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.
View: Text | PDF
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

×

Figure 3

The tumor cells located in the basal compartment of high-grade PIN and invasive adenocarcinomas express elevated levels of the β4 integrin.

Options: View larger image (or click on image) Download as PowerPoint
The tumor cells located in the basal compartment of high-grade PIN and i...
(A) Consecutive sections of high-grade PIN and well-differentiated adenocarcinomas were subjected to double staining with anti-β4 and anti-K14 followed by counterstaining with DAPI. Similar grade histological sections were immunostained for AR and counterstained with H&E. Whereas the PIN lesions retain K14+ basal cells, the adenocarcinomas have lost basal cells (yellow arrows). In both cases, the neoplastic cells adhering to the basement membrane express high levels of β4 as well as the AR. (B) Sections of high-grade PIN, invasive adenocarcinoma, and poorly differentiated adenocarcinoma from PB-TAg; β4-WT mice were stained with H&E, DAPI, and antibodies to β4, laminin-5, or E-cadherin. In PIN lesions, prostate carcinoma cells adhering to laminin-5 express high levels of β4 (yellow arrows), whereas suprabasal cells express lower levels of the integrin. The white arrows indicate the β4-positive basal cells beneath the basement membrane of adjacent normal gland. The β4 integrin continues to be expressed at high levels in invasive adenocarcinomas. At invasion fronts (yellow arrows), β4 losses its basal concentration and the staining for laminin-5 becomes fragmented. The poorly differentiated adenocarcinomas arising in this model exhibit neuroendocrine features. In these lesions, β4, E-cadherin, and laminin-5 are no longer detectable. β4 is still expressed in blood vessels (yellow arrows). The white asterisk marks a normal gland, and yellow asterisks mark laminin-5–positive muscle fibers. Scale bar: 50 μm.