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.
This grant will explore the effect of ovulatory follicular fluid exposure to fallopian epithelium. There is a positive association with the number of times a woman ovulates (i.e., releases follicular fluid) during her lifespan and ovarian carcinogenesis. Follicular fluid is known to induce changes associated with tumorigenesis in oviductal epithelial cells, yet the factors responsible remain unknown. Recently, small membrane vesicles known as exosomes were identified in follicular fluid. We are exploring their role in the carcinogenesis of oviductal epithelial cells in vitro and in vivo.