression of EV formation on the basis of non-specific biophysical mechanisms. The study, performed on artificial membrane models with controlled lipid composition – giant unilamellar vesicles (GUVs) - showed that budding and vesiculation of membranes can be affected by the surrounding solution.105 Theoretically and experimentaly it was shown that molecules and ions in the solution can mediate attractive interactions between membranes and cause adhesion.106,107 The composition and physical properties of the solution in the vicinity of the membrane108110 importantly affect these interactions and it was revealed that in the budding process the bud can adhere back to the mother membrane if the mediating effect of the solution is strong enough.106 It was found that plasma contains molecules that mediate attractive interaction between membranes and that added heparin enhances this effect.105 A mediating effect was also found for anticoagulant β2-glycoprotein I.107,111 It was suggested that similar mechanisms may take place in cells, but it is important to note that cell membranes are of more complex composition, making the described mechanisms somewhat distinct.105 Nevertheless, substances which mediate attractive interaction between membranes (e.g. heparin) are suppressors of membrane vesiculation and can therefore have anticoagulant, antimetastatic and anti-inflammatory effect.105


Conclusion

Recent investigations revealed that invasive tumours can be spread in the body not only by metastases travelling along tissues or being transported by body fluids and so seeding new tumours after anchoring to targeted tissues. Tumours can also be spread by much smaller carriers in the form of EVs containing genetic information or mutant growth factor receptors that are permanently active and provoke over-inducing signalling of cell division. Transfer of such vesicles can occur over short distances to neighbouring cells or long distances by body fluids. By finding appropriate target cells the transferred transforming molecules can induce cell transformation and cause cancer progression most efficiently in already immortalized precancerous or stem cells. As tumor cell transformation is usually a multistep process including several consecutive mutations it can be concluded that the transfer of a transforming molecules can serve as one of the steps in this process. By carrying certain enzymes such as metalloproteinases, the EVs can adapt the microenvironment of tumour cells in favour of metastatic dissemination or implantation into certain tissues. Blocking the spreading of EVs, by the use of molecules attaching the vesicles to the vesiculating cells could possibly slow down tumour growth or the spread of metastases. On the other hand, screening of cancer genetic markers transported by EVs could improve diagnostic methods for detection of certain cancerous diseases. A thorough understanding of the biological mechanisms involved in intercellular communication by EVs could provide a key complement to genetic factors in determination of cancer progression, while their controlled manipulation will likely develop into a powerful weapon in the battlefield of oncology.


References
1.. Al-Nedawi K,Meehan B,Rak J. Microvesicles: messengers and mediators of tumor progressionCell CycleYear: 2009820141819535896
2.. Rak J. Microparticles in cancerSemin Thromb HemostYear: 20103688890621049390
3.. Pap E. The role of microvesicles in malignanciesAdv Exp Med BiolYear: 201171418319921506015
4.. Camussi G,Deregibus MC,Bruno S,Grange C,Fonsato V,Tetta C. Exosome/microvesicle-mediated epigenetic reprogramming of cellsAm J Cancer ResYear: 201119811021969178
