Defining an Integrated Allostatic Load Index with Immune and Tumor Microenvironment Factors

研究项目2--项目总结 MUSC TCC项目的目标是开发更精确的前列腺癌发生和发展的生物标志物。 进展，并在此背景下决定如何治疗和管理少数族裔男性的前列腺癌 不良结局的生物学风险以及社会、心理和生理风险(例如，不平衡负荷/AL) 压力源。这将使用几种新的创新实验方法直接在存档的组织上完成 MUSC独有的，使用丰富的样本资源队列(n=570)，约占非洲的三分之一 美国(AA)受试者。根据AA男性中前列腺癌的流行病学(已在 该提案)，已经做出了相当大的努力，通过筛查来促进早期发现 前列腺特异性抗原(PSA)检测。然而，最近，筛查指南已经从表现转向 从50岁开始的年度筛查到明智的决策，因为出现了关于 PSA检测的有效性。由于早期检测在前列腺癌控制中的作用不那么突出，它变成了 更重要的是要确定在肿瘤的发生和发展过程中被激活的生物通路 并开发更有效的生物标记物进行早期检测。之前的几项研究表明， 在肿瘤微环境和免疫系统之间存在复杂的相互作用，这有助于 AA男性患上更具侵袭性的前列腺癌。然而，生物过程 与免疫功能有关，在内部运作，并受社会背景因素的影响。因此，识别 生物学机制，而不了解它们与社会决定因素的联系方式 对于减少前列腺癌结果中的种族差异的长期努力是必要的，但还不够 通过疾病的早期发现和临床处理。一个对这一应用至关重要的新兴假说 关于癌症健康的差异是社会条件和对社会压力的心理反应 影响对癌症的发生和发展至关重要的生物过程。在这个项目中， 南加州大学的调查人员将通过一项跨学科的研究来检验这一假设，该研究定义了 前列腺癌发生发展机制的研究 免疫系统、肿瘤糖类、社会决定因素和AL之间的微环境相互作用。 这些研究人员将确定前列腺中不同的肿瘤和间质N-糖链的组合 AA男性的癌症促进了更有利于肿瘤的炎症/免疫微环境。他们还将 考察这些生物过程和包括隔离在内的社会决定因素之间的关系， 感知到的压力，以及慢性社会经济压力。他们假设压力的组合- 诱导社会决定因素，独特的N-糖链，免疫/炎症平衡受损导致更多 AA人群中的侵袭性前列腺癌。

RESEARCH PROJECT 2- PROJECT SUMMARY The goal of this MUSC TCC project is to develop more precise biomarkers of prostate cancer initiation and progression, and determine how to treat and manage prostate cancer among minority men within the context of their biological risk for poor outcomes and social, psychological, and physiological (i.e., allostatic load/AL) stressors. This will be done using several new innovative experimental approaches directly on archived tissues unique to MUSC, using a rich resource cohort of samples (n=570) representing approximately one third African American (AA) subjects. Based on the epidemiology of prostate cancer among AA men (already described in the proposal), considerable efforts have been made to promote early detection through screening with prostate specific antigen (PSA) testing. Recently, however, screening guidelines have shifted from performance of annual screening starting at age 50 to informed decision-making as new data have emerged about the efficacy of PSA testing. As early detection plays a less prominent role in prostate cancer control, it becomes even more important to identify biological pathways that are activated in the initiation and progression of disease and develop more effective biomarkers for early detection. Several prior studies have shown that there is a complex interplay between the tumor microenvironment and the immune system that contributes to the development of more aggressive prostate cancer among AA men. However, biological processes related to immune functioning operate within and are influenced by social contextual factors. Thus, identifying biological mechanisms without understanding the ways in which they are associated with social determinants is necessary, but not sufficient to long-term efforts to reduce racial disparities in prostate cancer outcomes through early detection and clinical management of disease. An emerging hypothesis central to this application about cancer health disparities is that social conditions and psychological responses to social stressors influence biological processes that are important to the initiation and progression of cancer. In this project, MUSC investigators will examine this hypothesis through a transdisciplinary study that defines the molecular mechanisms involved in the initiation and progression of prostate cancer by evaluating the tumor microenvironment interactions between the immune system, the tumor glycome, social determinants and AL. These investigators will determine whether the combination of distinct tumor and stroma N-glycans in prostate cancers of AA men promotes a more pro-tumor inflammatory/immune microenvironment. They will also examine the relationship between these biological processes and social determinants that include isolation, perceived stress, and chronic socioeconomic stressors. They hypothesize that a combination of stress- inducing social determinants, distinct N-glycans, impaired immune/inflammatory balance contributes to more aggressive prostate cancers in the AA population.