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- Title
ß4 Integrin signaling induces expansion of prostate tumor progenitors.
- Authors
Yoshioka, Toshiaki; Otero, Javier; Yu Chen; Kim, Young-Mi; Koutcher, Jason A.; Satagopan, Jaya; Reuter, Victor; Carver, Brett; Stanchina, Elisa de; Enomoto, Katsuhiko; Greenberg, Norman M.; Scardino, Peter T.; Scher, Howard I.; Sawyers, Charles L.; Giancotti, Filippo G.
- Abstract
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 ß4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of ß4 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 ß4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant ß4 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 ß4 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 ß4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells.
- Subjects
INTEGRINS; CELLULAR signal transduction; PROSTATE tumors; PROGENITOR cells; CANCER invasiveness; CANCER cell proliferation
- Publication
Journal of Clinical Investigation, 2013, Vol 123, Issue 2, p682
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI60720