title: The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Lucas
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Heinlein
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Tom
authors.initials: T
authors.lastname: Kim
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Susana A
authors.initials: SA
authors.lastname: Hernandez
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Muzdah S
authors.initials: MS
authors.lastname: Malik
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Colm
authors.initials: C
authors.lastname: Morrissey
authors.affiliation: Department of Urology, University of Washington, Seattle, Washington.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Bruce
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Elahe
authors.initials: E
authors.lastname: Mostaghel
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Nigel
authors.initials: N
authors.lastname: Clegg
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Ilsa
authors.initials: I
authors.lastname: Coleman
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Brown
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Schneider
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.
authors.forename: Charles
authors.initials: C
authors.lastname: Craik
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Simon
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bedalov
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Pathology, University of Washington, Seattle, Washington. Department of Urology, University of Washington, Seattle, Washington. Department of Medicine, University of Washington, Seattle, Washington. pnelson@fhcrc.org.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000728:Androgens / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D016513:Mice, SCID; D019151:Peptide Library; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism*; D059016:Tumor Microenvironment
chemical_list: D000728:Androgens; D019151:Peptide Library; D011944:Receptors, Androgen; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D012697:Serine Endopeptidases; C000588699:TMPRSS2 protein, mouse