EFFECTS OF CYTOKINE-MEDIATED MODULATION OF NM23 EXPRESSION ON THE INVASION AND METASTATIC BEHAVIOR OF B16F10 MELANOMA-CELLS

The molecular mechanisms of tumor invasion and metastasis are yet to b e fully elucidated. A potential tumor-metastasis-suppressor gene nm23 has been described in certain rodent and human tumors. In the present study, we examined the potential anti-invasive and anti-metastatic eff ect of nm23 gene in B16F10 cells, a malignant murine melanoma cell lin e. Transfection of nm23 gene into B16F10 melanoma cells resulted in si gnificant suppression of the invasiveness and metastatic ability of me lanoma cells and significantly enhanced the survival of tumor-bearing mice. B16F10 melanoma cells transfected with nm23 produced significant ly less soluble ICAM-I and were more susceptible to LAK-cell-mediated cytotoxicity. Co-culture of B16F10 melanoma cells with IL-2 had no eff ect on nm23 expression, whereas treatment with PGE(2), TNF-alpha and I FN-gamma resulted in down-regulation of nm23 expression. Concomitantly , in vivo treatment with TNF-alpha or IFN-gamma in experimental mice i ncreased pulmonary metastases and lowered the overall survival period, as compared with IL-2 treatment alone. These results provide evidence that nm23, in addition to its antimetastatic function, could also be involved in modulating tumor-target-structure expression, in down-regu lating invasive potential and in production of soluble intracellular a dhesion molecules. The down-regulation of nm23 by TNF-alpha, IFN-gamma and particularly by PGE(2) warrants re-examination of current immunot herapeutic protocols and of the role played by PGE(2) in tumor progres sion. (C) 1995 Wiley-Liss, Inc.