Transmembrane Proteases and Prostate Carcinogenesis

跨膜蛋白酶和前列腺癌发生

• 批准号: 8303430
• 负责人: ROBERT Louis VESSELLA
• 金额: $ 56.15万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8303430
• 关键词: Androgens; Antibodies; Binding; Biological; Biological Models; Blood; CXCL12 gene; Carcinogenesis Mechanism; Cell Death; Cells; Characteristics; Chemistry; Chromosomal Rearrangement; Cleaved cell; Collaborations; Development; Digestion; Disease; Early Diagnosis; Ectopic Expression; Elastases; Endocrine; Environment; Enzymes; Epithelium; Exhibits; Extracellular Matrix; Family; Family member; Fertility; Functional disorder; Funding; Gene Proteins; Granzyme; Growth; Human; Human Glandular Kallikrein 2; In Situ; Inflammatory Response; Instruction; Location; Malignant neoplasm of prostate; Mediating; Membrane; Metastatic Prostate Cancer; Molecular; Molecular Profiling; Monitor; Neoplasm Metastasis; Pathogenesis; Patients; Peptide Hydrolases; Physiology; Process; Prostate; Prostate carcinoma; Prostate-Specific Antigen; Protease Gene; Proteins; Reagent; Recombinant Proteins; Regulation; Reporting; Research Personnel; Role; Serine Protease; Signal Pathway; Signal Transduction; Site; Stratum corneum; Substrate Specificity; TMPRSS2 gene; Thrombin; Tissues; Transgenic Mice; Trypsin; Tumor Cell Invasion; Tumor-Derived; acrosin; base; bone; cancer cell; design; family influence; hepsin; inhibitor/antagonist; insight; kallikrein 4; matriptase; member; metastatic process; migration; mouse model; novel therapeutic intervention; overexpression; paracrine; programs; prostate carcinogenesis; protein expression; research study; response; therapeutic target; tool; transcription factor; tumorigenic

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.

丝氨酸蛋白酶，特别是在前列腺上皮中表达的蛋白酶，已经出现很重要 相关分子，用于理解前列腺癌的病理生理学和机制 转移过程。此外，这些蛋白酶在异位位置表达时的酶活性 例如在骨骼中可能改变局部环境以有利于肿瘤细胞侵袭和生长。 该提案的目的是基于以下假设：转移到前列腺癌的进展是 由膜结合的丝氨酸蛋白酶的原位和异位表达驱动 TMPRSS2，Hepsin和Matriptase。这些丝氨酸蛋白酶通过蛋白酶影响转移性疾病 对入侵障碍（例如细胞外基质）和信号传导因子的相互改变的作用 来自肿瘤和微环境（例如IGF，HGF，CXCL12）。该提案的具体目的是： AIM 1。定义TMPRSS2蛋白酶的生物底物，将底物特异性与 Hepsin（和其他蛋白酶），并识别TMPRSS2功能的抑制剂（协作WTH项目3）。 AIM 2。确定受TMPRSS2活性影响的细胞信号通路并确定服务员 调节增殖，迁移和侵袭的致瘤特征的表型反应。 初步研究将集中于IGF，HGF和CXCL12信号传导。 （与项目3合作）。 目标3。确定TMPRSS2影响前列腺的生物学作用和分子机制 癌细胞的传播和骨环境中的生长（与项目1合作）。 完成该提案的具体目的将确定TMPRSS2影响的机制 前列腺癌细胞侵袭和转移，并将开发适合的模型系统和试剂 利用TMPRSS2作为治疗靶标。 相关性（请参阅说明）： 前列腺癌的致命形式表现为传播到骨骼和其他部位的疾病。我们有 确定膜锚定的丝氨酸蛋白酶TMPRSS2调节前列腺癌的特征 转移。该提案旨在确定TMPRSS2对的机制 侵入性和转移性生长，并鉴定能够废除Ti \/IPRSS2功能的抑制剂。