Transmembrane Proteases and Prostate Carcinogenesis

丝氨酸蛋白酶，特别是那些在前列腺上皮中表达的蛋白酶， 与了解前列腺癌的病理生理学和机制相关的分子 转移过程此外，当在异位位置表达时，这些蛋白酶的酶活性 例如在骨中，可以改变局部环境以有利于肿瘤细胞侵入和生长。 该提案的目的基于以下假设：进展为转移性前列腺癌是 由膜结合丝氨酸蛋白酶的持续原位和异位表达驱动 TMPRSS 2、肝蛋白酶和间质蛋白酶。这些丝氨酸蛋白酶通过蛋白酶影响转移性疾病 对侵袭屏障（例如细胞外基质）的作用和信号传导因子的相互改变 从肿瘤和微环境（如IGF，HGF，CXCL 12）。这项建议的具体目标是： 目标1。定义TMPRSS 2蛋白酶的生物底物，比较底物特异性与 hepsin（和其他蛋白酶），并鉴定TMPRSS 2功能抑制剂（与项目3合作）。 目标二。确定受TMPRSS 2活性影响的细胞信号传导途径，并确定伴随的 表型反应，调节增殖、迁移和侵袭的致瘤特征。 最初的研究将集中在IGF，HGF和CXCL 12信号转导。（项目3）。 目标3。确定TMPRSS 2影响前列腺的生物学作用和分子机制 癌细胞在骨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确定TMPRSS 2影响的机制 前列腺癌细胞的侵袭和转移，并将开发模型系统和试剂适用于 利用TMPRSS 2作为治疗靶点。 相关性（参见说明）： 前列腺癌的致命形式表现为扩散到骨骼和其他部位的疾病。我们有 确定膜锚定丝氨酸蛋白酶TMPRSS 2调节前列腺癌的特征， 转移本提案旨在确定TMPRSS 2有助于实现以下目标的机制： 侵袭性和转移性生长，并鉴定能够消除TI 1/IPRSS 2功能抑制剂。

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.