5.. Veranic P,Lokar M,Schutz GJ,Weghuber J,Wieser S,Hagerstrand H,et al. Different types of cell-to-cell connections mediated by nanotubular structuresBiophys JYear: 20089544162518658210
6.. Sustar V,Bedina-Zavec A,Stukelj R,Frank M,Bobojevic G,Jansa R,et al. Nanoparticles isolated from blood: a reflection of vesiculability of blood cells during the isolation processInt J NanomedicineYear: 2011627374822128248
7.. Wolf P. The nature and significance of platelet products in human plasmaBr J HaematolYear: 196713269886025241
8.. Junkar I,Sustar V,Frank M,Jansa V,Bedina Zavec A,Rozman B,et al. Blood and synovial microparticles as revealed by atomic force and scanning electron microscopeOpen Autoimmun JYear: 200915058
9.. Pisitkun T,Shen RF,Knepper MA. Identification and proteomic profiling of exosomes in human urineProc Natl Acad Sci USAYear: 2004101133687315326289
10.. Gonzales P,Pisitkun T,Knepper MA. Urinary exosomes: is there a future?Nephrol Dial TransplantYear: 200823179980118310721
11.. Graves LE,Ariztia EV,Navari JR,Matzel HJ,Stack MS,Fishman DA. Proinvasive properties of ovarian cancer ascites-derived membrane vesiclesCancer ResYear: 2004647045915466198
12.. Mrvar-Brecko A,Sustar V,Jansa V,Stukelj R,Jansa R,Mujagic E,et al. Isolated microvesicles from peripheral blood and body fluids as observed by scanning electron microscopeBlood Cells Mol DisYear: 2010443071220199878
13.. Skriner K,Adolph K,Jungblut PR,Burmester GR. Association of citrullinated proteins with synovial exosomesArthritis RheumYear: 20065438091417133577
14.. Bard MP,Hegmans JP,Hemmes A,Luider TM,Willemsen R,Severijnen LA,et al. Proteomic analysis of exosomes isolated from human malignant pleural effusionsAm J Respir Cell Mol BiolYear: 2004311142114975938
15.. Admyre C,Grunewald J,Thyberg J,Gripenback S,Tornling G,Eklund A,et al. Exosomes with major histocompatibility complex class II and costimulatory molecules are present in human BAL fluidEur Respir JYear: 20032257858314582906
16.. Sullivan R,Saez F,Girouard J,Frenette G. Role of exosomes in sperm maturation during the transit along the male reproductive tractBlood Cells Mol DisYear: 20053511015893944
17.. Admyre C,Johansson SM,Qazi KR,Filen JJ,Lahesmaa R,Norman M,et al. Exosomes with immune modulatory features are present in human breast milkJ ImmunolYear: 200717919697817641064
18.. Taylor DD,Akyol S,Gercel-Taylor C. Pregnancy-associated exosomes and their modulation of T cell signalingJ ImmunolYear: 200617615344216424182
19.. Asea A,Jean-Pierre C,Kaur P,Rao P,Linhares IM,Skupski D,et al. Heat shock protein-containing exosomes in mid-trimester amniotic fluidsJ Reprod ImmunolYear: 20087912718715652
20.. Perkumas KM,Hoffman EA,McKay BS,Allingham RR,Stamer WD. Myocilin-associated exosomes in human ocular samplesExp Eye ResYear: 2007842091217094967
21.. Ogawa Y,Kanai-Azuma M,Akimoto Y,Kawakami H,Yanoshita R. Exosome-like vesicles with dipeptidyl peptidase IV in human salivaBiol Pharm BullYear: 20083110596218520029
22.. Ratajczak J,Wysoczynski M,Hayek F,Janowska-Wieczorek A,Ratajczak MZ. Membrane-derived microvesicles: important and underappreciated mediators of cell-to-cell communicationLeukemiaYear: 20062014879516791265
23.. van der Vos KE,Balaj L,Skog J,Breakefield XO. Brain Tumor Microvesicles: Insights into Intercellular Communication in the Nervous SystemCell Mol NeurobiolYear: 2011319495921553248
24.. Skog J,Wurdinger T,van Rijn S,Meijer DH,Gainche L,Sena-Esteves M,et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkersNat Cell BiolYear: 2008101470U120919011622
25.. Janowska-Wieczorek A,Wysoczynski M,Kijowski J,Marquez-Curtis L,Machalinski B,Ratajczak J,et al. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancerInt J CancerYear: 20051137526015499615
