The Ron Receptor/Chemokine Axis in Prostate Cancer

描述（由申请人提供）：前列腺癌是北美男性中最常见的癌症，也是男性癌症相关死亡的第二大原因。本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。然而，我们对影响这些过程的基因的理解存在着重大差距。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的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，这种作用依赖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，我们发现前列腺癌细胞中Ron信号的阻断可抑制血管生成CXC趋化因子的产生，并导致NF-kB抑制蛋白IkB的稳定。利用基因靶向小鼠，我们还发现Ron或CXCR2的功能缺失显著延缓了体内前列腺肿瘤的发展。基于我们的初步数据，本提案将验证Ron信号通过刺激血管生成趋化因子产生导致cxcr2介导的血管生成来促进前列腺肿瘤生长的中心假设。本提案的研究将集中于Ron趋化因子轴在调节前列腺肿瘤生长中的独特作用，通过(i)描述Ron依赖性调节血管生成趋化因子产生的机制，（ii）确定Ron信号在体内前列腺肿瘤生长中的影响，（iii）通过检查趋化因子受体CXCR2在前列腺肿瘤生长和血管生成中的功能意义。（iv）通过验证前列腺癌细胞中ron介导的血管生成趋化因子的产生对cxcr2调节的血管生成的意义。总之，我们希望了解新的非趋化因子轴在前列腺癌的发展和扩散中的作用，并为这种疾病的新诊断或治疗方式提供科学依据。

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.