The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.
The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis.
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DOI：
10.1158/2159-8290.cd-13-1010
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发表时间：
2014-11
期刊：
影响因子：
28.2
通讯作者：
Nelson PS
中科院分区：
文献类型：
--
作者：
Lucas JM;Heinlein C;Kim T;Hernandez SA;Malik MS;True LD;Morrissey C;Corey E;Montgomery B;Mostaghel E;Clegg N;Coleman I;Brown CM;Schneider EL;Craik C;Simon JA;Bedalov A;Nelson PS
TMPRSS 2是主要在前列腺上皮中表达的雄激素调节的细胞表面丝氨酸蛋白酶。TMPRSS 2在局部高级别前列腺癌和大多数人前列腺癌转移中高度表达。通过生成具有靶向缺失Tmprss 2的小鼠模型，我们证明了这种蛋白酶的活性调节癌细胞侵袭和转移到远处器官。通过筛选组合肽库，我们鉴定了包括促肝细胞生长因子（HGF）的一系列TMPRSS 2底物。TMPRSS 2激活的HGF促进c-Met受体酪氨酸激酶信号传导，并启动促侵袭性EMT表型。化学文库筛选鉴定了抑制体内前列腺癌转移的有效生物可利用的TMPRSS 2抑制剂。总之，这些发现提供了雄激素调节的信号传导程序和前列腺癌转移之间的机制联系，通过与肿瘤微环境的细胞外成分的上下文依赖性相互作用进行操作。
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 metastasis. 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 pro-invasive EMT 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.