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Angiogenesis, Metastasis, and the Cellular Microenvironment

Secretion of Extracellular Superoxide Dismutase From Muscle Transduced With Recombinant Adenovirus Inhibits the Growth of B16 Melanomas in Mice

¹ Laboratory of Hepatobiology and Toxicology and ² Gene Therapy Center, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC

Requests for reprints: Michael D. Wheeler, Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina at Chapel Hill, CB 7178, 3013 Thurston-Bowles Building, Chapel Hill, NC 27599. Phone: (919) 966-1154; Fax: (919) 966-1893. E-mail: wheelmi{at}med.unc.edu

A number of reports have described the effects of oxidative stress on tumor growth. Therefore, these experiments were designed to test the hypothesis that overexpression of extracellular superoxide dismutase (ecSOD) would inhibit the growth of tumors arising from s.c. implantation of syngenic B16-F1 melanoma cells. C57BL/6 mice were infected i.m. with adenovirus containing either ß-galactosidase (Ad.lacZ) as control or the secreted extracellular isoform of SOD (Ad.ecSOD) 3 days before s.c. implantation of B16-F1 tumor cells. Serum SOD activity was elevated nearly 5-fold over control animals. Two weeks after implantation, B16-F1 tumor size was 65% smaller in mice infected with Ad.ecSOD in comparison with mice infected with Ad.lacZ. However, the presence of SOD did not affect growth rates of B16-F1 cells in vitro. Consistent with smaller tumor volume, tumors from Ad.ecSOD-infected mice also expressed less vascular endothelial growth factor (VEGF). Moreover, in vitro studies using B16-F1 cells confirm that SOD blunts oxidant-dependent VEGF expression. Importantly, CD31 expression and vessel density were markedly reduced in tumors from Ad.ecSOD-infected mice compared with controls. These data suggest that tumor oxidative stress may facilitate tumor vascularization and thus promote tumor growth.

Key Words: angiogenesis • cell proliferation • adenovirus • oxidative stress • VEGF • vessel density

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