The goal of this proposal is to determine whether elevated levels of gonadotropin hormones, as found in most ovarian cancer patients, contribute to recurrence of ovarian cancer by inducing tumor angiogenesis,a nd to test the possibility of adjuvant hormonal treatment for lowering the levels of the gonadotropins. For that end,, an experimental model system for following concomitantly and non-invasively tumor growth and vascularization using magnetic resonance imaging (MRI) was developed. Preliminary studies conducted with 3 lines of human ovarian cancer cells, showing that gonadotropins promote the ability of very small ovarian micro-tumors to recruit new blood vessels. The applicants propose to test the generality of this finding and resolve the hormonal regulation over secretion of growth factors mediating angiogenesis. Human ovarian epithelial cancer cells, as well as spontaneously immortalized cells from the rat ovarian epithelium will be cultured as multi-cellular spheroids. The angiogenic capacity of the spheroids in mice will be determined by MRI using an intrinsic contrast created by the paramagnetic properties of blood. Molecular analysis of hormonally induced ovarian cancer cells will reveal the specific angiogenic growth factors that induce recruitment or vasculature towards the tumor. The clinical implication of this study is that if the applicants' working hypothesis is correct, hormonal intervention leading to lowered gonadotropin levels, if given during remission, should delay tumor recurrence. To test this hypothesis such normal intervention will be evaluated on human ovarian cancer tumors of different sized implanted in immuno-deficient mice.
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