MIC-1 and its functional partners in prostate cancer racial disparity

 描述(申请人提供)：前列腺癌(PCa)是美国男性最常见的非皮肤恶性肿瘤，是导致男性癌症死亡的第二大原因。在这方面，流行病学数据也提供了种族差异的证据，包括年龄较小、确诊时前列腺癌的发病率和侵袭性较高，以及美国非裔美国人(AA)的存活率低于高加索患者。对这些差异的解释仍然是未知的。另一方面，我们最近的结果结合先前的研究表明，与高加索人相比，再生障碍性贫血患者MIC-1及其功能伙伴EGFR和CXCR4的频率更高。重要的是，最近的报道显示，EGFR和CXCR4介导了PCa细胞对多西紫杉醇的耐药性。因此，这一建议的中心假设是，MIC-1信号通路的上调可能与EGFR和CXCR4致癌途径协同作用，获得更具侵袭性的行为、生存和治疗耐药，并导致再生障碍性贫血和高加索患者之间的种族差异。总体目标是建立由MIC-1/转化生长因子受体(TGFR)调节的信号元件，以及它们与EGFR和CXCR4在前列腺癌发生和骨转移过程中肿瘤和肿瘤相关间质细胞中级联反应的功能交互作用，这是导致AA和白人患者种族差异的原因。还将使用AA和高加索男性的PCA细胞模型和人PCA组织来研究靶向MIC-1级联及其功能伙伴逆转PC细胞化疗耐药性的治疗益处。为了验证这一假设，我们提出了三个具体目标。目的通过免疫组织化学分析MIC-1、EGFR和CXCR4在一大批良恶性组织和DNA芯片上的表达，以及与再生障碍性贫血和高加索男性相关的PC细胞系，以确定MIC-1、EGFR和CXCR4在种族差异中的作用。目的利用再生障碍性贫血和高加索人前列腺癌患者的体外PCa细胞模型，研究MIC-1的分子机制及其与EGFR和CXCR4信号通路的相互作用，探讨MIC-1与EGFR和CXCR4级联反应参与细胞生长、侵袭和代谢途径改变的分子机制。目的利用体外和体内PCa细胞模型，确定靶向MIC-1级联疗法对提高多西紫杉醇抗癌作用的疗效。最后，我们还展示了与多西紫杉醇耐药相关的分子机制，以及与AA和高加索患者相关的PCa细胞中MIC-1的关系。综上所述，这些研究将描绘MIC-1与其相互作用的伙伴EGFR和CXCR4之间的功能相互作用，以及它们在疾病侵袭性和治疗抵抗中的潜在作用，以更好地了解它们参与再生障碍性贫血和高加索患者之间的种族差异。这项应用的总体结果将揭示联合使用MIC-1、EGFR和CXCR4作为分子生物标志物对AA和高加索患者的早期准确诊断、治疗反应和对治疗干预的影响的临床兴趣。

 DESCRIPTION (provided by applicant): Prostate cancer (PCa) is the most common non-cutaneous malignancy in the United States males and is the second leading cause of cancer deaths in men. In this regard, epidemiologic data have also provided evidence of racial disparity, including younger age, higher incidence and aggressiveness of PCa at diagnosis and inferior survival rates of African Americans (AA) relative to Caucasian patients in the Unites States. The explanation for these differences is still unknown. On the other hand, our recent results combined with prior studies have revealed that MIC-1 and its functional partners EGFR and CXCR4 were more frequent in AA compared to Caucasian PCa patients. Importantly, recent reports have revealed that EGFR and CXCR4 mediate Docetaxel resistance in PCa cells. Therefore, the central hypothesis of this proposal is that the up- regulation of MIC-1 signaling cascade may cooperate with EGFR and CXCR4 oncogenic pathways for the acquisition of a more aggressive behavior, survival and therapeutic resistance of PCa cells and contribute to the racial disparity between AA versus Caucasian patients. The overall objective is to establish the signaling elements modulated by MIC-1/transforming growth factor-ß receptors (TGF-ßRs) and their functional cross- talks with EGFR and CXCR4 cascades in tumor and tumor-associated stromal cells during prostate carcinogenesis and bone metastases that contribute to the ethnic disparity in AA vs. Caucasian patients. The therapeutic benefit to targeting MIC-1 cascade and its functional partners for reversing the chemoresistance of PC cells will also be investigated using PCa cell models and human PCa tissues from AA and Caucasian men. To test this hypothesis, three specific aims were proposed. Aim I will establish the involvement of MIC-1, EGFR and CXCR4 in racial disparity by performing immunohistochemical analyses of their expression on a large panel of benign and malignant tissues and DNA microarrays with PC cell lines relevant to AA and Caucasian men. Aim II will delineate molecular mechanisms of MIC-1 and its signaling cross-talks with EGFR and CXCR4 cascades involved in the growth, invasion and alterations of metabolic pathways using in vitro PCa cell models relevant to AA and Caucasian PCa patients. Aim III will determine the therapeutic benefit to target MIC-1 cascade for improving the anti-carcinogenic effects of docetaxel using in vitro and in vivo PCa cell models. Finally, we also demonstrate the molecular mechanism associated with Docetaxel resistance and its relationship with MIC-1 in PCa cells relevant to AA and Caucasian patients. Taken together, these studies will delineate the functional interplay between MIC-1 and its interacting partners EGFR and CXCR4 and their potential role in disease aggressiveness and therapy resistance to better understand their involvement in the racial disparity between AA and Caucasian patients. The overall outcome of this application will reveal the clinical interest to use combination of MIC-1, EGFR and CXCR4 as molecular biomarkers for an earlier and accurate diagnosis, response to therapy and impact on therapeutic intervention of AA and Caucasian patients.