Role of Follicular Fluid Exosomes on Ovarian/Fallopian Carcinogenesis

项目总结/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% 处于晚期低存活率可在很大程度上归因于缺乏筛查方法， 对导致卵巢癌的初始肿瘤起始事件的认识不足。最近的临床 研究已经确定卵巢癌起源于输卵管的伞端。上皮 在这种环境中的细胞有规律地暴露于源于周期性排卵的卵泡液（FF 一个女人的一生。有趣的是，排卵与卵巢癌的增加高度相关， 风险，抑制排卵的方法可降低卵巢癌的发病率。FF可以概括一些 当在体外检查时，癌症进展的早期标记，然而，FF中负责 这种影响是未知的。我们实验室的初步数据已经确定了细胞外膜囊泡， 称为外泌体，是FF的主要成分。这些外来体能够增加细胞的增殖， 上皮颗粒细胞，并在体外被人输卵管上皮细胞摄取。在本提案中，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 增殖性和致突变性，并有助于输卵管上皮的恶性转化。 此外，我们将评估FF在诱导胞苷家族基因表达和活性中的作用。 脱氨酶（APOBECs），这可能在FF暴露的DNA损伤效应中发挥作用。我们将测试这个 使用人和鼠FF及其各自的输卵管上皮细胞在体外和通过在体内的假设 在卵巢/输卵管癌小鼠模型中的分析。

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.