Role of chemokine receptor in disparities associated with prostate cancer progres

描述(申请人提供)：非裔美国人(AA)男性前列腺癌(PCA)的发病率高于欧洲裔美国人(EA)。再者，再生障碍性贫血患者的前列腺癌具有预后差、治疗效果差的特点。然而，与这种健康差距相关的机制/S仍不清楚。因此，为了开发有效的治疗和管理方法，迫切需要确定这种差异背后的分子机制。人们越来越认识到，趋化因子-配体轴在肿瘤细胞的转移和器官特异性转移的发展中起着至关重要的作用，而器官特异性转移是导致前列腺癌相关死亡的主要原因。本实验室首次发现CC趋化因子受体9(CCR9)在前列腺癌中选择性过度表达，而在正常前列腺上皮细胞中几乎不表达。我们令人兴奋的初步数据显示，CCR9在AA-PCa细胞系和临床样本中的表达显著高于来自EA的细胞系和临床样本。此外，作为CCR9天然配体的血清CCL25在AA和PCA细胞系(MDA-PCA-2b)中更高，并且在体外显示出更高的侵袭和迁移能力以及与EA细胞系(C4-2b)相比对化疗药物的反应性较低。基于这些令人鼓舞的数据，我们假设CCR9-CCL25轴是AA男性前列腺癌患者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CCR9-CCL25介导的与(I)AA样本中的侵袭性细胞表型，(Ii)归巢和骨中的肿瘤生长相关的机制，以及这种趋化因子-受体轴在改善AA患者临床方案的化疗效果方面的潜在作用。我们的进一步目标是建立CCR9作为PCa进展和侵袭性疾病的生物标记物。为了实现我们的目标，我们制备了针对CCR9和CCL25的CCR9抗体，将用于在体外检测中阻断这一轴，以确定其在迁移、侵袭、生存和化疗耐药中的作用；确定其在转移中的潜在作用；以及使用AA和EA细胞株在体内确定多西紫杉醇的治疗效果。此外，还将使用针对CCR9驱动的信号分子的siRNA双链或特异性药物抑制剂来剖析CCR9介导的参与迁移、侵袭、生存和化疗耐药的机制。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前列腺癌健康差异中的作用。此外，它还将使针对CCR9-CCL25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.