Exploring the role of progestin and vitamin D on inflammation and oxidative stress in in vitro and in vivo models of ovarian cancer

项目总结/文摘

Project Summary/Abstract In the early stages of ovarian carcinogenesis, it is now thought that the fimbria acquires molecular and genetic alterations when exposed to inflammatory mediators and associated oxidative stress (reactive oxygen species-ROS) released during ovulatory events from the adjacent ovary. These changes lead to the “p53 signature”- accumulation of mutant p53 protein (earliest genetic alteration in ovarian cancer), in the secretory cells of the fimbria ultimately leading to the development of serous tubal intraepithelial carcinoma (STIC), which spreads via shedding/exfoliation directly to the adjacent ovary and into the abdominal cavity. The p53 signatures and STIC lesions which evolve in an inflammatory, oxidative and DNA-toxic microenvironment are characterized by distinct features including loss of polarity, epithelial tufting, pleomorphic nuclei, abnormal p53 expression and a high-proliferative index. The discovery of these lesions and how they develop opens the door to the formulation of pharmacologic strategies that arrest and/or reverse the early transformative events in the fimbria, with immense potential to decrease ovarian cancer incidence and mortality through prevention. Previously, our work has focused primarily on the ovarian surface epithelium as the biologic target for ovarian cancer prevention using progestins and vitamin D. However, little is known regarding their biologic effects in the FTE. The objective of this study is to explore the impact of progestin and vitamin D on inflammation and oxidative stress in early carcinogenesis of ovarian cancer in in vitro and in vivo models of the disease. We hypothesize that inhibition of inflammatory and oxidative effects may comprise a biologic mechanism contributing to the cancer preventive effects of these agents. Furthermore, we will examine whether the combination of progestin and vitamin D is more effective than either agent alone. To test this hypothesis, we will utilize the following samples from the parent grant to evaluate inflammatory and oxidative stress pathways following administration of progestin and vitamin D: (1) cell cultures of primary FTE as well as transformed FTE harboring dominant negative mutant p53 obtained and established from pre- and postmenopausal women undergoing gynecologic surgery for benign indications, (2) paraffin sections of the fallopian tube and corresponding isolates (RNA, DNA, protein and plasma/serum) obtained from the mice (mogp-TAg and Dicer-PTEN) undergoing prevention trials with progestins and vitamin D.