Transmembrane Proteases and Prostate Carcinogenesis

丝氨酸蛋白酶，特别是那些在前列腺上皮细胞中表达的酶，已经成为重要的 前列腺癌病理生理学和发病机制的相关分子研究 转移过程。此外，这些酶在异位表达时的酶活性 例如在骨骼中，可能会改变局部环境，有利于肿瘤细胞的侵袭和生长。 这项建议的目的是基于这样的假设：进展为转移性前列腺癌 膜结合型丝氨酸蛋白酶的持续原位和异位表达 TMPRSS2、肝素和基质裂解酶。这些丝氨酸蛋白酶通过蛋白酶影响转移性疾病 对入侵屏障(如细胞外基质)的作用和衍生的信号因子的相互变化 来自肿瘤和微环境(如IGF、HGF、CXCL12)。这项建议的具体目标是： 目的1.确定TMPRSS2蛋白酶的生物底物，比较底物特异性与 肝酶(和其他蛋白酶)，并确定TMPRSS2功能的抑制剂(与项目3合作)。 目的2.确定受TMPRSS2活性影响的细胞信号通路并确定与之相关的信号通路 调节肿瘤发生的增殖、迁移和侵袭特征的表型反应。 最初的研究将集中在IGF、HGF和CXCL12信号。(与项目3合作)。 目的3.确定TMPRSS2影响前列腺的生物学作用(S)及其分子机制 癌细胞在骨骼环境中的扩散和生长(与项目1合作)。 完成本提案的具体目标将决定TMPRSS2影响的机制 前列腺癌细胞的侵袭和转移，并将开发适合于 利用TMPRSS2作为治疗靶点。 相关性(请参阅说明)： 前列腺癌的致命形式表现为播散性疾病到骨骼和其他部位。我们有 确定一种膜锚定的丝氨酸蛋白酶TMPRSS2调节前列腺癌的特征 转移。本提案旨在确定TMPRSS2有助于 侵袭性和转移性生长，并确定能够消除TIIPRSS2功能的抑制剂。

Serine proteases, and specifically those expressed in prostate epithelium, have emerged as important molecules of relevance for understanding the pathophysiology and mechanisms of the prostate cancer metastatic process. Further, the enzymatic activities of these proteases when expressed in ectopic locations such as in the bone may alter the local environment to favor tumor cell invasion and growth. The aims of this proposal are based upon the hypothesis that: Progression to metastatic prostate cancer is driven by the persistent in situ and ectopic expression of membrane-bound serine protease enzymes TMPRSS2, hepsin and matriptase. These serine proteases influence metastatic disease through protease action on barriers to invasion (e.g. extracellular matrix) and reciprocal alterations in signaling factors derived from the tumor and microenvironment (e.g. IGF, HGF, CXCL12). The specific aims of this proposal are: Aim 1. Define the biological substrates of the TMPRSS2 protease, compare the substrate specificities with hepsin (and other proteases), and identify inhibitors of TMPRSS2 function (Collaboration wth Project 3). Aim 2. Determine the cellular signaling pathways influenced by TMPRSS2 activity and identify the attendant phenotypic responses that modulate tumorigenic characteristics of proliferation, migration, and invasion. Initial studies will focus on IGF, HGF, and CXCL12 signaling. (Collaboration with Project 3). Aim 3. Determine the biological role(s) and molecular mechanisms by which TMPRSS2 influences prostate cancer cell dissemination and growth in the bone environment (Collaboration with Project 1). Completing the specific aims of this proposal will determine mechanisms by which TMPRSS2 influences prostate cancer cell invasion and metastasis, and will develop model systems and reagents suitable for exploiting TMPRSS2 as a therapeutic target. RELEVANCE (See instructions): The lethal form of prostate cancer manifests as disseminated disease to bone and other sites. We have determined that a membrane-anchored serine protease, TMPRSS2, modulates features of prostate cancer metastasis. This proposal is designed to determine the mechanisms by which TMPRSS2 contributes to invasive and metastatic growth, and identify inhibitors capable of abrogating TI\/IPRSS2 function.