AGING AND OVARIAN CANCER

University Of Kansas Medical Center, Kansas City KS

Investigators

Abstract

The objective of this application is to determine the effect of aging on the progression of ovarian cancer. A novel mouse model of ovarian cancer will be used. A stable cell line of mouse ovarian surface epithelial cells that has undergone an in vitro transformation event will be injected intraperitoneally into syngeneic C57BL6 mice. Multiple tumor implants develop throughout the peritoneal cavity, just as observed in women with ovarian cancer. Ovarian cancer is a disease of aging. The peak incidence of ovarian cancer is coincident with menopause and this epidemiological data has lead to the hypothesis that senescence of the female reproductive tract plays a role in the progression of ovarian cancer. Menopause results when the supply of ova in the ovaries is exhausted. Follicle development, and thus production of the ovarian steroids estradiol and progesterone, stops. Hormonal feedback mechanisms then trigger elevated secretion of pituitary gonadotropins. Thus, at the time of menopause in women, when the incidence of ovarian cancer is greatest, multiple hormonal changes occur, including decreased ovarian steroids and increased pituitary gonadotropins. In addition to reproductive senescence, age associated immunsenescence also occurs. Thus, the progression of ovarian cancer around the time of menopause likely may result from both reproductive and immune factors. The experiments in this proposal will investigate an area of aging and cancer not currently addressed. The First aim will determine progression of ovarian cancer in aged and young mice. In addition, a youthful reproductive hormonal phenotype will be re- established in chronologically aged mice by transplantation of young ovaries. Also, an aged reproductive hormonal profile will be induced in young mice by removing the ovaries. The progression of ovarian cancer will be assessed in each condition. The second aim will address the effects of estradiol. progesterone, and gonadotropins, alone and in combination, in aged and young mice on the progression of the cancer. Progression of ovarian cancer will be assessed by measuring overall tumor load, tumor vascularization and VEGF expression, immune parameters (macrophages, Natural Killer cells, T-cells, and IL-3 production), and expression of the CSF-llcfm5/plasminogen activator system involved in metastasis. These studies will utilize a novel model for the study of ovarian cancer. In addition, novel information will be obtained on the effects of aging, the aging reproductive system, and the aging immune system on the progression of ovarian cancer.