The Ron Receptor/Chemokine Axis in Prostate Cancer

前列腺癌中的 Ron 受体/趋化因子轴

• 批准号: 8136043
• 负责人: Susan E Waltz
• 金额: $ 31.4万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136043
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenocarcinoma; Binding; Blood Vessels; CXC Chemokines; Cancer Etiology; Cancer cell line; Cells; Cessation of life; Characteristics; Chemotaxis; Data; Development; Disease; Endothelial Cells; Epithelial Cells; Event; Extraprostatic; Gene Targeting; Genes; Goals; Growth; Growth Factor Receptors; Growth and Development function; Human; IL8RB gene; Immunocompromised Host; In Vitro; Interleukin-8B Receptor; Kinetics; Literature; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane; Metastatic to; Modality; Modeling; Mus; NF-kappa B; Neoplasm Metastasis; North America; Organ; PC3 cell line; Pathogenesis; Pathway interactions; Patients; Peptides; Phosphorylation; Primary Neoplasm; Process; Production; Prostate; Prostatic Neoplasms; Prostatic Tissue; Protein Tyrosine Kinase; Proteins; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Regulation; Research; Role; Severities; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Transgenic Organisms; Tumor Angiogenesis; Vascularization; angiogenesis; base; bone; cancer cell; cancer type; cell motility; chemokine; chemokine receptor; density; design; functional loss; in vivo; inhibitor/antagonist; male; men; migration; mortality; neoplastic cell; neutralizing antibody; novel; novel diagnostics; overexpression; public health relevance; receptor; research study; treatment strategy; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Prostate cancer is the most common cancer in men in North America and the second leading cause of cancer-related deaths in males. The high mortality rate of this disease is mainly due to the metastatic spread of malignant cells. Compelling evidence suggests that angiogenesis is a critical factor regulating the growth and spread of cancer. However, a significant gap exists in our understanding of the genes that impact these processes. Our preliminary data show that prostate cancer cell lines and tumors produce angiogenic CXC chemokines through a mechanism dependent on NF-kB activation. The angiogenic chemokines produced by these prostate cancer cells induce endothelial cell chemotaxis and this effect is dependent upon the angiogenic chemokine receptor CXCR2. Moreover, we also demonstrate that the Ron receptor tyrosine kinase is highly expressed in human prostate tumors and prostate cancer cell lines. In addition, we show that a blockade of Ron signaling in prostate cancer cells inhibits angiogenic CXC chemokine production and results in the stabilization of the NF-kB inhibitory protein IkB. Utilizing gene-targeted mice, we also show that a functional loss of Ron or CXCR2 significantly delays prostate tumor development in vivo. Based on our preliminary data, this proposal will test the central hypothesis that Ron signaling promotes prostate tumor growth by stimulating angiogenic chemokine production leading to CXCR2-mediated angiogenesis. The studies in this proposal will focus on the unique role of the Ron-chemokine axis in regulating prostate tumor growth by (i) delineating the mechanisms responsible for the Ron-dependent regulation of angiogenic chemokine production, (ii) determining the impact of Ron signaling in prostate tumor growth in vivo, (iii) by examining the functional significance of the chemokine receptor, CXCR2, in prostate tumor growth and angiogenesis, and (iv) by validating the significance of Ron-mediated angiogenic chemokine production in prostate cancer cells on CXCR2-regulated angiogenesis. In total, we hope to understand role of the novel Ron-chemokine axis in the development and spread of prostate cancer and provide a scientific rationale for new diagnostic or treatment modalities for this disease. PUBLIC HEALTH RELEVANCE: The research in this application will focus on a novel signaling pathway, driven by a protein termed the Ron receptor tyrosine kinase, in regulating the growth of prostate tumors. The goal of this proposal is to provide the scientific rationale to design new treatment strategies targeting this pathway for patients with prostate cancer.

描述（由申请人提供）：前列腺癌是北美男性最常见的癌症，也是男性与癌症相关死亡的第二大主要原因。该疾病的高死亡率主要是由于恶性细胞的转移扩散。令人信服的证据表明，血管生成是调节癌症生长和扩散的关键因素。但是，我们对影响这些过程的基因的理解存在很大的差距。我们的初步数据表明，前列腺癌细胞系和肿瘤通过依赖NF-KB激活的机制产生血管生成CXC趋化因子。这些前列腺癌细胞产生的血管生成趋化因子诱导内皮细胞趋化性，这种作用取决于血管生成趋化因子受体CXCR2。此外，我们还证明了RON受体酪氨酸激酶在人类前列腺肿瘤和前列腺癌细胞系中高度表达。此外，我们表明，前列腺癌细胞中RON信号传导的封锁抑制了血管生成CXC趋化因子的产生，并导致NF-KB抑制蛋白IKB的稳定。利用靶向基因的小鼠，我们还表明，RON或CXCR2的功能损失显着延迟了体内前列腺肿瘤的发展。根据我们的初步数据，该提案将检验中心假设，即RON信号传导通过刺激血管生成趋化因子产生促进前列腺肿瘤的生长，从而导致CXCR2介导的血管生成。该提案中的研究将侧重于通过（i）描述负责RON依赖性调节血管生成趋化因子产生的机制来调节前列腺肿瘤生长的独特作用，（ii）确定RON信号传导在Vivo（III III）中的作用中的RON信号的影响，（III）在功能中的作用，（IIII），（iii）的功能，（iii），（iii iii）的功能，（iii iii）的功能有效性。肿瘤生长和血管生成以及（IV）通过验证RON介导的血管生成趋化因子在前列腺癌细胞中对CXCR2调节的血管生成的重要性。总的来说，我们希望了解新型Ron-emokine轴在前列腺癌的发展和传播中的作用，并为该疾病的新诊断或治疗方式提供科学的理由。 公共卫生相关性：本应用程序中的研究将集中在一种新的信号通路上，这是由称为RON受体酪氨酸激酶的蛋白质驱动的，以调节前列腺肿瘤的生长。该提案的目的是为针对前列腺癌患者设计这种途径的新治疗策略提供科学原理。