Racial disparity of MIC-1 gene in prostate tumor biology

描述（由申请人提供）：癌症健康差异是美国主要的公共卫生问题。即使考虑到社会经济因素，少数民族人口的总体发病率也高于总体人口，结果也更差。前列腺癌是非洲裔美国人（AA）发病率和死亡率高于白种人的疾病之一。虽然社会经济因素可能在一定程度上受到指责，但人们认识到，肿瘤生物学的差异使AA男性更容易患侵袭性前列腺癌。因此，了解前列腺癌生物学变异的影响对于减少AA男性和白种人之间观察到的癌症结局差距至关重要。我们的目标是确定巨噬细胞抑制细胞因子（MIC-1）作为一种生物学因子在前列腺肿瘤生物学中发挥关键作用，导致癌症健康差异。由于MIC-1与前列腺癌的发生和进展的相关性增加，血清MIC-1水平的升高与骨转移的存在相关，因此引起了极大的关注。我们实验室的初步数据清楚地表明，AA男性前列腺癌患者血清MIC-1明显高于白种人。我们假设非裔美国男性前列腺肿瘤微环境中MIC-1水平的升高导致前列腺癌健康差异的增加。迄今为止，尚未研究MIC-1在AA男性和白种人中区分侵袭性前列腺癌的作用。为了验证上述假设，我们的具体目的是：1)确定MIC-1在非裔美国男性和白种人前列腺癌健康差异中的临床意义；2)通过小鼠模型研究MIC-1在免疫监视中导致前列腺癌差异的机制。利用多学科研究团队的技能，我们将测量前列腺癌复发转移患者和新诊断前列腺癌患者的血清MIC-1水平。我们还将分析MIC-1在AA男性和高加索人前列腺肿瘤组织档案标本中的间质和上皮表达。我们将利用免疫功能小鼠模型分析浸润淋巴细胞的性质，从而确定MIC-1调节侵袭性前列腺癌的机制作用。显然，AA男性和患有前列腺癌的白种人的血清MIC-1水平不同。这将对确定MIC-1对前列腺癌健康差异的生物学作用产生重大影响，并随后将其转化为临床，通过改进的治疗方式减少患有前列腺癌的非洲裔美国男性的痛苦。

DESCRIPTION (provided by applicant): Cancer health disparities represent a major public health concern in the United States. Even when socioeconomic factors are accounted for, minority populations have higher overall incidence rates and worse outcomes than the overall population. Prostate cancer is one of such disease with higher incidence and death rate in African American (AA) men than Caucasians. Although socioeconomic factors may be blamed to a certain extent, it is being appreciated that the differences in tumor biology make AA men more prone to the aggressive prostate cancer. Therefore, understanding the impact of biological variability in prostate cancer is vital to reduce the observed cancer outcome gaps between AA men and Caucasians. Our goal is to determine the role of macrophage inhibitory cytokine (MIC-1) as a biological factor that play a critical role in prostate tumor biology leading to cancer heath disparities. MIC-1 has drawn significant attention due to its increased association with the development and progression of prostate cancer, and increasing serum MIC-1 levels correlates with the presence of bone metastasis. Preliminary data from our laboratory clearly demonstrate that serum MIC-1 in prostate cancer patients is significantly higher in AA men than Caucasians. We hypothesize that increased level of MIC-1 in prostate tumor microenvironment of African American men contributes to an increase in prostate cancer health disparity. To date the role of MIC-1 to differentiate the aggressive prostate cancer among AA men and Caucasians has not been investigated. To test the above hypothesis, our specific Aims are: 1) To determine the clinical significance of MIC-1 in prostate cancer health disparity among African American men and Caucasians; and 2) To determine the mechanism of MIC-1 in immune surveillance leading to prostate cancer disparity using mouse models. Using the skills of multidisciplinary team of investigators, we will measure serum MIC-1 levels in prostate cancer patients with recurrent metastasis, and newly diagnosed prostate cancer. We will also analyze the stromal and epithelial expression of MIC-1 in archival specimens of human prostate tumor tissues from AA men and Caucasians. We will determine the mechanistic role of MIC-1 regulating aggressive prostate cancer by analyzing the nature of infiltrating lymphocytes using immuno- competent mouse models. Clearly, the serum MIC-1 levels differ in AA men and Caucasians with prostate cancer. This will have a significant impact to establish the biological role of MIC-1 contributing o prostate cancer health disparity for its subsequent translation into clinics to reduce the sufferin of African American men with prostate cancer using improved therapeutic treatment modalities.