β4 Integrin signaling induces expansion of prostate tumor progenitors
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
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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Research Article

β4 Integrin signaling induces expansion of prostate tumor progenitors

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 8

Simultaneous pharmacological inhibition of ErbB2 and c-Met inhibits prostate cancer growth in vivo.

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Simultaneous pharmacological inhibition of ErbB2 and c-Met inhibits pros...
(A) 5 × 106 DU1455 cells were injected subcutaneously together with Matrigel in 8-week-old NOD/SCID/Il2rg–/– mice. Once tumors reached approximately 200 mm3, mice were randomized to receive lapatinib alone, crizotinib alone, lapatinib and crizotinib in combination, or vehicle control. The following doses were given: 150 mg/kg lapatinib p.o. daily for 5 days per week for 3 weeks and 50 mg/kg crizotinib p.o. daily for 5 days per week for 3 weeks. The graph shows the mean (± SD) tumor size at the indicated times. (B) The mean weight of mice treated as indicated at the indicated times. (C) Tumor sections were stained with anti–Ki-67. The graph shows the mean (± SD) percentage of Ki-67+ tumor cells in the indicated treatment groups. (D) Tumor sections were stained with anti-cleaved caspase-3 (Casp-3). The graph shows the mean (± SD) percentage of apoptotic tumor cells in the indicated treatment groups. (E) Tumor sections were stained with anti–PECAM-1. The graph shows the mean (± SD) number of microvessels per microscopic field in the indicated treatment groups. Numbers in columns represent the number of mice.