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;它高于一般人群。虽然，如果在疾病局限于前列腺时早期诊断，前列腺癌可以得到有效的管理，但当癌症扩散到前列腺外组织时，有效的治疗在晚期疾病中受到限制。目前的研究表明，前列腺生长的两个主要途径在癌症中失调，一个是雄激素-雄激素受体调节的生长，另一个是肽激素，如表皮生长因子（EGF）和胰岛素样生长因子-1，刺激前列腺肿瘤的生长和存活。然而，在该提议中，提出存在由细胞因子和趋化因子及其受体的活性刺激的肿瘤生长的第三途径。此外，假设趋化因子受体（CXC受体7或CXCR 7）通过以潜在的配体非依赖性机制与EGF受体EGFR偶联来调节前列腺肿瘤细胞生长。揭示CXCR 7- EGFR相互作用导致肿瘤细胞生长、侵袭和转移的机制是所提出工作的主要目标。为实现上述目标，提出了三个具体目标。具体目标1是确定CXCR 7和EGFR相互作用的分子机制，其导致非恶性和/或恶性前列腺细胞的促有丝分裂活化。所提出的工作是基于这样的假设，即CXCR 7的过表达通过与质膜中的EGFR的组成性物理相互作用以及随后EGFR介导的促有丝分裂信号传导的激活而导致正常和恶性细胞中的细胞生长增加。将通过使用体外定点诱变、化学交联、免疫共沉淀、共聚焦显微镜和时间分辨荧光显微镜分析CXCR 7和EGFR的相互作用结构域来检验该假设。具体目的2是确定CXCR 7在肿瘤细胞运动、侵袭和CRPC细胞的血管生成潜力增强中的作用，并确定其与EGFR的相互作用是否是一种或多种该功能所需的，具体目的3是研究CXCR 7在CRPC骨转移中的作用，以及使用小分子位点抑制剂抑制CXCR 7在局部和转移生长中的治疗潜力。特异性磷酸化和促有丝分裂信号结构域。预计拟议的研究将能够通过CXCR 7和EGFR之间的异型相互作用提供对趋化因子受体控制前列腺癌生长的机制理解，并提出潜在的治疗途径来损害这种促肿瘤发生关系。 公共卫生相关性： 前列腺癌是老年人的疾病，60岁以上的男性中约有六分之一受到影响，50%的男性处于亚临床水平。美国退伍军人前列腺癌的患病率是所有其他群体中最高的。患有前列腺癌的退伍军人的治疗与提供给普通人群的治疗没有什么不同。目前的建议旨在确定新的治疗靶点，一种称为CXCR 7的多趋化因子受体，在晚期前列腺癌中表达，并通过激素治疗特异性升高。由于面临复发性前列腺癌的患者通常用激素疗法（雄激素剥夺）治疗，因此CXCR 7水平在此类患者中可能上调，因此，此类患者可能通过抑制CXCR 7而受益。所提出的实验测试CXCR 7抑制剂的功效。这项研究的一个可能的结果是出现新的药物激素难治性前列腺癌。因此，目前的建议是高度相关的退伍军人使命，确定有效的治疗前列腺癌，影响了大量的退伍军人人口。

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. PUBLIC HEALTH RELEVANCE: Prostate cancer is the disease of the elderly, affecting about 1 in 6 men over the age of 60, and 50% of all men at sub-clinical level. The prevalence of prostate cancer in American Veterans is the highest among all other groups. The treatment of veterans with prostate cancer is not different from that offered to general population. The present proposal seeks to identify novel therapeutic target, a multi-chemokine receptor called CXCR7, expressed in advanced prostate cancers, and specifically elevated by hormone therapy. Since patients who face the recurrent prostate cancer are commonly treated with hormone therapy (androgen deprivation) CXCR7 level may be up- regulated in such patients, therefore, such patients are likely to benefit by suppressing CXCR7. The experiments proposed tests the efficacy of inhibitors of CXCR7. A possible outcome of this research is the emergence of new drug for hormone refractory prostate cancer. Therefore, the present proposal is highly relevant to VA mission of identifying effective treatment for prostate cancer that affects a large veteran population.