(PQ3) AGEs and Race Specific Tumor Immune Response in Prostate Cancer

 描述(由申请人提供)：前列腺癌患者的年龄和种族特异性肿瘤免疫反应非裔美国人(AA)前列腺癌患者比美国任何其他种族或民族更有可能死于他们的疾病。在南卡罗来纳州(SC)，AA男性的年龄调整后前列腺癌发病率比EA男性高78%，死亡率是EA男性的三倍。虽然护理质量问题和社会经济地位显然是癌症健康差异的原因，但越来越明显的是，肿瘤生物学中的分子和遗传差异也发挥着关键作用。糖基化是糖与蛋白质、脂类和DNA的非酶糖基化反应，导致产生称为晚期糖基化终末产物(AGE‘s)的反应性代谢物。随着我们年龄的增长，AGE在我们的组织中积累，从而促进与年龄增长相关的疾病，如糖尿病和心血管疾病。糖化作用发生在正常新陈代谢过程中，但与癌症差异相关的因素，如不良饮食和缺乏锻炼，显着增加了AGE在我们体内的积累。这项研究将进行机制研究，以调查年龄积累作为已知的导致前列腺癌差异的因素的生物学后果。我们最近的研究引出了我们的假设：在前列腺癌中，特定种族的年龄升高会改变肿瘤相关的免疫反应。AGEs是大多数免疫细胞表面表达的RAGE的配体激活剂。AGE对RAGE的刺激可诱导NFkB、STAT3和HIF1a(4-6)等多种致炎因子的转录激活。这种激活导致免疫相关细胞因子如IL1、IL6和TNFa的表达，这些细胞因子对于调节癌细胞和间质之间的串扰至关重要。目标1将使用原代和永生化的种族特异性细胞系模型来定义AGEs对免疫反应的机制影响。目的2将使用喂养高年龄和低年龄饮食的小鼠模型来确定饮食年龄对体内免疫反应和前列腺癌生长的贡献。这一概念表明，年龄代谢物可能代表癌症差异的生物学后果，这是一种解释特定人群中观察到的发病率和死亡率增加的新方法。糖基化和免疫反应改变之间的机制联系也没有被研究过，特别是在特定的种族背景或前列腺癌微环境的背景下。通过确定癌症健康差异的分子后果，这项研究可能有助于降低少数族裔人群的癌症发病率和死亡率，并确定新的潜在生物标志物，并定义一个新的治疗潜力领域。

 DESCRIPTION (provided by applicant): AGEs and Race Specific Tumor Immune Response in Prostate Cancer African American (AA) prostate cancer patients are more likely to die of their disease than any other race or ethnic group in the US. Here in South Carolina (SC), age-adjusted prostate cancer incidence rates are 78% higher among AA men than EA men and mortality rates three times higher. While quality of care issues and socioeconomic status clearly contribute to cancer health disparities it is becoming increasing clear that molecular and genetic differences in tumor biology also play a critical role. Glycation is the non-enzymatic glycosylatio of sugars with proteins, lipids and DNA that lead to the production of reactive metabolites called advanced glycation end products (AGE's). AGEs accumulate in our tissues as we age to promote diseases associated with growing older such as diabetes and cardiovascular disease. Glycation occurs during normal metabolism but factors associated with cancer disparity such as poor diet and a lack of exercise significantly increase the accumulation of AGEs in our bodies. This study will conduct mechanistic research to investigate AGE accumulation as a biological consequence of the factors known to contribute to prostate cancer disparity. Our recent studies have led to our hypothesis that: "Race specific elevations in AGEs alter tumor associated immune responses in prostate cancer". AGEs function as a ligand activator for RAGE which is expressed on the surface of most immune cells. RAGE stimulation by AGE induces the transcriptional activation of a number of factors critical for the generation of an inflammatory environment including NFkB, STAT3 and HIF1a (4-6). Such activation results in the expression of immune associated cytokines such as IL1, IL6 and TNFa which are critical for mediating crosstalk between cancer cells and the stroma. Aim 1 will use primary and immortalized race specific cell line models to define the mechanistic implications of AGEs to the immune response. Aim 2 will use mouse models fed high and low AGE diets to determine the contribution of dietary AGEs to immune response and prostate cancer growth in vivo. The concept suggesting that AGE metabolites may represent a biological consequence of cancer disparity is a novel approach to explaining the increased incidence and mortality figures observed within specific populations. Associating the mechanistic links between glycation and altered immune response has also not been examined especially within the context of a race specific background or the prostate tumor microenvironment. By identifying a molecular consequence of cancer health disparity this study may contribute to reducing the cancer incidence and mortality rates among minority populations and identify novel potential biomarkers and define a novel area of therapeutic potential.