Role of chemokine Receptor CXCR7 in prostate cancer progression

描述(由申请人提供)： 摘要：前列腺癌是美国退伍军人癌症相关发病率和死亡率的主要原因，其发病率高于普通人群。虽然，前列腺癌如果在疾病局限于前列腺时及早诊断可以得到有效的治疗，但当癌症扩散到前列腺癌外组织时，晚期疾病的有效治疗是有限的。目前的研究表明，在癌症中有两条主要的前列腺生长途径，一条是雄激素-雄激素受体调节的生长，另一条是多肽激素，如表皮生长因子(EGF)和胰岛素样生长因子-1，刺激前列腺癌的生长和生存。然而，在这一建议中，提出了由细胞因子和趋化因子及其受体的活性刺激肿瘤生长的第三条途径。此外，假设趋化因子受体(CXC受体7或CXCR7)通过与EGF受体EGFR偶联来调节前列腺癌细胞的生长，这是一种潜在的配体无关的机制。解开CXCR7-EGFR相互作用导致肿瘤细胞生长、侵袭和转移的机制是提出的工作的主要目标。为了实现既定的目标，提出了三个具体目标。具体目的1是确定CXCR7和EGFR相互作用导致非恶性和/或恶性前列腺细胞有丝分裂激活的分子机制。这项工作是基于这样的假设，即CXCR7的过度表达通过与质膜上的EGFR发生结构性的物理相互作用，进而激活EGFR介导的有丝分裂信号，从而导致正常和恶性细胞的生长增加。这一假说将通过分析CXCR7和EGFR的相互作用结构域，使用体外定点突变、化学交联、共免疫沉淀、共聚焦显微镜和时间分辨荧光显微镜来验证。特异性目的2是确定CXCR7在肿瘤细胞运动、侵袭和增强CRPC细胞血管生成能力中的作用，并确定CXCR7与EGFR的相互作用是否需要其中一个或多个功能；特异性目的3是研究CXCR7在CRPC骨转移中的作用，以及通过位点特异性磷酸化和有丝分裂信号结构域的小分子抑制物抑制CXCR7在局部和转移生长中的治疗潜力。预计这项拟议的研究将能够从机制上了解趋化因子受体通过CXCR7和EGFR之间的异型相互作用控制前列腺癌的生长，并提出潜在的治疗途径来破坏这一促肿瘤联系。

DESCRIPTION (provided by applicant): Abstract: Prostate cancer is the major cause of cancer-related morbidity and mortality in United States Veterans; it ranks above that found among general population. Although, prostate cancer can be effectively managed if diagnosed early when the disease is confined to prostate, effective cure is limited in advanced disease when the cancer has spread to extra-prostatic tissues. Current research has shown two main pathways of prostate growth that are deregulated in cancer, the one is androgen-androgen receptor regulated growth and the other peptide hormones, such as Epidermal Growth Factor (EGF) and Insulin-like growth factor-1, stimulated prostate tumor growth and survival. However, in this proposal it is proposed that there is a third pathway of tumor growth stimulated by the activities of cytokines and chemokines and their receptors. Further, it is hypothesized that a Chemokine receptor (CXC Receptor 7 or CXCR7) regulates prostate tumor cell growth by coupling with the EGF Receptor, EGFR in a potentially ligand-independent mechanism. Unraveling the mechanism of CXCR7- EGFR interaction that leads to tumor cell growth, invasion and metastasis is the main objective of proposed work. Three specific aims are proposed to achieve stated objective. Specific Aim 1 is to determine the molecular mechanism of CXCR7 and EGFR interaction that leads to mitogenic activation of non-malignant and/or malignant prostate cells. The proposed work is based on the hypothesis that that over-expression of CXCR7 leads to increase in cell growth in normal and malignant cells via constitutive physical interaction with EGFR in plasma membrane and subsequent activation of EGFR-mediated mitogenic signaling. The hypothesis will be tested, by analyzing the interacting domains of CXCR7 and EGFR, using in vitro site-directed mutagenesis, chemical-cross linking, co-immunoprecipitation, confocal microscopy and time- resolved fluorescence microscopy. Specific Aim 2 is to determine the role of CXCR7 in tumor cell motility, invasion and enhancement of angiogenic potential of CRPC cells and determine whether its interaction with EGFR is needed for one or more of this function, and Specific Aim 3 is to investigate the role of CXCR7 in CRPC bone metastasis and the therapeutic potential of inhibiting CXCR7 in local and metastatic growth using small molecule-inhibitors of site-specific phosphorylation and mitogenic signaling domains. It is anticipated that the proposed research will be able to provide mechanistic understanding of the Chemokine receptor controlled prostate cancer growth by heterotypic interaction between CXCR7 and EGFR and suggest potential therapeutic avenue to compromise this pro-tumorigenic nexus.