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Nitric Oxide Synthase II Gene Disruption

Implications for Tumor Growth and Vascular Endothelial Growth Factor Production¹

Department of Pharmacology, University of Melbourne, Victoria 3010 [T. E. K., T. L. B., E. G., A. G. S.]; Bernard O’Brien Institute of Microsurgery, St. Vincent’s Hospital, Victoria 3065 [J. E. B.]; and Peter MacCallum Cancer Institute, Victoria 8006 [R. L. A.] Australia

The expression of a primary initiator of tumor angiogenic responses, vascular endothelial growth factor (VEGF), may be induced by nitric oxide (NO) in carcinoma cells. However, the net impact of NO on carcinogenesis remains unclear, because manipulation of NO levels has been shown to either stimulate or inhibit tumor growth. We have investigated the relationship between inducible NO synthase (NOS II), VEGF expression, and growth of B16-F1 melanoma over 14 days in wild-type (NOS II^+/+) mice and in those in which the gene for NOS II has been deleted (NOS II^-/-). B16-F1 tumor growth was measured as wet weight of the excised tissue. Tumor NOS II and VEGF localization were evaluated by immunohistochemistry, and VEGF mRNA levels were measured by Northern blot analysis. In NOS II^+/+ mice inoculated with B16-F1 melanoma cells, macroscopic tumors were always observed at 14 days; however, 22% of NOS II^{-/ -} mice had no detectable tumor mass. Immunoreactive NOS II was detected in tumor cells of tumors grown in NOS II^+/+ but not in NOS II^{-/ -} mice. Although immunoreactive VEGF was detected in the granules of tumor-associated mast cells from both NOS II^+/+ and NOS II^-/- mice, VEGF mRNA expression in tumors from NOS II^-/- was half that in NOS II^+/+ mice. Neither NOS II inhibition, exogenous NO, nor peroxynitrite influenced DNA synthesis in culture B16-F1 melanoma cells. The NO donor did not alter either VEGF mRNA levels or degranulation in cultures of the mast cell line RBL-2H3, but peroxynitrite increased both VEGF mRNA expression and degranulation. We conclude that host expression of NOS II contributes to induction of NOS II in the tumor and to melanoma growth in vivo, possibly by regulating the amount and availability of VEGF.

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