26.. Safaei R,Larson BJ,Cheng TC,Gibson MA,Otani S,Naerdemann W,et al. Abnormal lysosomal trafficking and enhanced exosomal export of cisplatin in drug-resistant human ovarian carcinoma cellsMol Cancer TherYear: 20054159560416227410
27.. Shedden K,Xie XT,Chandaroy P,Chang YT,Rosania GR. Expulsion of small molecules in vesicles shed by cancer cells: association with gene expression and chemosensitivity profilesCancer ResYear: 2003634331712907600
28.. Hakulinen J,Junnikkala S,Sorsa T,Meri S. Complement inhibitor membrane cofactor protein (MCP; CD46) is constitutively shed from cancer cell membranes in vesicles and converted by a metalloproteinase to a functionally active soluble formEur J ImmunolYear: 2004342620915307194
29.. Valenti R,Huber V,Filipazzi P,Pilla L,Sovena G,Villa A,et al. Human tumor-released microvesicles promote the differentiation of myeloid cells with transforming growth factor-beta-mediated suppressive activity on T lymphocytesCancer ResYear: 2006669290816982774
30.. Abid Hussein MN,Boing AN,Sturk A,Hau CM,Nieuwland R. Inhibition of microparticle release triggers endothelial cell apoptosis and detachmentThromb HaemostYear: 200798109610718000616
31.. Kim HK,Song KS,Park YS,Kang YH,Lee YJ,Lee KR,et al. Elevated levels of circulating platelet microparticles, VEGF, IL-6 and RANTES in patients with gastric cancer: possible role of a metastasis predictorEur J CancerYear: 2003391849112509950
32.. Jansa R,Sustar V,Frank M,Susanj P,Bester J,Mancek-Keber M,et al. Number of microvesicles in peripheral blood and ability of plasma to induce adhesion between phospholipid membranes in 19 patients with gastrointestinal diseasesBlood Cells Mol DisYear: 2008411243218387323
33.. Baran J,Baj-Krzyworzeka M,Weglarczyk K,Szatanek R,Zembala M,Barbasz J,et al. Circulating tumour-derived microvesicles in plasma of gastric cancer patientsCancer Immunol ImmunotherYear: 2010598415020043223
34.. Lipowsky R. The conformation of membranesNatureYear: 1991349475811992351
35.. Kralj-Iglic V,Babnik B,Gauger DR,May S,Iglic A. Quadrupolar ordering of phospholipid molecules in narrow necks of phospholipid vesiclesJ Stat PhysYear: 200612572752
36.. Hagerstrand H,Isomaa B. Morphological characterization of exovesicles and endovesicles released from human erythrocytes following treatment with amphiphilesBiochim Biophys ActaYear: 19921109117261520690
37.. Black PH. Shedding from Normal and Cancer-Cell SurfacesNew Engl J MedYear: 1980303141567001235
38.. Kralj-Iglic V,Batista U,Hägerstrand H,Iglic A,Majhenc J,Sok M. On mechanisms of cell plasma membrane vesiculationRadiol OncolYear: 19983211923
39.. Kralj-Iglic V,Veranic P. Curvature-Induced Sorting of Bilayer Membrane Constituents and Formation of Membrane RaftsLeitmannova Liu AAdvances in planar lipid bilayers and liposomes5ElsevierYear: 200712949
40.. Kralj-Iglic V,Iglic A,Hagerstrand H,Peterlin P. Stable tubular microexovesicles of the erythrocyte membrane induced by dimeric amphiphilesPhys Rev E Stat Phys Plasmas Fluids Relat Interdiscip TopicsYear: 2000614230411088219
41.. Sheetz MP,Singer SJ. Biological-membranes as bilayer couples - molecular mechanism of drug-erythrocyte interactionsProc Natl Acad Sci USAYear: 1974714457614530994
42.. Helfrich W. Blocked lipid exchange in bilayers and its possible influence on the shape of vesiclesZ. NaturforschYear: 197429c510
43.. Evans EA. Bending resistance and chemically induced moments in membrane bilayersBiophys JYear: 197414923314429770
44.. Kralj-Iglic V. Stability of membranous nanostructures: a possible key mechanism in cancer progressionInt J NanomedicineYear: 2012735799622888223
45.. Zachowski A,Devaux PF. Transmembrane movements of lipidsExperientiaYear: 199046644562193828
