Psychological stress, associate biologic mediators, and ovarian cancer risk

描述(由申请人提供)：卵巢癌是女性癌症死亡的第五大常见原因，部分原因是存在侵袭性亚型，而且很少有预防建议。因此，识别可改变的危险因素对于靶向预防和阐明卵巢癌的生物学至关重要。在卵巢癌小鼠模型中，处于慢性压力下的动物比对照组的肿瘤更大、更具侵袭性。应激通过2-肾上腺素能受体和增加MMPs的表达起作用。在这一高度翻译的应用程序中，我们建议调查以下各项验证指标之间的关联 在护士健康研究队列(NHS和NHSII)前瞻性收集的950多例病例中，心理社会压力，包括心理困扰(焦虑、抑郁症状)和心理社会压力源(护理压力、工作压力、社会孤立)与卵巢癌的风险。我们假设，压力与侵袭性肿瘤的相关性最强。β-受体阻滞剂药物可阻断应激途径的核心--2-肾上腺素能受体，因此可能与降低卵巢癌风险有关，尤其是在压力较大的人群中。此外，已经确定了许多应激反应的生物介质，包括基质金属蛋白酶-2、催乳素、催产素和端粒长度。我们建议在NHS、NHSII、妇女健康研究、纽约大学妇女健康研究和瑞典北部健康与疾病研究中从662例卵巢癌患者中前瞻性收集的血浆样本中评估这些具有疾病风险的生物标记物。随着大量的样本，详细的随访和可用的血液和DNA样本，我们的研究提供了一个独特的机会，对卵巢癌发生的新机制进行第一次前瞻性评估。了解心理社会压力是否与卵巢癌风险相关，将有助于阐明关键的致癌途径。此外，这项研究可能会在预防方面带来实质性的改进，因为行为干预(例如瑜伽)可以减少感知到的压力。这一创新应用将把实验研究转化为预期的人体研究，并有可能提高我们对卵巢癌发生的理解，以及我们预防这种致命疾病的能力。

DESCRIPTION (provided by applicant): Ovarian cancer is the fifth most common cause of cancer death among women, in part due to the existence of aggressive subtypes and few prevention recommendations. Thus, the identification of modifiable risk factors is critical to target prevention and elucidate the biology of ovarian cancer. In an ovarian cancer mouse model, animals under chronic stress had larger and more aggressive tumors than controls. Stress acted through the ¿2-adrenergic receptor and increased expression of MMPs. In this highly translational application, we propose to investigate the association of validated metrics of psychosocial stress, including psychological distress (anxiety, depressive symptoms) and psychosocial stressors (care-giving stress, job strain, social isolation), with risk of ovarian cancer in over 950 prospectively-collected cases from the Nurses' Health Study cohorts (NHS and NHSII). We hypothesize that stress will be most strongly associated with aggressive tumors. Beta blocker medications block the ¿2-adrenergic receptor, a centerpiece of the stress pathway, and thus may be associated with a reduced ovarian cancer risk, particularly among those with high stress. Further, a number of biologic mediators of the stress response have been identified, including MMP-2, prolactin, oxytocin, and telomere length. We propose to evaluate these biomarkers with disease risk in prospectively-collected plasma samples from 662 ovarian cancer cases within the NHS, NHSII, the Women's Health Study, the New York University Women's Health Study, and the Northern Sweden Health and Disease Study. With the large sample size, detailed follow-up and available blood and DNA specimens, our study provides a unique opportunity to conduct the first prospective assessment of a novel mechanism of ovarian carcinogenesis. Understanding whether psychosocial stress is related to ovarian cancer risk will elucidate key carcinogenic pathways. Further, this research could lead to substantial improvements in prevention, since behavioral interventions (e.g., yoga) can reduce perceived stress. This innovative application will translate experimental research into prospective human studies and potentially could improve our understanding of ovarian carcinogenesis and our ability to prevent this fatal disease.