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

 描述（由申请人提供）：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，诊断时PCa的发病率和侵袭性较高，以及非洲裔美国人（AA）相对于美国白人患者的生存率较低。对这些差异的解释仍然是未知的。另一方面，我们最近的研究结果与先前的研究相结合，揭示了MIC-1及其功能伴侣EGFR和CXCR 4在AA中比白人PCa患者更常见。重要的是，最近的报道已经揭示EGFR和CXCR 4介导PCa细胞中的多西他赛抗性。因此，该提议的中心假设是MIC-1信号级联的上调可能与EGFR和CXCR 4致癌途径合作，以获得PCa细胞的更具侵袭性的行为、存活和治疗抗性，并导致AA与高加索人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-β受体（TGF-β R）调节的信号传导元件及其在前列腺癌发生和骨转移过程中与肿瘤和肿瘤相关基质细胞中的EGFR和CXCR 4级联的功能性交叉对话，其导致AA与高加索患者的种族差异。还将使用来自AA和高加索男性的PCa细胞模型和人PCa组织研究靶向MIC-1级联及其功能伴侣逆转PC细胞的化学抗性的治疗益处。为了验证这一假设，提出了三个具体目标。目的通过免疫组化分析MIC-1、EGFR和CXCR 4在一组良性和恶性组织中的表达，以及与AA和高加索人相关的PC细胞系的DNA微阵列，确定MIC-1、EGFR和CXCR 4在种族差异中的作用。目的II将描述MIC-1的分子机制及其与EGFR和CXCR 4级联信号的交叉会谈参与的生长，侵袭和代谢途径的改变使用体外PCa细胞模型相关的AA和高加索人PCa患者。目的III将使用体外和体内PCa细胞模型确定靶向MIC-1级联的治疗益处，以改善多西他赛的抗癌作用。最后，我们还展示了与多西他赛耐药相关的分子机制及其与AA和高加索患者相关的PCa细胞中MIC-1的关系。总之，这些研究将描述MIC-1及其相互作用伙伴EGFR和CXCR 4之间的功能相互作用，以及它们在疾病侵袭性和治疗耐药性中的潜在作用，以更好地了解它们在AA和白人患者之间的种族差异中的作用。本申请的总体结果将揭示使用MIC-1、EGFR和CXCR 4的组合作为分子生物标志物用于AA和高加索患者的早期和准确诊断、对治疗的反应和对治疗干预的影响的临床意义。

 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.