Diet, Endocrine-Immune Interactions & Prostate Cancer

描述(由申请人提供) 前列腺癌是最常见的非皮肤癌，也是美国男性癌症死亡的第二大原因。已有研究表明，在睾酮水平较高的情况下，血中雌激素水平升高是前列腺癌发生的重要危险因素。饮食因素可能与前列腺癌有关的因素很多；然而，对某些营养素保护前列腺免受与肿瘤发生相关的基因损害的机制(S)的了解尚不清楚。这项应用的目的是确定性激素(雌激素/睾酮)刺激与慢性炎症、活性氧物种(ROS)的产生和不受控制的前列腺细胞增殖之间的分子机制，并评估针对这些过程的饮食策略的有效性。这一应用的中心假设是，在高睾酮存在的情况下，升高的雌激素通过雌激素受体介导的过程导致氧化还原敏感的转录因子NFkappaB的长期激活。NFkappaB的长期激活启动并放大了前列腺内的炎性级联反应，导致持续的氧化损伤和前列腺细胞增殖的信号。我们进一步假设，食用含有抗雌激素、抗炎和抗增殖成分的富含抗氧化剂的食物将有效地降低前列腺癌的患病率。本项目的目的是：1)确定暴露于雌激素/睾酮升高导致Noble大鼠前列腺组织慢性炎症的分子机制，2)表征在性激素诱导的前列腺癌发生过程中导致前列腺氧化应激和增殖信号的慢性炎症的联系，以及3)评估新型全食物饮食改进预防Noble大鼠性激素诱导的前列腺癌的能力。我们的研究的成功完成有望揭示前列腺癌相关不同因素之间的新关系，并有助于确定前列腺癌预防饮食干预的关键分子靶点。我们以‘全食’为基础的癌症预防方法与制定基于证据和广泛适用的公共健康建议高度相关，这些建议将显著减轻前列腺癌的负担。

DESCRIPTION (provided by applicant) Prostate cancer is the most frequently diagnosed non-cutaneous cancer, and is the second leading cause of cancer death in American men. It has been observed that elevated blood estrogen in the presence of high testosterone is an important risk factor that contributes to the prostate carcinogenesis. Dietary factors potentially linked to prostate cancer are numerous; however, an understanding of the mechanism(s) by which certain nutrients would protect the prostate from the genetic damage that is associated with tumor development remains unclear. The objectives of this application are to define the molecular mechanisms that link sex hormonal (estrogens/testosterone) stimulation to chronic inflammation, generation of reactive oxygen species (ROS) and uncontrolled prostate cell proliferation, and to evaluate the effectiveness of dietary strategies that target these processes. The central hypothesis of this application is that elevated estrogen, in the presence of high testosterone, causes prolonged activation of a redox-sensitive transcription factor, NFkappaB, through an estrogen receptor-mediated process. Prolonged NFkappaB activation initiates and amplifies an inflammatory cascade within the prostate and results in sustained oxidative damage and signals for cell proliferation in the prostate. We further hypothesize that consumption of antioxidant-rich foods containing a combination of anti-estrogenic, anti-inflammatory and anti-proliferative components will be effective in reducing the prevalence of prostate cancer. The Aims of this project are: 1) to identify the molecular mechanisms by which exposure to elevated estrogen/testosterone causes chronic inflammation in prostate tissues of Noble rats, 2) to characterize the links of chronic inflammation leading to oxidative stress and proliferation signals in the prostate during sex hormone-induced prostate carcinogenesis, and 3) to evaluate the ability of novel whole food-based dietary modifications to prevent sex hormone-induced prostate carcinogenesis in Noble rats. The successful completion of our study is expected to reveal novel relationships among divergent factors involved in prostate cancer and aid in identifying key molecular targets for dietary intervention for prostate cancer prevention. Our 'whole food' based approach to cancer prevention is highly relevant to the development of evidence based and broadly applicable public health recommendations that will significantly reduce the burden of prostate cancer.