The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis

Cancer Discov. 2014 Nov;4(11):1310-25. doi: 10.1158/2159-8290.CD-13-1010. Epub 2014 Aug 13.

Abstract

TMPRSS2 is an androgen-regulated cell-surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastases. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries, we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-MET receptor tyrosine kinase signaling, and initiated a proinvasive epithelial-to-mesenchymal transition phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment.

Significance: The vast majority of prostate cancer deaths are due to metastasis. Loss of TMPRSS2 activity dramatically attenuated the metastatic phenotype through mechanisms involving the HGF-c-MET axis. Therapeutic approaches directed toward inhibiting TMPRSS2 may reduce the incidence or progression of metastasis in patients with prostate cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / metabolism
  • Animals
  • Cell Line, Tumor
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Male
  • Mice, Knockout
  • Mice, SCID
  • Peptide Library
  • Prostatic Neoplasms / metabolism*
  • Prostatic Neoplasms / pathology*
  • Proteolysis
  • Proto-Oncogene Proteins c-met / metabolism
  • Receptors, Androgen / metabolism
  • Serine Endopeptidases / metabolism*
  • Tumor Microenvironment

Substances

  • Androgens
  • Peptide Library
  • Receptors, Androgen
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Serine Endopeptidases
  • TMPRSS2 protein, mouse