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Significant Expression of Vascular Endothelial Growth Factor/Vascular Permeability Factor in Mouse Ascites Tumors¹

Department of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108 [J. L., S. Y., M. S.]; Division of Immunology, Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Asahi-Machi, Machida-Shi, Tokyo 194 [A. S., K. Y.], Japan

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is believed to be a potent mediator of peritoneal fluid accumulation and angiogenesis and of tumor growth in ascites tumor. Such roles, however, have not been generally established because of insufficient quantitative and systemic analyses. To address this, we examined the expression of VEGF in 13 mouse ascites tumors (5 sarcomas, 3 carcinomas, 2 lymphomas, 1 leukemia, 1 mastocytoma, and 1 plasmacytoma). Using a newly developed sensitive and specific radioreceptor binding assay and functional assays, we found that active VEGF was significantly accumulated (6–850 ng/ml) in the ascites fluids of all 13 tumors. VEGF concentrations are higher in the tumors of sarcoma and carcinoma origin (430.4 ± 234.2 ng/ml) than in those of lymphoma and hematological tumor origin (19.2 ± 10.45 ng/ml). VEGF that accumulated in the peritoneal fluids or expressed in the ascites tumor cells was easily visualized with immunoprecipitation Western blot analysis with a rough correlation to the expression levels of VEGF gene in these tumor cells, suggesting that the tumor cells, at least in part, contributed to the production of the VEGF that accumulated in the ascites fluid. Most ascites tumors expressed VEGF; the 164-amino acid isoform was predominant, the 120-amino acid isoform was less abundant, and the 188-amino acid isoform was least abundant. Several representative ascites tumors expressed similar, if not higher, levels of VEGF when they were cultured at normoxic states, suggesting that they expressed VEGF at high levels in a constitutive manner. The microvessel densities in the peritoneal walls of tumor-bearing mice, which are significantly higher than those in normal mice, basically correlated to but did not parallel the VEGF concentrations in their respective ascites fluids. Thus, a complicated relationship may exist between the VEGF production and angiogenesis associated with ascites tumor in vivo. Taken together, our observations suggest that VEGF plays a fundamental role in ascites tumor formation; however, its importance may vary according to tumor origin.

¹ This work was supported by Grant-in-Aid for Special Project Research on Cancer-Bioscience 04253204 from the Ministry of Education and by research grants from the Yakult Bioscience Foundation and the Mitsubishi Foundation in Japan.

² To whom requests for reprints should be addressed, at Department of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108, Japan. Phone: 81-3-5449-5550; Fax: 81-3-5449-5425.

Received 12/ 9/97. Accepted 4/ 6/98.

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