|The transient and constitutive inflammatory signaling in tumorigenesis.|
|Jump to Full Text|
|PMID: 22751429 Owner: NLM Status: MEDLINE|
|Matjaz Rokavec; Jun-Li Luo|
Related Documents :
|19795989 - Poly (n-isopropylacrylamide)-coated multifunctional nanoparticles for cell tracking.
18634929 - Immunohistochemical analysis of nestin, osteopontin, and proliferating cells in the rep...
14973159 - Identification of multivesicular bodies as prevacuolar compartments in nicotiana tabacu...
25430909 - Fluorescent probes of the apoptolidins and their utility in cellular localization studies.
13937309 - Passive transfer of contact sensitivity by tritiated thymidine-labeled lymphoid cells.
7407859 - Mitotic polyploidization of mouse heart myocytes during the first postnatal week.
3545359 - Cancer induction and non-stochastic effects.
10660549 - Apolipoprotein b, a paradigm for proteins regulated by intracellular degradation, does ...
19462449 - Triterpenes augment the inhibitory effects of anticancer drugs on growth of human esoph...
|Type: Editorial Date: 2012-07-15|
|Title: Cell cycle (Georgetown, Tex.) Volume: 11 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2012 Jul|
|Created Date: 2012-07-25 Completed Date: 2012-11-26 Revised Date: 2014-03-19|
Medline Journal Info:
|Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: United States|
|Languages: eng Pagination: 2587-8 Citation Subset: IM|
|APA/MLA Format Download EndNote Download BibTex|
Cell Transformation, Neoplastic*
Epithelial Cells / cytology
Estrogen Receptor alpha / metabolism
Inflammation / metabolism, pathology
Interleukin-6 / genetics, metabolism
MicroRNAs / metabolism
Mitogen-Activated Protein Kinase 9 / metabolism
Monocytes / cytology, immunology
Receptor-Like Protein Tyrosine Phosphatases, Class 5 / metabolism
STAT3 Transcription Factor / metabolism
Transcription Factors / metabolism
|R01 CA140956/CA/NCI NIH HHS|
|0/Estrogen Receptor alpha; 0/Interleukin-6; 0/MicroRNAs; 0/STAT3 Transcription Factor; 0/Transcription Factors; EC 126.96.36.199/Mitogen-Activated Protein Kinase 9; EC 188.8.131.52/PTPRZ1 protein, human; EC 184.108.40.206/Receptor-Like Protein Tyrosine Phosphatases, Class 5|
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
Publisher: Landes Bioscience
Copyright © 2012 Landes Bioscience
Print publication date: Day: 15 Month: 7 Year: 2012
pmc-release publication date: Day: 15 Month: 7 Year: 2012
Volume: 11 Issue: 14
First Page: 2587 Last Page: 2588
PubMed Id: 22751429
Publisher Id: 2012FT0694
Publisher Item Identifier: 21139
|The transient and constitutive inflammatory signaling in tumorigenesis|
|Department of Cancer Biology; The Scripps Research Institute; Jupiter, FL USA
|*Correspondence to: Jun-Li Luo, Email: firstname.lastname@example.org
It is estimated that about 25% of cancers appear due to chronic infection or other types of chronic inflammation. However, almost all cancers have abnormal or/and constitutive inflammatory signaling activation. Much progress has been made in elucidating the mechanisms by which inflammatory signaling drives tumor progression and metastasis. However, how the abnormal and constitutive inflammatory signaling is initiated and maintained in transforming cells, and its roles in the early stages of tumorigenesis, such as cell transformation, are largely unknown.1-3 In a recent study,4 we established an in vitro co-culture cell transformation system. Using this system we discovered that a constitutively activated, feed forward inflammatory signaling circuit normally harnessed by miR-200c is established during cell transformation, and that this circuit plays crucial roles in cell transformation and tumorigenesis. This circuit is comprised of IL6, miR-200c, PTPRZ1 and JNK2 and the transcription factors HSF1, estrogen receptor (ERα), ZEB1, p65/RelA and c-Jun (Fig. 1A). Importantly, this constitutive inflammatory signaling circuit is manifest in human cancer cells and in ErbB2 (Neu)-driven breast cancer transgenic mouse models, where deletion of IL6 disables this circuit and dramatically impairs mammary tumorigenesis.
