Cause and Effect Relationships Between Glycation and the Ancestry Specific Tumor Stroma

项目摘要/摘要 全基因组分析支持肿瘤间质是分子变化的主要部位 促进非洲裔美国男性患上致命的前列腺癌。然而，免费提供基本服务 显示出直接因果关系的研究还很缺乏。 当我们的身体使用糖时，我们消耗能量，它们会产生已知的废物化学物质 作为代谢物。一组这样的代谢物被称为晚期糖基化终产物或 简称年龄。我们的组织和器官中的年龄积累会导致它们的功能衰退和 加速衰老过程。年龄代表着健康差距中的内在生物因素 与影响非裔美国人前列腺癌的间质特征相一致的危险因素 男人。该研究小组此前已经证明，AGEs在血液循环和肿瘤中升高 前列腺癌患者中非洲血统的男性和 更具侵袭性的肿瘤。将饮食作为健康不平等的替代品，这是来自 本研究表明，饮食摄入AGEs可直接加速前列腺癌的生长。 饮食-年龄对肿瘤生长的影响依赖于基质 通过跨膜AGE受体(RAGE)传递信号。年龄-愤怒信号与 有一种激活的间质，类似于在患有前列腺癌的非裔美国人身上观察到的。 这是由癌症相关成纤维细胞(CAF)的增加和 基质相关基因的下调。 长期的目标是将祖先肿瘤生物学整合到 健康不平等构成了癌症差异结果的信息。研究假设是 年龄生物利用度的提高有助于患有前列腺癌的AA男性患者肿瘤的快速进展 癌症“。这项研究将使用前列腺癌细胞系和独特的小鼠肿瘤的组合 定义年龄和特定祖先之间的直接因果关系的模型 肿瘤相关间质中的串扰。它还将评估年龄的消费是否有 使用来自大型人类队列研究的数据与前列腺癌风险呈正相关。 通过建立在食物链中发现的对祖先的机械性后果年龄 特定的肿瘤生物学，确定了限制其在高危人群中积累的策略，例如 患有前列腺癌的非裔美国男性可能被视为癌症预防或治疗 与现有治疗方案相结合时的策略。

PROJECT SUMMARY/ABSTRACT Whole genome analyses support the tumor stroma as the main site of molecular change that promotes deadly prostate cancer in African American men. However, complimentary basic research studies showing a direct cause-and-effect relationship are lacking. As our bodies use the sugars, we consume for energy they generate waste chemicals known as metabolites. One such group of metabolites is known as advanced glycation end products or AGEs for short. AGE accumulation in our tissues and organs causes their functional decline and accelerates the aging process. AGEs represent intrinsic biological elements within health disparity risk factors that align with the stromal profiles that influence prostate cancer in African American men. This group has previously shown that AGEs are elevated in the circulation and tumors of prostate cancer patients with highest levels being observed in men with African ancestry and in more aggressive tumors. Using diet as a surrogate for health inequity, a key and novel finding from this research is that dietary consumption of AGEs can directly accelerate prostate tumor growth. Dietary-AGE mediated effects on tumor growth were shown to be dependent upon stromal signaling by the transmembrane receptor for AGE (RAGE). AGE-RAGE signaling was associated with an activated stroma similar to that observed in African American men with prostate cancer. This was defined by the increased presence of cancer associated fibroblasts (CAFs) and the downregulation of matrix associated genes. The long-term, objective is to integrate ancestral tumor biology into the multilevel framework of health inequity constructs to inform on cancer disparity outcomes. The study hypothesis is that “increased AGE bioavailability contributes to rapid tumor progression in AA men with PCa cancer”. The study will use a combination of prostate cancer cell lines and unique mouse tumor models to define a direct cause-and-effect relationship between AGEs and ancestry specific crosstalk in the tumor associated stroma. It will also assess if the consumption of AGEs has a positive correlation with prostate cancer risk using data from large human cohort studies. By establishing the mechanistic consequences AGEs found in the food chain on ancestry specific tumor biology, defined strategies to limit their accumulation in at risk populations, such as African American men with prostate cancer, may be viewed as cancer preventive or therapeutic strategies when combined with existing treatment regimens.