β4 Integrin signaling induces expansion of prostate tumor progenitors Academic Article uri icon

Overview

MeSH Major

  • Integrin beta4
  • Neoplastic Stem Cells
  • Prostatic Neoplasms

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.

publication date

  • February 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3561800

Digital Object Identifier (DOI)

  • 10.1172/JCI60720

PubMed ID

  • 23348745

Additional Document Info

start page

  • 682

end page

  • 99

volume

  • 123

number

  • 2