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β4 Integrin signaling induces expansion of prostate tumor progenitors
Toshiaki Yoshioka, … , Charles L. Sawyers, Filippo G. Giancotti
Toshiaki Yoshioka, … , Charles L. Sawyers, Filippo G. Giancotti
Published January 25, 2013
Citation Information: J Clin Invest. 2013;123(2):682-699. https://doi.org/10.1172/JCI60720.
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Research Article

β4 Integrin signaling induces expansion of prostate tumor progenitors

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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 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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Figure 1

Expression of the β4 integrin in human prostate cancer.

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Expression of the β4 integrin in human prostate cancer.
(A) Summary of C...
(A) Summary of COPA of ITGB4 in 11 prostate cancer DNA microarray data sets (source Oncomine). COPA of ITGB4 in the LaTulippe data set reveals ITGB4 as outlier in 2 bone metastases (mets) (34). (B) COPA of ITGB4 in the Singh and LaTulippe data sets (34, 35), in which samples were classified on the basis of Gleason grade. (C) Total lysates of LNCaP cells transduced with empty vector or vector encoding human β4 were subjected to immunoblotting with the anti-β4 mAb ELF1. (D) Sections from the indicated samples were stained with anti-β4 and counterstained with hematoxylin. The asterisk indicates blood vessels, the purple arrow points to high-grade PIN lesions, and red arrows point to invasive adenocarcinomas. The metastatic lesions are from bone (top) and soft tissue (bottom). The anti-β4 staining intensity of prostate cancer samples was as indicated in the top right corner of each of the relevant panels (neg, negative; ++, moderate; +++, strong). Scale bar: 50 μm (metastases and bottom normal prostate); 100 μm (prostate adenocarcinoma and top normal prostate).

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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