The Ron Receptor/Chemokine Axis in Prostate Cancer

描述（由申请人提供）： 摘要前列腺癌是北美男性最常见的癌症，也是男性癌症相关死亡的第二大原因。这种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。然而，我们对影响这些过程的基因的理解存在重大差距。我们的初步数据表明，前列腺癌细胞系和肿瘤通过依赖于NF-：B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，这种作用依赖于血管生成趋化因子受体CXCR 2。此外，我们还证明了罗恩受体酪氨酸激酶在人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罗恩信号的阻断抑制血管生成CXC趋化因子的产生，并导致NF-：B抑制蛋白I：B的稳定。利用基因靶向小鼠，我们还表明，罗恩或CXCR 2的功能损失显着延迟体内前列腺肿瘤的发展。基于我们的初步数据，该提议将测试中心假设，即罗恩信号通过刺激血管生成趋化因子的产生导致CXCR 2介导的血管生成来促进前列腺肿瘤生长。本提案中的研究将重点关注Ron-趋化因子轴在调节前列腺肿瘤生长中的独特作用，方法是（i）阐明Ron依赖性调节血管生成趋化因子产生的机制，（ii）确定体内前列腺肿瘤生长中罗恩信号传导的影响，以及（iii）检查趋化因子受体CXCR 2在前列腺肿瘤生长和血管生成中的功能意义。总之，我们希望了解新的Ron-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。 公共卫生相关性： 前列腺癌是最常见的癌症，也是男性癌症的第二大原因。大约200，000例新的前列腺癌病例将被诊断出来，估计大约40，000名男性将死于这种疾病。随着人口老龄化，前列腺癌的患病率和发病率可能会增加，退伍军人管理局对这种疾病患者的支出和护理也会相应增加。虽然VA和其他机构在治疗这种疾病方面做出了重大努力和进展，但我们对前列腺癌患者新治疗方案的了解仍存在重大差距。在我们的实验室，我们有令人兴奋的新数据表明一种新的蛋白质，称为罗恩，可能参与前列腺肿瘤的形成和生长。罗恩是一种存在于细胞表面的蛋白质。罗恩的功能是将细胞外的信号传递到细胞内的信息中。罗恩被归类为受体酪氨酸激酶，许多这些蛋白质家族在各种癌症中过度产生。罗恩的过量产生导致细胞内促进细胞生长的几个信号通路的激活。为了使肿瘤生长和转移（或扩散到身体的其他部位），肿瘤必须招募自己的血液供应。形成新血管的过程称为血管生成。肿瘤细胞，特别是前列腺癌细胞，分泌小分子，如血管生成趋化因子，这对血管生成很重要，因为它们吸引血管到达生长的肿瘤。血管生成对于肿瘤细胞维持持续的营养和氧气供应以及清除废物至关重要。如果没有血管生成，肿瘤细胞将永远不会扩散到身体的其他器官，肿瘤的生长将受到限制。前列腺癌细胞产生血管生成趋化因子并转移，因此了解这一过程是如何调节的非常重要。我们最近的数据显示，罗恩在人类前列腺癌中过量产生，并且罗恩是促进前列腺癌细胞产生血管生成趋化因子的关键因素。基于我们的研究，我们提出罗恩是一个有前途的和新的蛋白质研究在前列腺癌，我们认为，罗恩可以刺激前列腺肿瘤的生长和转移，通过刺激血管生成。本提案中的研究将确定高水平罗恩在前列腺癌中的重要性，并将确定阻断罗恩是否会降低前列腺肿瘤细胞生长和招募血管的能力。拟议的研究对于加深我们对前列腺癌和潜在治疗方案的了解非常重要。除了我们初期的研究，对前列腺癌中的罗恩或罗恩与血管生成趋化因子的调节一无所知。有了这项申请的资助，我们将对罗恩作为前列腺癌的潜在靶点进行第一次详细研究。我的实验室致力于前列腺癌研究，我们拥有完成本提案中研究所需的所有专业知识和设备。此外，我们对罗恩成为这种疾病的临床相关治疗靶点的潜力感到非常兴奋。

DESCRIPTION (provided by applicant): Abstract 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-:B 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-:B inhibitory protein I:B. 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, and (iii) by examining the functional significance of the chemokine receptor, CXCR2, in prostate tumor growth and 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: Prostate cancer is the most common cancer and is the second leading cause of cancer in men. Approximately 200,000 new cases of prostate cancer will be diagnosed and about 40,000 men are estimated to die of this disease. The prevalence and morbidity of prostate cancer are likely to increase with the aging population and the Veteran's Administration's expenditures and care for patients with this disease will increase accordingly. While significant effort and advancement into the treatment of this disease have occurred at the VA and other institutions, a significant gap still exists in our knowledge of new treatment options for patients with prostate cancer. In our laboratory, we have exciting new data which suggests a novel protein, termed Ron, may be involved in prostate tumor formation and growth. Ron is a protein that resides on the surface of cells. The function of Ron is to transmit signals from outside the cell into intracellular messages. Ron is classified as a receptor tyrosine kinase and many of these families of proteins are overproduced in various cancer. The overproduction of Ron leads to the activation of several signaling pathways inside the cell that promote cell growth. In order for a tumor to grow and metastasize (or spread to other parts of the body), the tumor must recruit it's own blood supply. The process of forming new blood vessels is called angiogenesis. Tumor cells, and in particular prostate cancer cells, secret small molecules, such as angiogenic chemokines, that are important for angiogenesis because they attract blood vessels to come to the growing tumor. Angiogenesis is vital for tumor cells to maintain a constant supply of nutrients and oxygen, and to get rid of waste. Without angiogenesis, the tumor cells will never spread to other organs in the body and the tumor would be limited in growth. Prostate cancer cells produce angiogenic chemokines and metastasize and it is therefore important to understand how this process is regulated. Our very recent data show that Ron is overproduced in human prostate cancer and that Ron is a key factor that promotes the production of angiogenic chemokines from prostate cancer cells. Based on our research, we propose that Ron is a promising and novel protein to study in prostate cancer, and we suggest that Ron can stimulate prostate tumor growth and metastasis by stimulating angiogenesis. The studies in this proposal will define the importance of the high levels of Ron in prostate cancer and will determine if blocking Ron will lessen the ability of prostate tumor cells to grow and recruit blood vessels. The proposed studies are very important in furthering our understanding of prostate cancer and potential treatment options. Apart from our nascent studies, nothing is known about Ron in prostate cancer or Ron and the regulation of angiogenic chemokines. With the funding of this application, we will perform the first detailed studies of Ron as a potential target in prostate cancer. My laboratory is dedicated to prostate cancer research and we have all of the necessary expertise and equipment to complete the studies in this proposal. Moreover, we are very excited about the potential of Ron to be a clinically relevant therapeutic target in this disease.