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: 7789448
• 负责人: Susan E Waltz
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7789448
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adenocarcinoma; Blood Vessels; Body part; CXC Chemokines; Cancer Etiology; Cancer cell line; Cell surface; Cells; Cessation of life; Characteristics; Chemotaxis; Data; Development; Diagnosis; Disease; Endothelial Cells; Epithelial Cells; Equipment; Event; Expenditure; Extraprostatic; Funding; Gene Targeting; Genes; Growth; Growth Factor Receptors; Growth and Development function; Health; Human; IL8RB gene; Immunocompromised Host; Institution; Interleukin-8B Receptor; Kinetics; Knowledge; Laboratories; Literature; Lung; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic to; Modality; Modeling; Morbidity - disease rate; Mus; NF-kappa B; Neoplasm Metastasis; North America; Nutrient; Organ; Oxygen; PC3 cell line; Pathogenesis; Pathway interactions; Patient Care; Patients; Peptides; Phosphorylation; Prevalence; Primary Neoplasm; Process; Production; Prostate; Prostatic Neoplasms; Prostatic Tissue; Protein Family; Protein Tyrosine Kinase; Proteins; Publishing; Receptor Activation; Receptor Protein-Tyrosine Kinases; Receptor Signaling; Recruitment Activity; Regulation; Research; Role; Severities; Signal Pathway; Signal Transduction; Testing; Therapeutic; Tissues; Transgenic Organisms; Tumor Angiogenesis; United States Department of Veterans Affairs; Vascular blood supply; abstracting; aging population; angiogenesis; anticancer research; base; bone; cancer cell; cancer type; cell growth; cell motility; chemokine; chemokine receptor; clinically relevant; density; functional loss; in vivo; inhibitor/antagonist; male; men; migration; mortality; neoplastic cell; neutralizing antibody; novel; novel diagnostics; overexpression; receptor; research study; small molecule; therapeutic target; tumor; tumor growth; tumor progression; wasting

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.

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。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于NF-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--：B抑制蛋白I I：b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调节的机制，（ii）确定RON信号在Vivo和III中的功能中确定RON信号在CONSCRINE cons cons cons cons cons cons cons cons cons cons cons cons cons cons cons cons cons cons cons con的影响，并通过（i）描述负责RON依赖性调节的机制来调节前列腺肿瘤生长的独特作用（II）。前列腺肿瘤生长和血管生成。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： 前列腺癌是最常见的癌症，是男性癌症的第二主要原因。将诊断出大约200,000例新的前列腺癌病例，估计约有40,000名男性死于这种疾病。前列腺癌的患病率和发病率可能随着人口老龄而增加，而退伍军人政府对这种疾病患者的支出和护理将相应增加。尽管在VA和其他机构发生了重大的努力和进步，但在我们对前列腺癌患者的新治疗方案的了解中仍然存在很大的差距。在我们的实验室中，我们有令人兴奋的新数据，表明一种新型蛋白质称为罗恩，可能参与了前列腺肿瘤的形成和生长。罗恩（Ron）是一种位于细胞表面的蛋白质。 RON的功能是将信号从单元外传输到细胞内消息。罗恩被归类为一种受体酪氨酸激酶，其中许多蛋白质家族在各种癌症中都过量生产。 RON的过量产生导致细胞内部几种信号通路的激活，从而促进细胞生长。为了使肿瘤生长和转移（或传播到身体的其他部位），肿瘤必须招募其自身的血液供应。形成新血管的过程称为血管生成。肿瘤细胞，尤其是前列腺癌细胞，秘密的小分子，例如血管生成趋化因子，对于血管生成很重要，因为它们吸引了血管进入生长的肿瘤。血管生成对于肿瘤细胞保持恒定的营养和氧气供应并消除废物至关重要。没有血管生成，肿瘤细胞将永远不会扩散到体内其他器官，并且肿瘤在生长中受到限制。前列腺癌细胞产生血管生成趋化因子并转移，因此了解如何调节该过程很重要。我们最近的数据表明，罗恩（Ron）在人类前列腺癌中过量生产，而罗恩（Ron）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，我们建议罗恩是一种有前途且新颖的蛋白质研究前列腺癌的蛋白质，我们建议罗恩可以通过刺激血管生成来刺激前列腺肿瘤的生长和转移。该提案中的研究将定义罗恩在前列腺癌中的重要性，并将确定阻塞罗恩是否会降低前列腺肿瘤细胞生长和募集血管的能力。拟议的研究在进一步了解前列腺癌和潜在治疗方案方面非常重要。除了我们的新生研究外，对前列腺癌或罗恩的罗恩以及血管生成趋化因子的调节一无所知。通过此应用的资助，我们将对罗恩（Ron）进行首次详细研究，作为前列腺癌的潜在目标。我的实验室致力于前列腺癌研究，我们拥有所有必要的专业知识和设备来完成该提案中的研究。此外，我们对罗恩成为该疾病中临床相关的治疗靶点的潜力感到非常兴奋。