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

(PQ3) 前列腺癌中的 AGE 和种族特异性肿瘤免疫反应

• 批准号: 8876216
• 负责人: David Paul Turner
• 金额: $ 14.04万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-06 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8876216
• 关键词: Advanced Glycosylation End Products; African American; Age; American; Area; Automobile Driving; Biological; Biological Markers; Cancer Patient; Carbohydrates; Cardiovascular Diseases; Cell Line; Cells; Cessation of life; Chronic; Community Outreach; Cultured Tumor Cells; DNA; Development; Diabetes Mellitus; Diet; Disease; Education and Outreach; Environment; Environmental Risk Factor; Epithelial; Ethnic group; European; Exercise; Failure; Figs - dietary; Gene Expression; Generations; Goals; Growth; HIF1A gene; Health; Human; IL6 gene; Immune; Immune response; Incidence; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Lead; Life Style; Ligands; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Membrane; Metabolism; Minority; Modeling; Molecular; Molecular Genetics; Molecular Profiling; Neurodegenerative Disorders; Not Hispanic or Latino; Nutritional; Obesity; Organ; Outcome; Pathway interactions; Patients; Pattern; Play; Population; Production; Prostatic Neoplasms; Proteins; Quality of Care; Race; Research; Role; STAT3 gene; Signal Transduction; Socioeconomic Factors; Socioeconomic Status; South Carolina; Stromal Cells; Surface; Therapeutic; Time; Tissues; Transcriptional Activation; Tumor Biology; Tumor Necrosis Factor-alpha; Variant; Work; age group; base; cancer cell; cancer health disparity; cancer prevention; cancer risk; cell stroma; cytokine; defined contribution; disease phenotype; feeding; glycation; glycosylation; health disparity; immune activation; in vivo; men; molecular phenotype; mortality; mouse model; novel; novel strategies; overexpression; prostate cancer cell; prostate cancer cell line; public health relevance; racial and ethnic; response; sedentary lifestyle; sugar; transcription factor; tumor; tumor growth; tumor initiation; tumor microenvironment

 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.

 描述（由申请方提供）：前列腺癌中的AGEs和种族特异性肿瘤免疫应答非裔美国人（AA）前列腺癌患者比美国任何其他种族或族裔群体更有可能死于其疾病。在南卡罗来纳州，AA男性的年龄调整前列腺癌发病率比EA男性高78%，死亡率高3倍。虽然护理质量问题和社会经济地位明显导致癌症健康差异，但越来越清楚的是，肿瘤生物学中的分子和遗传差异也起着关键作用。糖基化是糖与蛋白质、脂质和DNA的非酶促糖基化，其导致称为晚期糖基化终产物（AGE）的反应性代谢物的产生。随着年龄的增长，AGEs在我们的组织中积累，促进与年龄增长相关的疾病，如糖尿病和心血管疾病。糖基化发生在正常代谢过程中，但与癌症差异相关的因素，例如不良饮食和缺乏运动，会显着增加AGEs在我们体内的积累。本研究将进行机制研究，以调查AGE积累作为已知导致前列腺癌差异的因素的生物学后果。我们最近的研究导致了我们的假设：“AGEs的种族特异性升高改变了前列腺癌中的肿瘤相关免疫反应”。AGEs作为一种配体激活剂，在大多数免疫细胞的表面表达。AGE的刺激可诱导许多对炎症环境产生至关重要的因子的转录激活，包括NF κ B、STAT 3和HIF 1a（4-6）。这种激活导致免疫相关细胞因子（例如IL 1、IL 6和TNFa）的表达，这些细胞因子对于介导癌细胞和基质之间的串扰至关重要。目的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对免疫应答的机制影响。目的2将使用喂食高和低AGE饮食的小鼠模型来确定饮食AGE对体内免疫应答和前列腺癌生长的贡献。AGE代谢物可能代表癌症差异的生物学后果的概念是解释特定人群中观察到的发病率和死亡率增加的新方法。糖化和免疫应答改变之间的机制联系也没有得到研究，特别是在种族特异性背景或前列腺肿瘤微环境的背景下。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，并确定一个新的治疗潜力领域。