Project 2: The impact of biobehavioral factors and aspirin on ovarian cancer biology

摘要|完整研究项目2 越来越多的证据表明，对慢性压力和随之而来的痛苦的生物反应可以 交感神经延长激活促进上皮性卵巢癌进展 系统和持续的去甲肾上腺素释放。去甲肾上腺素暴露的下游后果 包括前列腺素相关炎症增加和免疫抑制。相反， 越来越多的证据支持阿司匹林在卵巢癌预防和生存中的作用。然而，关键是 关于慢性应激/痛苦和阿司匹林的潜在生物学作用机制仍有疑问 使用(分别考虑低剂量和标准剂量)及其与卵巢癌生物学的相互关系。 具体地说，我们建议评估这一假设，即痛苦通过以下方式促进卵巢癌进展 促进炎症和免疫过程，而阿司匹林可以消除这些影响。我们的创新研究 使用独特的基于人口和实验的资源。目标1将使用来自四个长期项目的数据 不同人群中的预期队列，基于人群的病例对照研究，医院病例系列 收集自我报告的慢性压力和痛苦(如抑郁)和卵巢肿瘤组织的测量结果。 目标1将测量大量高级别浆液性肿瘤样本中的基因表达(以捕获完整的肿瘤 微环境)利用整个外显子RNAseq。我们假设苦恼与上行有关- 炎症相关和免疫抑制基因表达途径的调节已归一化 在阿司匹林使用者中。我们还将评估痛苦与卵巢癌风险之间的联系是否减弱 在阿司匹林使用者中。值得注意的是，我们正在利用种族和民族多样性的研究，这些研究具有高度的 特色化的卵巢癌病例，允许按种族评估相关性差异(Black， 白人)和种族(西班牙裔、非西班牙裔)，以及对痛苦-- 相关基因表达谱和临床结果。使用正交和互动的方法，目标2 将使用实验性卵巢癌小鼠模型来表征随着时间的推移每天的进展效果 抑制应激对肿瘤炎症和免疫以及卵巢肿瘤生长的影响 应激激素通过酶联免疫吸附试验测定。我们还将检查阿司匹林(概括等价物)是否 低剂量和标准剂量的阿司匹林)抵消了慢性应激对肿瘤进展和 炎症和免疫基因表达网络。该项目将利用 几个核心，包括波多黎各生物库(PRBB)和量化科学核心(QSC)，具有 与外联核心、规划和评价核心进行实质性互动，并与受训人员在 研究教育的核心。这一创新应用将为未来开发新型免疫球蛋白的工作提供信息。 预防和治疗侵袭性疾病的预防策略、药物治疗和心理社会干预 经历慢性压力和痛苦的女性患上卵巢癌。

ABSTRACT | FULL RESEARCH PROJECT 2 Growing evidence indicates that the biological response to chronic stress and subsequent distress can promote the progression of epithelial ovarian cancer via prolonged activation of the sympathetic nervous system and sustained norepinephrine release. Downstream consequences of norepinephrine exposure include increased prostaglandin-related inflammation and an immunosuppressive landscape. Conversely, increasing evidence supports the role of aspirin use in ovarian cancer prevention and survival. Yet, key questions remain about the underlying biological mechanism of action of chronic stress/distress and aspirin use (considering low and standard doses separately) and their interrelationship with ovarian cancer biology. Specifically, we propose to evaluate the hypothesis that distress enhances ovarian cancer progression by promoting inflammatory and immune processes and that aspirin abrogates these effects. Our innovative study uses unique population-based and experimental resources. Aim 1 will use data from four long-term prospective cohorts in diverse populations, a population-based case-control study, a hospital case series that collected self-reported measures of chronic stress and distress (e.g., depression), and ovarian tumor tissue. Aim 1 will measure gene expression in bulk high grade serous tumor samples (to capture the full tumor microenvironment) using whole exome RNASeq. We hypothesize that distress is associated with the up- regulation of inflammation-related and immune suppression gene expression pathways that is normalized among aspirin users. We will also assess if the association of distress with ovarian cancer risk is attenuated among aspirin users. Notably, we are leveraging racially and ethnically diverse studies that have highly characterized ovarian cancer cases, allowing assessment of differences in association by race (Black, White) and ethnicity (Hispanic, non-Hispanic), as well as the examination of associations between distress- related gene expression profiles and clinical outcomes. Using an orthogonal and interactive approach, Aim 2 will use experimental ovarian cancer mouse models to characterize the progressive effect over time of daily restraint stress on tumor inflammation and immunity as well as ovarian tumor growth, using RNASeq and stress hormones measured via ELISA assays. We also will examine if aspirin (recapitulating equivalents of low and standard dose aspirin in humans) counteracts the effects of chronic stress on tumor progression and inflammatory and immune gene expression networks. This project will leverage the scientific services of several cores, including the Puerto Rico BioBank (PRBB) and the Quantitative Science Core (QSC), with substantial interaction with the Outreach Core, the Planning and Evaluation Core, and working with trainees in the Research Education Core. This innovative application will inform future work to develop novel immuno- preventive strategies, pharmacotherapies, and psychosocial interventions to prevent and treat invasive ovarian cancer in women who experience chronic stress and distress.