46.. Sims PJ,Wiedmer T. Unraveling the mysteries of phospholipid scramblingThromb HaemostYear: 2001862667511487015
47.. Wydro P,Hac-Wydro K. Thermodynamic description of the interactions between lipids in ternary Langmuir monolayers: the study of cholesterol distribution in membranesJ Phys Chem BYear: 2007111249550217315916
48.. Pap E,Pallinger E,Pasztoi M,Falus A. Highlights of a new type of intercellular communication: microvesicle-based information transferInflamm ResYear: 2009581819132498
49.. van Meer G. Dynamic transbilayer lipid asymmetryCsh Perspect BiolYear: 20113
50.. Camussi G,Deregibus MC,Bruno S,Cantaluppi V,Biancone L. Exosomes/ microvesicles as a mechanism of cell-to-cell communicationKidney IntYear: 2010788384820703216
51.. Davizon P,Lopez JA. Microparticles and thrombotic diseaseCurr Opin HematolYear: 2009163344119606028
52.. Mrówczyńska L,Salzer U,Iglič A,Hägerstrand H. Curvature factor and membrane solubilisation, with particular reference to membrane raftsCell Biol IntYear: 201135991521438858
53.. Simons K,Ikonen E. Functional rafts in cell membranesNatureYear: 1997387569729177342
54.. Brown DA,London E. Functions of lipid rafts in biological membranesAnnu Rev Cell Dev BiYear: 19981411136
55.. Ikonen E. Roles of lipid rafts in membrane transportCurr Opin Cell BiolYear: 200113470711454454
56.. Flaumenhaft R. Formation and fate of platelet microparticlesBlood Cells Mol DisYear: 200636182716466949
57.. Huttner WB,Zimmerberg J. Implications of lipid microdomains for membrane curvature, budding and fissionCurr Opin Cell BiolYear: 2001134788411454455
58.. Schmidt A,Wolde M,Thiele C,Fest W,Kratzin H,Podtelejnikov AV,et al. Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acidNatureYear: 19994011334110490020
59.. Kozlov MM. Fission of biological membranes: interplay between dynamin and lipidsTrafficYear: 20012516511208168
60.. Heijnen HFG,Schiel AE,Fijnheer R,Geuze HJ,Sixma JJ. Activated platelets release two types of membrane vesicles: Microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granulesBloodYear: 1999943791910572093
61.. Pap E,Pallinger E,Falus A. The role of membrane vesicles in tumorigenesisCrit Rev Oncol HematolYear: 2011792132320884225
62.. Di Vizio D,Kim J,Hager MH,Morello M,Yang W,Lafargue CJ,et al. Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic diseaseCancer ResYear: 2009695601919549916
63.. Del Conde I,Shrimpton CN,Thiagarajan P,Lopez JA. Tissue-factor-bearing microvesicles arise from lipid rafts and fuse with activated platelets to initiate coagulationBloodYear: 200510616041115741221
64.. Kharaziha P,Ceder S,Li Q,Panaretakis T. Tumor cell-derived exosomes: A message in a bottleBiochim Biophys ActaYear: 201218261031122503823
65.. Miyanishi M,Tada K,Koike M,Uchiyama Y,Kitamura T,Nagata S. Identification of Tim4 as a phosphatidylserine receptorNatureYear: 2007450435917960135
66.. Segura E,Nicco C,Lombard B,Veron P,Raposo G,Batteux F,et al. ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell primingBloodYear: 20051062162315790784
67.. Feng D,Zhao WL,Ye YY,Bai XC,Liu RQ,Chang LF,et al. Cellular Internalization of exosomes occurs through phagocytosisTrafficYear: 2010116758720136776
68.. Teissier E,Pecheur EI. Lipids as modulators of membrane fusion mediated by viral fusion proteinsEur Biophys JYear: 2007368879917882414
69.. Parolini I,Federici C,Raggi C,Lugini L,Palleschi S,De Milito A,et al. Microenvironmental pH is a key factor for exosome traffic in tumor cellsJ Biol ChemYear: 2009284342112219801663
70.. Escrevente C,Keller S,Altevogt P,Costa J. Interaction and uptake of exosomes by ovarian cancer cellsBMC CancerYear: 20111110821439085
71.. Taraboletti G,D’Ascenzo S,Giusti I,Marchetti D,Borsotti P,Millimaggi D,et al. Bioavailability of VEGF in tumor-shed vesicles depends on vesicle burst induced by acidic pHNeoplasiaYear: 200689610316611402
