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From the Reproductive Endocrinology Center,*
Department
of Obstetrics, Gynecology and Reproductive Sciences, University of
California, San Francisco, San Francisco, and Department of
Cardiovascular Research,
Genentech, Inc.,
South San Francisco, California
Ovarian cancer is characterized by the rapid growth of solid intraperitoneal tumors and large volumes of ascitic fluid. Vascular endothelial growth factor (VEGF) augments tumor growth by inducing neovascularization and may stimulate ascites formation by increasing vascular permeability. We examined the role of VEGF in ovarian carcinoma using in vivo models in which intraperitoneal or subcutaneous tumors were induced in immunodeficient mice using the human ovarian carcinoma cell line SKOV-3. After tumor engraftment (7 to 10 days), some mice were treated with a function-blocking VEGF antibody (A4.6.1) specific for human VEGF. A4.6.1 significantly (P < 0.05) inhibited subcutaneous SKOV-3 tumor growth compared with controls. However, tumor growth resumed when A4.6.1 treatment was discontinued. In mice bearing intraperitoneal tumors (IP mice), ascites production and intraperitoneal carcinomatosis were detected 3 to 7 weeks after SKOV-3 inoculation. Importantly, A4.6.1 completely inhibited ascites production in IP mice, although it only partially inhibited intraperitoneal tumor growth. Tumor burden was variable in A4.6.1-treated IP mice; some had minimal tumor, whereas in others tumor burden was similar to that of controls. When A4.6.1 treatment was stopped, IP mice rapidly (within 2 weeks) developed ascites and became cachectic. These data suggest that in ovarian cancer, tumor-derived VEGF is obligatory for ascites formation but not for intraperitoneal tumor growth. Neutralization of VEGF activity may have clinical application in inhibiting malignant ascites formation in ovarian cancer.
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Y.-L. Hu, M.-K. Tee, E. J. Goetzl, N. Auersperg, G. B. Mills, N. Ferrara, and R. B. Jaffe Lysophosphatidic Acid Induction of Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells J Natl Cancer Inst, May 16, 2001; 93(10): 762 - 767. [Abstract] [Full Text] [PDF]
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N. Auersperg, A. S. T. Wong, K.-C. Choi, S. K. Kang, and P. C. K. Leung Ovarian Surface Epithelium: Biology, Endocrinology, and Pathology Endocr. Rev., April 1, 2001; 22(2): 255 - 288. [Abstract] [Full Text]
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D. Salani, V. Di Castro, M. R. Nicotra, L. Rosano, R. Tecce, A. Venuti, P. G. Natali, and A. Bagnato Role of Endothelin-1 in Neovascularization of Ovarian Carcinoma Am. J. Pathol., November 1, 2000; 157(5): 1537 - 1547. [Abstract] [Full Text] [PDF]
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R. A. Brekken, J. P. Overholser, V. A. Stastny, J. Waltenberger, J. D. Minna, and P. E. Thorpe Selective Inhibition of Vascular Endothelial Growth Factor (VEGF) Receptor 2 (KDR/Flk-1) Activity by a Monoclonal Anti-VEGF Antibody Blocks Tumor Growth in Mice Cancer Res., September 1, 2000; 60(18): 5117 - 5124. [Abstract] [Full Text]
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A. Saaristo, T. A. Partanen, J. Arola, L. Jussila, M. Hytonen, A. Makitie, S. Vento, A. Kaipainen, H. Malmberg, and K. Alitalo Vascular Endothelial Growth Factor-C and Its Receptor VEGFR-3 in the Nasal Mucosa and in Nasopharyngeal Tumors Am. J. Pathol., July 1, 2000; 157(1): 7 - 14. [Abstract] [Full Text] [PDF]
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 R. E. Favoni and A. De Cupis The Role of Polypeptide Growth Factors in Human Carcinomas: New Targets for a Novel Pharmacological Approach Pharmacol. Rev., June 1, 2000; 52(2): 179 - 206. [Abstract] [Full Text] [PDF]
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H.M.W. Verheul, K. Hoekman, A.S. Jorna, E.F. Smit, and H.M. Pinedo Targeting Vascular Endothelial Growth Factor Blockade: Ascites and Pleural Effusion Formation Oncologist, April 1, 2000; 5(90001): 45 - 50. [Abstract] [Full Text]
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L. Hu, C. Zaloudek, G. B. Mills, J. Gray, and R. B. Jaffe In Vivo and in Vitro Ovarian Carcinoma Growth Inhibition by a Phosphatidylinositol 3-Kinase Inhibitor (LY294002) Clin. Cancer Res., March 1, 2000; 6(3): 880 - 886. [Abstract] [Full Text]
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Y. Kondo, S. Arii, A. Mori, M. Furutani, T. Chiba, and M. Imamura Enhancement of Angiogenesis, Tumor Growth, and Metastasis by Transfection of Vascular Endothelial Growth Factor into LoVo Human Colon Cancer Cell Line Clin. Cancer Res., February 1, 2000; 6(2): 622 - 630. [Abstract] [Full Text]
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 G. Thurston, C. Suri, K. Smith, J. McClain, T. N. Sato, G. D. Yancopoulos, and D. M. McDonald Leakage-Resistant Blood Vessels in Mice Transgenically Overexpressing Angiopoietin-1 Science, December 24, 1999; 286(5449): 2511 - 2514. [Abstract] [Full Text]
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 Y. Aoki and G. Tosato Role of Vascular Endothelial Growth Factor/Vascular Permeability Factor in the Pathogenesis of Kaposi's Sarcoma-Associated Herpesvirus-Infected Primary Effusion Lymphomas Blood, December 15, 1999; 94(12): 4247 - 4254. [Abstract] [Full Text] [PDF]
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