Tumor Cell Nitric Oxide Inhibits Cell Growthin Vitro,but Stimulates Tumorigenesis and Experimental Lung Metastasisin Vivo

• Published in: The Journal of surgical research 1996-06, Vol.63 (1), p.49-52
• Main Authors: Edwards, Paul, Cendan, Juan C., Topping, Dan B., Moldawer, Lyle L., MacKay, Sally, Copeland III, Edward M., Lind, D.Scott
• Format: Article
• Language: English
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1996.0221

Arginine-derived nitric oxide (NO) has been identified in some tumor cell lines and solid human tumors. The effect of tumor cell NO on tumor biology is poorly understood. The purpose of this study was to investigate the effect of NO production by EMT-6 murine breast cancer cells on tumor cell growthin vitroand subcutaneous tumor growth and experimental pulmonary metastasisin vivo.EMT-6 cells were incubated with endotoxin (LPS, 10 μg/ml) and interferon-γ (IFN, 50 U/ml), in the presence or absence of the NO synthase inhibitor, ω-nitro-L-arginine methyl ester (L-NAME, 2 mM), and NO production and cell number were assessed 24 hr later. EMT-6 cells were also treated overnight with LPS/IFN, in the presence or absence of L-NAME, washed and injected either subcutaneously in the dorsal flank (n= 40) or via the tail vein (n= 40) of syngeneic BALB/c mice. Two weeks following tumor cell injection, tumor size and number of pulmonary metastases were assessed. LPS/IFN stimulated NO production in EMT-6 cells and inhibited cell growthin vitroby 50%. L-NAME blocked LPS/IFN stimulation of NO production and restored cell growth to near control levels. When injected into BALB/c mice, LPS/IFN-stimulated tumor cells demonstrated a two-fold increase in subcutaneous tumor growth and experimental pulmonary metastases over control cells. L-NAME reduced tumor size and number of lung metastases to control levels, suggesting that tumor cell NO production was responsible for this effect. In summary, LPS/IFN-stimulated NO production in EMT-6 tumor cells inhibits tumor cell growthin vitro,yet paradoxically augments tumor growth and metastasisin vivo.