期刊
CANCER DISCOVERY
卷 4, 期 11, 页码 1310-1325出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-13-1010
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资金
- Prostate Cancer Foundation
- NIH [P01CA85859, R01CA165573, U01CA164188]
- Pacific Northwest Prostate Cancer SPORE [P50CA97186]
TMPRSS2 is an androgen-regulated cell-surface serine protease expressed predominantly in prostate epithelium. IMPRSS2 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 IMPRSS2 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 IMPRSS2 may reduce the incidence or progression of metastasis in patients with prostate cancer. (C) 2014 AACR.
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