Research is designed to investigate interactions between stromal/mesenchymal cells and ovarian surface epithelium (i.e., ovarian germinal epithelium) in normal and tumorigenic ovarian tissue. Over 90% of all ovarian cancers originate in the ovarian surface epithelium (OSE) that covers the surface of the ovary. An ovarian surface stromal cell population of mesenchymal origin underlie and provide structural support to the OSE. THE HYPOTHESIS TO BE TESTED IS THAT NORMAL AND TUMORIGENIC OVARIAN SURFACE EPITHELIUM IS REGULATED BY MESENCHYMAL-EPITHELIAL CELL INTERACTIONS MEDIATED BY THE LOCAL PRODUCTION AND ACTION OF GROWTH STIMULATORS AND GROWTH INHIBITORS. Abnormal cell growth associated with ovarian carcinogenesis is speculated to in part be the result of alterations in these normal cell-cell interactions. Preliminary observations indicate that ovarian stromal cell secretory products can regulate normal and tumorigenic OSE growth in vitro. A nude mouse model revealed that ovarian stromal cells also have a dramatic effect on ovarian tumor growth and progression in vivo. Ovarian tumors may be potentially subcategorized as stromally dependent for an inhibition versus stimulation of tumor growth and progression. The limited availability of normal human ovarian cell types requires an animal model to be utilized. Due to the similarity between bovine and human ovarian physiology and reproductive endocrinology, basic information will be obtained using a bovine ovarian model system. Normal and tumorigenic human tissue subsequently will be used to confirm and extend the basic hypothesis. The experimental approach consists of the following specific aims; 1) Investigate Bovine Ovarian Surface Epithelium (OSE) and Stromal/Mesenchymal Cell Function and Growth. 2) Investigate bovine OSE - Stromal Cell Interactions. 3) Investigate OSE - Stromal Interactions in normal and tumorigenic human tissue. The completion of these specific aims will provide a better understanding of cell-cell interactions between OSE and ovarian stromal cells in the control of OSE function and growth. Results will provide insight into the roles of specific mesenchymally derived growth factors in the regulation of normal and tumorigenic cell growth. The antagonistic actions of growth simulators and inhibitors provide an efficient mechanism to control the growth of OSE. It is anticipated that alterations in the cell-cell interactions identified will be an important factor in abnormal growth associated with carcinogenesis of the ovary. These observations will be essential for the future design of pharmacologic agents to detect, prevent and/or treat ovarian cancer.
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