Role of Follicular Fluid Exosomes on Ovarian/Fallopian Carcinogenesis

卵泡液外泌体在卵巢/输卵管癌发生中的作用

• 批准号: 9191057
• 负责人: Pavla Brachova
• 金额: $ 5.85万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-08 至 2018-07-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9191057
• 关键词: Area; Cancer Biology; Cause of Death; Cell Culture Techniques; Cell Line; Cell Proliferation; Clinical Research; Complex; Country; Cytidine Deaminase; DNA; DNA Damage; Data; Diagnosis; Early Diagnosis; Environment; Epithelial; Epithelial Cells; Epithelium; Event; Exposure to; Family; Fimbriated End of the Fallopian Tube; Follicular Fluid; Funding; Gene Activation; Gene Expression; Genes; Goals; Grant; Greater sac of peritoneum; Gynecologic; High-Throughput Nucleotide Sequencing; Human; In Vitro; Incidence; Investigation; Laboratories; Lead; Liquid substance; Longevity; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Membrane; Methods; Molecular; Mus; Mutation; National Research Service Awards; Neoplastic Cell Transformation; Oncogenic; Oocytes; Ovarian; Ovarian Carcinoma; Ovarian Granulosa Cell; Ovary; Ovulation; Patients; Physiological; Physiology; Plasma; Play; Proteins; RNA Editing; Research; Research Personnel; Research Training; Risk Factors; Role; Serous; Somatic Cell; Staging; Symptoms; Testing; Time; Training; Vesicle; Woman; Work; advanced disease; base; cancer genome; cancer risk; carcinogenesis; exosome; extracellular; extracellular vesicles; granulosa cell; high risk; in vivo; medical specialties; microvesicles; mouse model; neoplastic; novel; programs; screening; transversion mutation; tumor; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY / ABSTRACT Advanced ovarian cancer is the most deadly gynecologic malignancy, with a 5-year survival of less than 50% in advanced stages. The low survival can be greatly attributed to an absence of screening methods due to an inadequate understanding of the initial tumor initiating events leading to ovarian cancers. Recent clinical studies have identified ovarian carcinomas originating in the fimbriated ends of fallopian tubes. The epithelial cells in this environment are regularly exposed to the follicular fluid (FF) originating from cyclic ovulations throughout a woman’s lifespan. Interestingly, ovulation is highly associated with an increased ovarian cancer risk, and methods inhibiting ovulation decrease ovarian cancer incidence. FF can recapitulate some of the early markings of cancer progression when examined in vitro, however the factors within the FF responsible for this effect are unknown. Preliminary data from our laboratory has identified extracellular membrane vesicles, known as exosomes, as a major component of FF. These exosomes are able to increase proliferation of epithelial granulosa cells, and are taken up in vitro by human oviduct epithelial cells. In this proposal, we hypothesize that FF exosomes may have a physiological function on the oviduct epithelium, but may also be proliferative and mutagenic and contribute to the malignant transformation of oviductal epithelium. Furthermore, we will assess the role of FF in inducing gene expression and activity of a family of cytidine deaminases (APOBECs), which may play a role in the DNA damage effects of FF exposure. We will test this hypothesis using human and murine FF and their respective oviductal epithelial cells in vitro, and via in vivo analyses in an ovarian/oviductal cancer mouse model.

项目概要/摘要 晚期卵巢癌是最致命的妇科恶性肿瘤，5年生存率低于50% 处于高级阶段。低存活率很大程度上归因于缺乏筛查方法 对导致卵巢癌的最初肿瘤起始事件了解不足。近期临床 研究已发现卵巢癌起源于输卵管伞状末端。上皮细胞 这种环境中的细胞定期暴露于源自周期性排卵的卵泡液 (FF) 贯穿女人的一生。有趣的是，排卵与卵巢癌发病率增加高度相关 风险和抑制排卵的方法可降低卵巢癌的发病率。 FF可以概括一些 体外检查时发现癌症进展的早期标志，然而 FF 内的因素负责 这种影响尚不清楚。我们实验室的初步数据已鉴定出细胞外膜囊泡， 称为外泌体，是 FF 的主要组成部分。这些外泌体能够增加增殖 上皮颗粒细胞，并在体外被人输卵管上皮细胞摄取。在这个提案中，我们 假设 FF 外泌体可能对输卵管上皮具有生理功能，但也可能是 增殖和诱变，并有助于输卵管上皮的恶性转化。 此外，我们将评估 FF 在诱导基因表达和胞苷家族活性中的作用 脱氨酶 (APOBEC)，可能在 FF 暴露造成的 DNA 损伤中发挥作用。我们将测试这个 使用人类和小鼠 FF 及其各自的输卵管上皮细胞在体外和体内进行的假设 在卵巢/输卵管癌小鼠模型中进行分析。