(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.



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