Role of Follicular Fluid Exosomes on Ovarian/Fallopian Carcinogenesis

项目摘要/摘要 晚期卵巢癌是最致命的妇科恶性肿瘤，5年生存率不到50%。 在高级阶段。存活率低在很大程度上可以归因于缺乏筛查方法，因为 对导致卵巢癌的最初肿瘤启动事件的了解不足。近期临床 研究发现卵巢癌起源于输卵管的伞状末端。上皮细胞 这种环境中的细胞经常暴露在源自周期排卵的卵泡液中。 在女人的一生中。有趣的是，排卵与卵巢癌的增加高度相关。 风险，以及抑制排卵的方法降低卵巢癌的发病率。FF可以概括一下一些 当在体外检查时，癌症进展的早期标志，然而，在FF内的因素负责 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， 被称为外体，作为FF的主要成分。这些外切体能够促进肿瘤细胞的增殖 颗粒上皮细胞，体外被人输卵管上皮细胞摄取。在这项提案中，我们 假设FF外切体可能对输卵管上皮具有生理功能，但也可能是 它具有增殖性和突变性，并有助于输卵管上皮细胞的恶变。 此外，我们将评估Ff在诱导胞苷家族的基因表达和活性方面的作用 脱氨酶(APOBECs)，这可能在接尘的DNA损伤效应中起作用。我们将对此进行测试 利用人和小鼠卵泡刺激素及其各自的输卵管上皮细胞进行体外和体内实验的假说 卵巢/输卵管癌小鼠模型的分析。

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.