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

(PQA3) 为什么卵巢癌主要是绝经后妇女的疾病

• 批准号: 9062409
• 负责人: SANDRA ORSULIC
• 金额: $ 19.03万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9062409
• 关键词: Accounting; Acute; Age; Aging; Area; Atrophic; Cancer Detection; Cancer Etiology; Cell Aging; Cells; Chemotaxis; Cicatrix; Collagen; Collagen Fiber; Color; Corpora Albicantia; Development; Diagnosis; Diagnostic Neoplasm Staging; Disease; Early Diagnosis; Enzymes; Epidemiology; Epithelial; Epithelial Cells; Epithelial cyst; Epithelial ovarian cancer; Event; Exposure to; Extracellular Matrix; Fertilization; Fiber; Fibroblasts; Fibrosis; Genes; Growth; Health; Hormonal Change; Hormones; Human; Image; Imagery; Immune; Immunity; Implant; Incidence; Infiltration; Inflammation; Intervention; Laboratories; Lead; Left; Lesion; Life; Loose connective tissue; Malignant Epithelial Cell; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Mammary Neoplasms; Mammographic Density; Menopausal Status; Menopause; Molecular; Myofibroblast; Neoplasm Metastasis; Ovarian; Ovarian Follicle; Ovarian Serous Adenocarcinoma; Ovary; Ovulation; Pathogenesis; Phagocytes; Phase; Play; Postmenopause; Premature Menopause; Premenopause; Prevention; Preventive Intervention; Process; Production; Reactive Oxygen Species; Reproductive Periods; Research; Risk; Role; Screening for Ovarian Cancer; Seed Implantation; Seeds; Shapes; Signaling Molecule; Soil; Specimen; Staging; Structure; Surface; Survival Rate; Testing; Tissues; Transgenic Mice; Trichrome stain; Tube; Woman; base; calcification; cancer cell; cancer initiation; cancer prevention; cancer risk; cancer type; clinical practice; corpus luteum; crosslink; epidemiologic data; fimbria; genetic signature; implantation; impression; insight; macrophage; malignant breast neoplasm; mouse model; neoplastic; neoplastic cell; ovarian cancer prevention; reproductive; theories; tumor; tumor microenvironment; tumor progression; tumorigenesis

 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.

 描述（申请人提供）：上皮性卵巢癌主要是绝经后女性的疾病，80-90%的卵巢癌病例发生在40岁以后。更年期的发病高峰发生在51岁，而浸润性上皮性卵巢癌的发病高峰发生在63岁。关于绝经后卵巢癌发病的许多理论被提出，包括 持续排卵和炎症、荷尔蒙变化、免疫力下降、细胞衰老加剧以及活性氧不受控制的产生。对卵巢癌起始事件的了解不足严重阻碍了我们早期卵巢癌检测和预防的努力。人们越来越认识到，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形成于卵巢而不是输卵管，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，卵巢癌风险随着排卵周期数的增加而增加，表明排卵在卵巢癌病因学中发挥着重要作用。然而，矛盾的是，女性通常在最后一次排卵十多年后患上卵巢癌。在绝经后几年，卵巢卵泡耗尽，剩余的卵巢大部分被重塑，形成纤维化疤痕组织。与目前将萎缩的卵巢视为非功能性纤维化疤痕的观点相反，我们假设绝经后卵巢富含胶原蛋白的微环境为肿瘤性输卵管细胞的播种提供了肥沃的土壤。该假设基于纤维化和胶原蛋白的公认作用 重塑在促进几种癌症类型的肿瘤发生中的作用，以及我们最近发现类似的胶原蛋白重塑基因组在卵巢癌进展和卵巢卵泡退化过程中丰富。为了检验我们的假设，我们将首先确定哪些分子事件与人类卵巢衰老和绝经状态相关（目标 1），然后在小鼠模型中测试卵巢衰老和/或纤维化是否有助于增加输卵管细胞植入卵巢（目标 2）。我们的假设的证明将重塑当前关于卵巢癌病因学的范式。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识别预防和早期检测目标提供所需的见解。

项目成果

Suboptimal cytoreduction in ovarian carcinoma is associated with molecular pathways characteristic of increased stromal activation.

• DOI: 10.1016/j.ygyno.2015.08.026
• 发表时间: 2015-12
• 期刊: Gynecologic oncology
• 影响因子: 4.7
• 作者: Liu Z;Beach JA;Agadjanian H;Jia D;Aspuria PJ;Karlan BY;Orsulic S
• 通讯作者: Orsulic S

Sphingosine kinase 1 is required for TGF-β mediated fibroblastto- myofibroblast differentiation in ovarian cancer.

• DOI: 10.18632/oncotarget.6703
• 发表时间: 2016-01-26
• 期刊: Oncotarget
• 作者: Beach JA;Aspuria PJ;Cheon DJ;Lawrenson K;Agadjanian H;Walsh CS;Karlan BY;Orsulic S
• 通讯作者: Orsulic S