(PQA3) Why is Ovarian Cancer Primarily a Disease of Postmenopausal Women

 描述（由申请人提供）：上皮性卵巢癌主要是绝经后妇女的疾病，80-90%的卵巢癌病例发生在40岁以后。绝经的高峰发生在51岁，而侵袭性上皮性卵巢癌的高峰发生在63岁。绝经后卵巢癌发病的许多理论已被提出，包括不断排卵和炎症，激素变化，免疫力下降，细胞衰老增加和活性氧的不受控制的生产。对卵巢癌的起始事件的认识不足，严重阻碍了我们对卵巢癌早期检测和预防的努力。越来越多的人认为，卵巢癌实际上起源于输卵管，恶性细胞脱落到邻近的卵巢。由于大部分肿瘤通常在卵巢而不是输卵管中形成，因此卵巢在癌症发展的早期阶段必须发挥重要作用。流行病学数据一致表明，卵巢癌的风险随着排卵周期的增加而增加，表明排卵在卵巢癌病因中起作用。然而，自相矛盾的是，女性通常在最后一次排卵后十多年才患上卵巢癌。在绝经后的几年里，卵巢卵泡被耗尽，剩余的卵巢大部分被重塑形成纤维化瘢痕组织。与目前认为萎缩性卵巢为无功能性纤维化瘢痕的观点相反，我们推测绝经后卵巢富含胶原的微环境为肿瘤性输卵管细胞的种植提供了肥沃的土壤。这一假说是基于纤维化和胶原蛋白的公认作用 我们最近发现，在卵巢癌进展和卵泡退化过程中，胶原蛋白重塑基因的相似集合得到了富集。为了验证我们的假设，我们将首先确定哪些分子事件与人类卵巢老化和绝经状态相关（目标1），然后在小鼠模型中测试卵巢老化和/或纤维化是否有助于增加输卵管细胞植入卵巢（目标2）。我们假设的证明将重新塑造目前关于卵巢癌病因的范式。此外，确定哪些细胞和分子过程促进和抑制癌细胞植入卵巢将为预防和早期检测提供所需的靶标识别。

 DESCRIPTION (provided by applicant): Epithelial ovarian cancer is predominantly a disease of postmenopausal women, with 80-90% of ovarian cancer cases occurring after the age of 40. The peak incidence of menopause occurs at age 51, while the peak incidence of invasive epithelial ovarian cancer occurs at age 63. Many theories of postmenopausal onset of ovarian cancer have been proposed, including incessant ovulation and inflammation, hormonal changes, reduced immunity, increased cell senescence and uncontrolled production of reactive oxygen species. A poor understanding of the initiating events in ovarian cancer has significantly hampered our efforts towards early ovarian cancer detection and prevention. It is increasingly accepted that ovarian cancer actually originates in the fallopian tube with malignant cells shedding to the adjacent ovary. Since the bulk of the tumor typically forms in the ovary, rather than the fallopian tube, ovaries must play a significant role in the early stages of cancer development. Epidemiologic data consistently show that ovarian cancer risk increases with the number of ovulatory cycles, indicating that ovulation plays a role in ovarian cancer etiology. However, it is paradoxical that women typically develop ovarian cancer more than a decade after their last ovulation. During the postmenopausal years, the ovarian follicles are depleted and much of the remaining ovary is remodeled to form fibrotic scar tissue. In contrast to the current view of the atrophic ovary as a nonfunctional fibrotic scar, we postulate that the collagen-rich microenvironment of the postmenopausal ovary provides fertile soil for the seeding of neoplastic tubal cells. This hypothesis is based on the recognized role of fibrosis and collagen remodeling in facilitating tumorigenesis in several cancer types and on our recent finding that similar sets of collagen- remodeling genes are enriched during ovarian cancer progression and ovarian follicle regression. To test our hypothesis, we will first identify which molecular events are associated with human ovarian aging and menopausal status (Aim 1) and then test in a mouse model whether ovarian aging and/or fibrosis contribute to increased implantation of tubal cells into the ovary (Aim 2). Proof of our hypothesis will re-shape the current paradigms about ovarian cancer etiology. Moreover, determining which cellular and molecular processes promote and inhibit implantation of cancer cells into the ovary will provide needed insight into the identiy of targets for prevention and early detection.