The feed forward nature of this constitutive inflammatory signaling circuit provides explanations for the common phenomenon that many (inflammatory) signaling pathways are interplayed and simultaneously constitutively activated in the same cancer cells. It also demonstrated that the cause and maintenance of the constitutive activation of inflammatory signaling are different from those of the transient activation of inflammatory signaling. For example, the maintenance of constitutive p65 in this circuit is not dependent on IKK, whose activation leads to transient activation of NFκB. Therefore, therapeutic strategies that target constitutively activated pathways should be different from those that target transient activation of pathways.
The roles of transiently and constitutively activated inflammatory signaling in tumorigenesis are different. A transient inflammatory signal is clearly insufficient to transform normal cells. However, as demonstrated in our co-culture model, the transient inflammatory signaling from immune cells can trigger the transformation of those cells (MCF-10a) that have already accumulated some genetic or/and epigenetic alterations that provide the basis for the oncogenic transformation. Although the transient inflammatory signaling initiates the transformation process, the maintenance of the transformed state of malignant cells is dependent on the constitutively activated inflammatory signaling circuit that is formed during the transformation process. Therefore, it is speculated that like MCF-10a cells, “normal” cells in human body accumulated with pre-cancerous mutations will be at high risk for inflammatory cytokine-driven oncogenic transformation.
Abnormal and constitutive inflammatory signaling in cancer cells may not only be provoked by extrinsic inflammatory signals from the tumor microenvironment, but can also occur in a cancer cell-intrinsic fashion.6 Activated oncogenes or inactivated tumor suppressors in cancer cells can induce abnormal and constitutive inflammatory signaling through various means.2,6 While our co-culture model showed that the constitutive activation of this circuit was triggered by transient inflammatory signaling that activates IL6, it is most likely that in other pathological circumstances this circuit can also be triggered by other extrinsic signaling from microenvironment or intrinsic signaling in pre-transformed cells (such as oncogene activation and tumor suppressor inactivation) that activates anyone of p65, JNK2, IL6, STAT3, ZEB1 or HSF1 or suppresses microRNA-200c or PTPRZ1 expression. Once activated, the circuit keeps its constant activation through its positive feed forward nature. While the constitutive activation of the components in the circuit is interdependent, each constitutively activated component regulates its downstream genes that together drive transformation and tumorigenesis (Fig. 1B). Therefore, interventions that target any component of the circuit should trigger a therapeutic response.
Another interesting observation from our study was the loss of ERα in transformed cells. The inflammatory signaling circuit was constitutively activated in all tested ER-negative human breast cancer cell lines. ERα signaling suppresses inflammation and ER-negative breast cancers are usually more aggressive and metastatic,7 which is in accordance with our observations that the cells with the active circuit are more mesenchymal. On the other hand, inflammation also suppresses ERα signaling in ER-positive breast cancer cells,8 and loss of ERα has been observed during the progression from benign to invasive carcinoma.9 In addition, deregulation or loss of ERα expression is one of the mechanisms that have been suggested to confer endocrine resistance in patients with ER-positive breast cancer.10 Thus, we speculate that the inflammatory circuit described in our study may play an important role in ER-negative breast tumorigenesis and in the development of endocrine resistance in ER-positive breast cancer.
Previously published online: www.landesbioscience.com/journals/cc/article/21139
|1.||Husisan SP,et al. Int J CancerYear: 200712123738010.1002/ijc.2317317893866|
|2.||Grivennikov SI,et al. CellYear: 20101408839910.1016/j.cell.2010.01.02520303878|
|3.||Coussens LM,et al. NatureYear: 2002420860710.1038/nature0132212490959|
|4.||Rokavec M,et al. Mol CellYear: 2012457778910.1016/j.molcel.2012.01.01522364742|
|5.||Hanahan D,et al. CellYear: 2000100577010.1016/S0092-8674(00)81683-910647931|
|6.||Schetter AJ,et al. CarcinogenesisYear: 201031374910.1093/carcin/bgp27219955394|
|7.||Platet N,et al. Crit Rev Oncol HematolYear: 200451556710.1016/j.critrevonc.2004.02.00115207254|
|8.||Stossi F,et al. OncogeneYear: 20123118253410.1038/onc.2011.37021860415|
|9.||McCune K,et al. Oncol RepYear: 2010241233920878115|
|10.||Musgrove EA,et al. Nat Rev CancerYear: 200996314310.1038/nrc271319701242|
Keywords: Keywords: breast cancer, cell transformation, constitutive inflammatory signaling, estrogen receptor, inflammation, signaling circuit, transient inflammatory signaling, tumorigenesis.
Previous Document: Computational tools for prioritizing candidate genes: boosting disease gene discovery.
Next Document: PIASy-mediated Tip60 sumoylation regulates p53-induced autophagy.