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The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.
Cancer Discov 2014; 4(11):1310-25CD

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.

Authors+Show Affiliations

Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.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 Urology, University of Washington, Seattle, Washington.Department of Medicine, University of Washington, Seattle, Washington.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.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.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.

Pub Type(s)

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

Language

eng

PubMed ID

25122198

Citation

Lucas, Jared M., et al. "The Androgen-regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis." Cancer Discovery, vol. 4, no. 11, 2014, pp. 1310-25.
Lucas JM, Heinlein C, Kim T, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov. 2014;4(11):1310-25.
Lucas, J. M., Heinlein, C., Kim, T., Hernandez, S. A., Malik, M. S., True, L. D., ... Nelson, P. S. (2014). The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discovery, 4(11), pp. 1310-25. doi:10.1158/2159-8290.CD-13-1010.
Lucas JM, et al. The Androgen-regulated Protease TMPRSS2 Activates a Proteolytic Cascade Involving Components of the Tumor Microenvironment and Promotes Prostate Cancer Metastasis. Cancer Discov. 2014;4(11):1310-25. PubMed PMID: 25122198.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. AU - Lucas,Jared M, AU - Heinlein,Cynthia, AU - Kim,Tom, AU - Hernandez,Susana A, AU - Malik,Muzdah S, AU - True,Lawrence D, AU - Morrissey,Colm, AU - Corey,Eva, AU - Montgomery,Bruce, AU - Mostaghel,Elahe, AU - Clegg,Nigel, AU - Coleman,Ilsa, AU - Brown,Christopher M, AU - Schneider,Eric L, AU - Craik,Charles, AU - Simon,Julian A, AU - Bedalov,Antonio, AU - Nelson,Peter S, Y1 - 2014/08/13/ PY - 2014/8/15/entrez PY - 2014/8/15/pubmed PY - 2015/6/27/medline SP - 1310 EP - 25 JF - Cancer discovery JO - Cancer Discov VL - 4 IS - 11 N2 - UNLABELLED: 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. SN - 2159-8290 UR - https://www.unboundmedicine.com/medline/citation/25122198/The_androgen_regulated_protease_TMPRSS2_activates_a_proteolytic_cascade_involving_components_of_the_tumor_microenvironment_and_promotes_prostate_cancer_metastasis_ L2 - http://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=25122198 DB - PRIME DP - Unbound Medicine ER -