72.. Cocucci E,Racchetti G,Meldolesi J. Shedding microvesicles: artefacts no moreTrends Cell BiolYear: 200919435119144520
73.. Rak J,Guha A. Extracellular vesicles - vehicles that spread cancer genesBioessaysYear: 2012344899722442051
74.. Lee TH,D’Asti E,Magnus N,Al-Nedawi K,Meehan B,Rak J. Microvesicles as mediators of intercellular communication in cancer - the emerging science of cellular ‘debris’Semin ImmunopatholYear: 2011334556721318413
75.. Al-Nedawi K,Meehan B,Micallef J,Lhotak V,May L,Guha A,et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cellsNat Cell BiolYear: 2008106192418425114
76.. Peinado H,Aleckovic M,Lavotshkin S,Matei I,Costa-Silva B,Moreno-Bueno G,et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through METNat MedYear: 2012188839122635005
77.. Sidhu SS,Mengistab AT,Tauscher AN,LaVail J,Basbaum C. The microvesicle as a vehicle for EMMPRIN in tumor-stromal interactionsOncogeneYear: 20042395696314749763
78.. McCready J,Sims JD,Chan D,Jay DG. Secretion of extracellular hsp90alpha via exosomes increases cancer cell motility: a role for plasminogen activationBMC CancerYear: 20101029420553606
79.. Andre F,Schartz NE,Movassagh M,Flament C,Pautier P,Morice P. Malignant effusions and immunogenic tumour-derived exosomesLancetYear: 200236029530512147373
80.. Koga K,Matsumoto K,Akiyoshi T,Kubo M,Yamanaka N,Tasaki A,et al. Purification, characterization and biological significance of tumor-derived exosomesAnticancer ResYear: 2005253703716302729
81.. Dinger ME,Mercer TR,Mattick JS. RNAs as extracellular signaling moleculesJ Mol EndocrinolYear: 200840151918372404
82.. Lagos-Quintana M,Rauhut R,Lendeckel W,Tuschl T. Identification of novel genes coding for small expressed RNAsScienceYear: 2001294853811679670
83.. Esquela-Kerscher A,Slack FJ. Oncomirs - microRNAs with a role in cancerNat Rev CancerYear: 200662596916557279
84.. Tsui NB,Ng EK,Lo YM. Stability of endogenous and added RNA in blood specimens, serum, and plasmaClin ChemYear: 20024816475312324479
85.. Tsui NB,Ng EK,Lo YM. Molecular analysis of circulating RNA in plasmaMethods Mol BiolYear: 20063361233416916258
86.. Valadi H,Ekstrom K,Bossios A,Sjostrand M,Lee JJ,Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cellsNat Cell BiolYear: 20079654917486113
87.. Hong BS,Cho JH,Kim H,Choi EJ,Rho S,Kim J,et al. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cellsBMC GenomicsYear: 20091055619930720
88.. Baj-Krzyworzeka M,Szatanek R,Weglarczyk K,Baran J,Urbanowicz B,Branski P,et al. Tumour-derived microvesicles carry several surface determinants and mRNA of tumour cells and transfer some of these determinants to monocytesCancer Immunol ImmunotherYear: 2006558081816283305
89.. Kogure T,Lin WL,Yan IK,Braconi C,Patel T. Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growthHepatologyYear: 20115412374821721029
90.. Ohshima K,Inoue K,Fujiwara A,Hatakeyama K,Kanto K,Watanabe Y,et al. Let-7 microRNA family is selectively secreted into the extracellular environment via exosomes in a metastatic gastric cancer cell linePLoS OneYear: 20105e1324720949044
91.. Taylor DD,Gercel-Taylor C. MicroRNA signatures of tumor-derived exosomes as diagnostic biomarkers of ovarian cancerGynecol OncolYear: 2008110132118589210
92.. Bergsmedh A,Szeles A,Henriksson M,Bratt A,Folkman MJ,Spetz AL,et al. Horizontal transfer of oncogenes by uptake of apoptotic bodiesProc Natl Acad Sci USAYear: 20019864071111353826
93.. Balaj L,Lessard R,Dai L,Cho YJ,Pomeroy SL,Breakefield XO,et al. Tumour microvesicles contain retrotransposon elements and amplified oncogene sequencesNat CommunYear: 2011218021285958
