Role of chemokine receptor in disparities associated with prostate cancer progres

描述（由申请人提供）：非洲裔美国人（AA）男性的前列腺癌（PCa）发病率高于欧洲裔美国人（EA）。此外，AA男性中的PCa的特征在于预后不良和令人沮丧的治疗结果。然而，与这种健康差异相关的机制仍不清楚。因此，为了开发有效的治疗和管理方法，非常需要鉴定这种差异背后的分子机制。趋化因子-配体轴在肿瘤细胞运输和器官特异性转移的发展中起关键作用，这是PCa相关死亡的主要原因。我们的实验室是第一个表明CC趋化因子受体9（CCR 9）在前列腺癌中选择性过表达，而在正常前列腺上皮中的表达可忽略不计。我们令人兴奋的初步数据显示，与源自EA的细胞系和临床样品相比，CCR 9在AA PCa细胞系和临床样品中的表达显著更高。此外，与EA细胞系（C4-2b）相比，血清CCL 25（其是CCR 9的天然配体）在AA和来自AA的PCa细胞系（MDA-PCa-2b）中更高，并且显示出更高的侵袭和迁移潜力以及对体外化疗剂的更低响应。基于这些令人鼓舞的数据，我们假设CCR 9-CCL 25轴是患有PCa的AA男性的不良预后和治疗结果的基础。为了验证我们的假设，我们建议研究CCR 9-CCL 25介导的机制与（i）AA样品中的侵袭性细胞表型，（ii）骨中的归巢和肿瘤生长以及该趋化因子-受体轴在改善AA患者临床方案的化疗疗效中的潜在作用。我们进一步的目标是建立CCR 9作为PCa进展和侵袭性疾病的生物标志物。为了实现我们的目标，我们已经产生了针对CCR 9和CCL 25的CCR 9抗体，其将用于在体外测定期间阻断该轴以确定其在迁移、侵袭、存活和化学抗性中的作用;确定其在转移中的潜在作用以及使用AA和EA细胞系确定多西他赛的体内治疗功效。此外，针对CCR 9驱动的信号分子的siRNA双链体或特异性药理学抑制剂将用于剖析涉及迁移、侵袭、存活和化学抗性的CCR 9介导的机制。我们乐观地认为，这些研究的成功完成将确定这种新发现的趋化因子在PCa健康差异中的作用。此外，它将使针对CCR 9-CCL 25的合理疗法的设计和开发成为可能，以减少/消除治疗结果的差异。

DESCRIPTION (provided by applicant): African-American (AA) men have higher incidence of prostate cancer (PCa) than European American (EA). Furthermore, PCa in AA men is characterized by poor prognosis and dismal therapeutic outcomes. However, the mechanism/s associated with this health disparity remain unclear. Thus, identification of molecular mechanisms underlying such disparity is greatly desired in order to develop effective therapeutic and management approaches. It is becoming well appreciated that the chemokine-ligand axis is crucially involved in tumor cell trafficking and the development of organ-specific metastases, which is the major cause of PCa associated deaths. Our laboratory is the first to show that CC chemokine receptor 9 (CCR9) is selectively overexpressed in prostate cancers with negligible expression in normal prostate epithelia. Our exciting preliminary data show significantly higher expression of CCR9 in AA PCa cell lines and clinical samples compared to cell lines and clinical samples derived from EA. Furthermore, serum CCL25, which is natural ligand for CCR9 was higher in AA and PCa cell lines from AA (MDA-PCa-2b) and showed higher invasive and migratory potential as well as less response to chemotherapeutics in vitro compared to EA cell lines (C4-2b). Based upon these encouraging data, we hypothesize that CCR9-CCL25 axis underlies the poor prognosis and therapeutic outcome in AA men with PCa. To test our hypothesis, we propose to investigate the CCR9- CCL25 mediated mechanism associated with (i) aggressive cell phenotype in AA samples, (ii) homing and tumor growth in bone and the potential role of this chemokine-receptor axis in improving chemotherapeutic efficacy of clinical regimens in AA patients. We further aim to establish CCR9 as a biomarker for PCa progression and aggressive disease. To accomplish our aims, we have generated CCR9 anti-body against CCR9 and CCL25, which will be used to block this axis during in vitro assays to determine its role in migration, invasion, survival and chemoresistance; determining its potential role in metastasis as well as determining therapeutic efficacy of Docetaxel in vivo using AA and EA cell lines. In addition, siRNA duplexes or specific pharmacological inhibitors against CCR9 driven signaling molecules will be used to dissect the CCR9 mediated mechanism involved in migration, invasion, survival and chemoresistance. We are optimistic that the successful completion of these studies will define the role of this newly identified chemokine in PCa health disparity. Furthermore, it will enable the design and development of rational therapies directed against the CCR9-CCL25 to reduce/eliminate disparity in therapeutic outcomes.