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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 Article has an altmetric score of 19

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 4

Deletion of the β4 signaling domain inhibits the manifestation of cancer stem cell traits.

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Deletion of the β4 signaling domain inhibits the manifestation of cancer...
(A) High-grade PIN lesions from 3- and 4-month-old PB-TAg; β4-WT and PB-TAg; β4-1355T mice were stained with anti–Ki-67 and counterstained with hematoxylin (H). Scale bar: 50 μm. (B) The mean percentage of Ki-67–positive cells (± SD) at the indicated times (n = 3 per group). (C) Mice were injected with EdU for 3 consecutive days. Lin– cells were stained for β4 and EdU and analyzed by FACS. The graph shows the mean (± SEM) percentage of EdU+ cells in the indicated subpopulations of cells (n = 4 per group). (D) Tumors cells from 4.5-month-old PB-TAg; β4-WT and 6.5-month-old PB-TAg; β4-1355T mice were sorted into 4 subpopulations after gating for Lin– cells. EpCAM– cells were excluded from the DN cells. (E) The mean (± SEM) spheres (n = 6 per group). (F) Prostate epithelial cells from β4-WT and β4-1355T mice were infected in vitro with a lentiviral vector encoding a shRNA targeting Pten and xenotransplanted together with urogenital sinus mesenchymal cells under the renal capsule of NOD/SCID/Il2rg–/– mice. The graphs show the mean (± SD) number of PIN lesions per transplanted kidney and the mean (± SD) number of normal glands per section (right). (G) Sections across the subcapsular injection site were stained with anti–P-AKT and counterstained with hematoxylin. Adjacent sections were stained with H&E. Arrows point to PIN lesions exhibiting high-level activation of AKT. Representative images are shown. Scale bar: 500 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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