TUMOR-CELL NITRIC-OXIDE INHIBITS CELL-GROWTH IN-VITRO, BUT STIMULATESTUMORIGENESIS AND EXPERIMENTAL LUNG METASTASIS IN-VIVO

Arginine-derived nitric oxide (NO) has been identified in some tumor c ell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to invest igate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growth in vitro and subcutaneous tumor growth and experi mental pulmonary metastasis in vivo. EMT-6 cells were incubated with e ndotoxin (LPS, 10 mu g/ml) and interferon-gamma (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, omega-nitro-L-arsni ne methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-B cells were also treated overnight with LP S/IFN, in the presence or absence of L-NAME, washed and injected eithe r subcutaneously in the dorsal flank (n = 40) or via the tail vein (n = 40) of syngeneic BALB/c mice. Two weeks following tumor cell injecti on, tumor size and number of pulmonary metastases were assessed. LPS/I FN stimulated NO production in EMT-6 cells and inhibited cell growth i n vitro by 50%. L-NAME blocked LPS/IFN stimulation of NO production an d restored cell growth to near control levels. When injected into BALB /c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increa se in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metas tases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO product ion in EMT-6 tumor cells inhibits tumor cell growth in vitro, yet para doxically augments tumor growth and metastasis in vivo. (C) 1996 Acade mic Press, Inc.