94.. Desler C,Marcker ML,Singh KK,Rasmussen LJ. The importance of mitochondrial DNA in aging and cancerJ Aging ResYear: 2011201140753621584235
95.. Guescini M,Genedani S,Stocchi V,Agnati LF. Astrocytes and Glioblastoma cells release exosomes carrying mtDNAJ Neural TransmYear: 20101171419680595
96.. Bannert N,Kurth R. Retroelements and the human genome: new perspectives on an old relationProc Natl Acad Sci USAYear: 200410114572915310846
97.. Cordaux R,Batzer MA. The impact of retrotransposons on human genome evolutionNat Rev GenetYear: 20091069170319763152
98.. Wiemels JL,Hofmann J,Kang M,Selzer R,Green R,Zhou M,et al. Chromosome 12p deletions in TEL-AML1 childhood acute lymphoblastic leukemia are associated with retrotransposon elements and occur postnatallyCancer ResYear: 20086899354419047175
99.. Bretscher MS. Membrane structure: some general principlesScienceYear: 197318162294724478
100.. Dahiya R,Boyle B,Goldberg BC,Yoon WH,Konety B,Chen K,et al. Metastasis-associated alterations in phospholipids and fatty acids of human prostatic adenocarcinoma cell linesBiochem Cell BiolYear: 199270548541333235
101.. Kim CW,Lee HM,Lee TH,Kang C,Kleinman HK,Gho YS. Extracellular membrane vesicles from tumor cells promote angiogenesis via sphingomyelinCancer ResYear: 2002626312712414662
102.. McGarry LJ,Thompson D. Retrospective database analysis of the prevention of venous thromboembolism with low-molecular-weight heparin in acutely III medical inpatients in community practiceClin TherYear: 2004264193015110135
103.. Smorenburg SM,Hettiarachchi RJ,Vink R,Buller HR. The effects of unfractionated heparin on survival in patients with malignancy-a systematic reviewThromb HaemostYear: 1999821600410613641
104.. Stevenson JL,Choi SH,Wahrenbrock M,Varki A,Varki NM. Heparin effects in metastasis and Trouseeau syndrome: anticoagulation is not the primary mechanismHaem RepYear: 200515960
105.. Sustar V,Jansa R,Frank M,Hagerstrand H,Krzan M,Iglic A,et al. Suppression of membrane microvesiculation - a possible anticoagulant and anti-tumor progression effect of heparinBlood Cells Mol DisYear: 200942223719261492
106.. Urbanija J,Tomsic N,Lokar M,Ambrozic A,Cucnik S,Rozman B,et al. Coalescence of phospholipid membranes as a possible origin of anticoagulant effect of serum proteinsChem Phys LipidsYear: 2007150495717662972
107.. Urbanija J,Babnik B,Frank M,Tomsic N,Rozman B,Kralj-Iglic V,et al. Attachment of beta 2-glycoprotein I to negatively charged liposomes may prevent the release of daughter vesicles from the parent membraneEur Biophys JYear: 20083710859518188552
108.. May S,Iglič A,Reščič J,Maset S,Bohinc K. Bridging like-charged macroions through long divalent rod-like ionsJ Phys Chem BYear: 200811216859218205341
109.. Velikonja A,Perutkova Š,Gongadze E,Kramar P,Polak A,Maček-Lebar A,Iglič A. Monovalent ions and water dipoles in contact with dipolar zwitterionic lipid headroups - theory and MD simulationsInt J Mol SciYear: 20131428466123434651
110.. Gongadze E,Iglič A. Excluded volume effect of counterions and water dipoles near a highly charged surface due to a rotationally averaged Boltzmann factor for water dipolesGen Phys BiophysYear: 2013211435
111.. Ambrožič A,Čučnik S,Tomšič N,Urbanija J,Lokar M,Babnik B,et al. Interaction of giant phospholipid vesicles containing cardiolipin and cholesterol with beta 2-glycoprotein-I and anti-beta2-glycoprotein-I antibodiesAutoimmun RevYear: 2006610517110310

Article Categories:
  • Review

Keywords: extracellular vesicles, exosomes, microvesicles, cancer progression.

Previous Document:  The jubilee of medical informatics in bosnia and herzegovina - 20 years anniversary.
Next Document:  Comparison between whole-body MRI and Fluorine-18-Fluorodeoxyglucose PET or PET/CT in oncology: a sy...