TUMOR-CELLS SUPPRESS CYTOKINE-INDUCED NITRIC-OXIDE (NO) PRODUCTION INCEREBRAL ENDOTHELIAL-CELLS

Nitric oxide (NO) produced by endothelial cells (EC) has been shown to exert cytotoxic activity on tumor cells. In order to analyze events i nvolved in brain metastasis, the modulation of NO production in rat-br ain-derived EC was investigated. NO release was increased by tumor nec rosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleu kin-1 beta, lipopolysaccharide or forskolin in EC219 cells, a rat-brai n-micvovessel-derived EC line. Dexamethasone decreased NO release by c ytokine-activated EC219 cells. Tumor cells (DHD/K12/PROb, a rat colon- carcinoma cell line) were highly adherent to EC219 cells, and adhesion was not modified by TNF-alpha plus IFN-gamma, or by dexamethasone. Ad dition of tumor cells or tumor-cell-conditioned medium significantly i nhibited NO release induced by any of the stimuli examined, but only i f added during the initial phase of endothelial-cell activation. Tumor -derived suppression of NO release was also observed in primary cultur es of cerebral EC. NO synthase (NOS) activity in cytosol extracts of t he cerebral EC line was Ca2+-independent and required both NADPH and t etrahydrobiopterin. NOS activity was increased by TNF-alpha and IFN-ga mma, and significantly reduced by tumor-cell-conditioned medium. These results suggest that rat colon-carcinoma cells may have developed a p rotective mechanism involving the release of (a) soluble factor(s) whi ch inhibit(s) NO production by cerebral EC. (C) 1994 Wiley-Liss, Inc.