Document Detail


β4 Integrin signaling induces expansion of prostate tumor progenitors.
MedLine Citation:
PMID:  23348745     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.
Authors:
Toshiaki Yoshioka; Javier Otero; Yu Chen; Young-Mi Kim; Jason A Koutcher; Jaya Satagopan; Victor Reuter; Brett Carver; Elisa de Stanchina; Katsuhiko Enomoto; Norman M Greenberg; Peter T Scardino; Howard I Scher; Charles L Sawyers; Filippo G Giancotti
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-25
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-05-13     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  682-99     Citation Subset:  AIM; IM    
Affiliation:
Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Disease Models, Animal
Disease Progression
Gene Expression
Gene Targeting
Humans
Integrin beta4 / chemistry,  genetics,  metabolism*
Male
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mice, Transgenic
Neoplasm Invasiveness / genetics,  pathology
Neoplastic Stem Cells / metabolism*,  pathology*
Prostatic Intraepithelial Neoplasia / genetics,  metabolism,  pathology
Prostatic Neoplasms / genetics,  metabolism*,  pathology*
Proto-Oncogene Proteins c-met / genetics,  metabolism
Receptor, erbB-2 / genetics,  metabolism
Signal Transduction
Grant Support
ID/Acronym/Agency:
CA129023/CA/NCI NIH HHS; K08 CA140946/CA/NCI NIH HHS; P30 CA08748/CA/NCI NIH HHS; P50 CA092629/CA/NCI NIH HHS; P50 CA92629/CA/NCI NIH HHS; R01 CA113996/CA/NCI NIH HHS; R24 CA83084/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Integrin beta4; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Erbb2 protein, mouse; EC 2.7.10.1/MET protein, human; EC 2.7.10.1/Proto-Oncogene Proteins c-met; EC 2.7.10.1/Receptor, erbB-2
Comments/Corrections
Comment In:
J Clin Invest. 2013 Feb 1;123(2):563-5   [PMID:  23348735 ]

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