The development of a vascular supply is an essential component of tumor growth. Our preliminary studies in immunodeficient mice indicate that vascular endothelial growth factor (VEGF) mediates tumor-directed angiogenesis in ovarian epithelial carcinoma, at least during early stages of tumor growth. Inhibition of VEGF action with a neutralizing antibody to VEGF inhibited the neovascularization and growth of SKOV3-derived tumors in the subcutaneous and intraperitoneal tissue of immunodeficient mice. With cessation of treatment, tumor, neovascularization and growth resumed. Our underlying hypothesis is that angiogenesis is necessary to promote the growth and spread of primary human ovarian epithelial carcinomas. To test this hypothesis, neovascularization and growth of subcutaneous and intraperitoneal tumors derived from SKOV3, OVCAR-3 and primary human ovarian cancer cells will be examined following treatment with a neutralizing antibody to VEGF. We will asses whether inhibition of tumor- directed angiogenesis by passive immunization against tumor-derived VEGF inhibits the growth of both initial and advanced tumors and prolongs survival in these animals. The effect of other anti-angiogenic agents (e.g., 2-methoxyestradiol, thrombospondin, 16kDa fragment of prolactin) on tumor neovascularization and growth also will be examined. Furthermore, we will characterize VEGF and VEGF receptor expression in ovarian cancer and assess whether expression of VEGF and/or its receptors correlates with cancer stage and degree of vascularization, and whether VEGF is an independent negative prognostic indicator of patient survival. This proposal is designed to elucidate the role of angiogenesis in the basic biology of ovarian epithelial carcinoma. We will assess the usefulness of VEGF expression and tumor vascularization as prognostic indicators of patient outcome and examine the anti-tumor effects of inhibiting angiogenesis in biologically relevant models of this malignancy. Elucidating the growth factors involved in, and blocking the angiogenic process necessary for, ovarian cancer neovascularization represents a novel method for inhibiting the growth of this malignancy, potentially leading to advances in prognosis, treatment and survival.
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