Modeling Early Events Associated with Serous Ovarian Cancer Formation from Fallopian Tube Epithelium

Epithelial ovarian cancer is the most lethal gynecological malignancy and fifth leading cause of cancer death among US women. High mortality rates can be attributed to the lack of early detection strategies and an incomplete understanding of disease etiology. Historically, ovarian cancer was thought to arise from the ovarian surface epithelium (OSE) but evidence suggests that the epithelial cells of the distal fallopian tube (TEC) may be progenitors to some high-grade serous ‘ovarian’ cancers. Although a heterogeneous disease, 96% of high-grade serous ovarian tumors contain mutations in p53 and the “p53 signature”, or overexpression of p53 is a potential precursor lesion to the disease. In order to examine the role of both cell types in the development of serous cancer, as well as potential initiation factors that might be involved in early disease formation, a three-dimensional culture system was developed to study normal mouse and human epithelium in contact with its stromal microenvironment. This system allowed for the discovery that transforming growth factor beta (TGFβ) leads to growth inhibition of normal mouse ovarian surface epithelium, but not normal mouse tubal epithelial cells despite transcriptional activation by TGFβ. In addition, ex vivo cultures of human fimbriae resulted in induction of p53 expression and could be used in the future to model the p53 signature. Mouse models to conditionally target floxed genes in the TEC were also optimized. Intraoviductal injection of adenovirus expressing Cre recombinase lead to limited infectivity of the TEC. Tissue specific promoters should be employed to target these cells while the OSE is best targeted through intrabursal injections. A mouse oviductal epithelial cell line that spontaneously immortalized and was stably transfected with the R273H TP53 mutation was used to study the role of mutant p53 in ovarian tumorigenesis. Mutation in p53 led to increased migration and upregulation of pro-migratory genes in TEC, but not OSE. The R273H TP53 mutation combined with oncogenic KRAS (G12V) expression transformed TEC. Understanding the mechanisms required to transform normal fallopian tube epithelium may help identify early biomarkers, develop chemoprevention strategies, and elucidate novel treatments to improve overall survival rates.