Role of chemokine Receptor CXCR7 in prostate cancer progression

趋化因子受体 CXCR7 在前列腺癌进展中的作用

• 批准号: 8246659
• 负责人: Bal L Lokeshwar
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8246659
• 关键词: Affect; Age; American; Androgen Receptor; Androgens; Animal Model; Binding; Bone Growth; CXCL12 gene; CXCR4 gene; Cancer Control; Cancer Etiology; Cardiac; Castration; Cell Proliferation; Cell membrane; Cells; Chemicals; Chronic; Clinical; Co-Immunoprecipitations; Confocal Microscopy; Coupling; DNA biosynthesis; Data; Development; Disease; Disease-Free Survival; Early Diagnosis; Elderly; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Face; Fluorescence Microscopy; Funding; Gap Junctions; Gefitinib; General Population; Genes; Goals; Growth; Growth Factor Receptors; Habits; Immunoblotting; In Vitro; Incidence; Indolent; Infection; Inflammatory; Injection of therapeutic agent; Insulin-Like Growth Factor I; Integral Membrane Protein; Interleukin 8A Receptor; Interleukin-8; Knock-out; Life Style; Ligands; Link; Localized Disease; Luciferases; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metastatic Neoplasm to the Bone; Mission; Modification; Molecular; Morbidity - disease rate; Mutagenesis; Neoplasm Metastasis; Non-Malignant; Normal Cell; Nude Mice; Outcomes Research; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Population; Prevalence; Prostate; Prostatic Neoplasms; Prostatic Tissue; Protein Binding; Publications; Quality of life; Receptor Activation; Recurrence; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Role; Seminal; Signal Transduction; Site; Site-Directed Mutagenesis; Staging; Testing; Therapeutic; Time; Treatment Failure; United States; Up-Regulation; Veterans; Work; Wound Healing; abstracting; advanced disease; angiogenesis; base; bone; cancer cell; cell growth; cell motility; chemokine; chemokine receptor; crosslink; cytokine; deprivation; effective therapy; efficacy testing; hormone refractory prostate cancer; hormone therapy; inhibitor/antagonist; insight; killings; men; mortality; neoplastic cell; new therapeutic target; novel; overexpression; peptide hormone; receptor; receptor coupling; receptor function; research study; small molecule; tumor; tumor growth; tumor progression; tumorigenic

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.

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。它的排名高于一般人群。虽然前列腺癌如果在疾病仅限于前列腺时早期诊断，可以得到有效的治疗，但在癌症已扩散到前列腺外组织的晚期疾病中，有效的治愈是有限的。目前的研究表明，前列腺生长的两种主要途径在癌症中失调，一种是雄激素-雄激素受体调节的生长，另一种肽激素，如表皮生长因子 (EGF) 和胰岛素样生长因子-1，刺激前列腺肿瘤生长和存活。然而，在该提案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第三种肿瘤生长途径。此外，据推测，趋化因子受体（CXC 受体 7 或 CXCR7）通过与 EGF 受体 EGFR 以潜在的配体独立机制偶联来调节前列腺肿瘤细胞的生长。阐明CXCR7-EGFR相互作用导致肿瘤细胞生长、侵袭和转移的机制是本研究的主要目标。为了实现既定目标，提出了三个具体目标。具体目标 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。所提出的工作基于这样的假设：CXCR7 的过度表达通过与质膜中 EGFR 的组成性物理相互作用以及随后激活 EGFR 介导的有丝分裂信号传导，导致正常和恶性细胞的细胞生长增加。该假设将通过分析 CXCR7 和 EGFR 的相互作用结构域、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进行检验。具体目标 2 是确定 CXCR7 在肿瘤细胞运动、侵袭和 CRPC 细胞血管生成潜力增强中的作用，并确定该功能中的一项或多项是否需要其与 EGFR 的相互作用，具体目标 3 是研究其作用CXCR7 在 CRPC 骨转移中的作用以及使用位点特异性磷酸化和有丝分裂信号传导域的小分子抑制剂抑制 CXCR7 在局部和转移生长中的治疗潜力。预计拟议的研究将能够通过 CXCR7 和 EGFR 之间的异型相互作用提供对趋化因子受体控制的前列腺癌生长的机制理解，并提出损害这种促肿瘤发生关系的潜在治疗途径。 公共卫生相关性： 前列腺癌是老年人的疾病，约六分之一的60岁以上男性患有前列腺癌，占所有男性的50%处于亚临床水平。美国退伍军人中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普通人群的治疗没有什么不同。本提案旨在确定新的治疗靶点，一种称为 CXCR7 的多趋化因子受体，该受体在晚期前列腺癌中表达，并通过激素治疗特别升高。由于面临复发性前列腺癌的患者通常接受激素治疗（雄激素剥夺），因此此类患者中CXCR7水平可能上调，因此，此类患者可能通过抑制CXCR7而受益。建议的实验测试 CXCR7 抑制剂的功效。这项研究的一个可能结果是出现了治疗激素难治性前列腺癌的新药。因此，本提案与 VA 的使命高度相关，即确定影响大量退伍军人的前列腺癌的有效治疗方法。