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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA064602-03
Application #
6269669
Study Section
Project Start
1998-02-01
Project End
1999-01-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lu, Z; Yang, H; Sutton, M N et al. (2014) ARHI (DIRAS3) induces autophagy in ovarian cancer cells by downregulating the epidermal growth factor receptor, inhibiting PI3K and Ras/MAP signaling and activating the FOXo3a-mediated induction of Rab7. Cell Death Differ 21:1275-89
Cheng, Kwai Wa; Agarwal, Roshan; Mitra, Shreya et al. (2012) Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. EMBO Mol Med 4:125-41
Badgwell, D B; Lu, Z; Le, K et al. (2012) The tumor-suppressor gene ARHI (DIRAS3) suppresses ovarian cancer cell migration through inhibition of the Stat3 and FAK/Rho signaling pathways. Oncogene 31:68-79
Zou, Chun-Fang; Jia, Luoqi; Jin, Hongyan et al. (2011) Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel. BMC Cancer 11:22
Cheong, Jae-Ho; Park, Eun Sung; Liang, Jiyong et al. (2011) Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther 10:2350-62
Agarwal, Roshan; Carey, Mark; Hennessy, Bryan et al. (2010) PI3K pathway-directed therapeutic strategies in cancer. Curr Opin Investig Drugs 11:615-28
Ishida, Seiko; McCormick, Frank; Smith-McCune, Karen et al. (2010) Enhancing tumor-specific uptake of the anticancer drug cisplatin with a copper chelator. Cancer Cell 17:574-83
Short, John D; Dere, Ruhee; Houston, Kevin D et al. (2010) AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability. Mol Carcinog 49:429-39
Liu, Shuying; Murph, Mandi; Panupinthu, Nattapon et al. (2009) ATX-LPA receptor axis in inflammation and cancer. Cell Cycle 8:3695-701
Huang, Shaoyi; Chang, In Soon; Lin, Wenbo et al. (2009) ARHI (DIRAS3), an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci Rep 30:159-68

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