TRANSFECTION OF CELLS WITH TRANSFORMING GROWTH-FACTOR-ALPHA LEADS TO CELLULAR-RESISTANCE TO THE ANTIPROLIFERATIVE EFFECTS OF TUMOR-NECROSIS-FACTOR

Tumor necrosis factor (TNF) is a growth-modulatory cytokine that inhib its the growth of certain cell lines, stimulates the growth of some, a nd has no effect on the growth of still others. The molecular basis fo r this differential regulation of growth by TNF is not understood. We postulate that the growth of normal or tumor cells is determined by th e balance between growth-stimulatory and -inhibitory signals. In the p resent study, we demonstrate that the transfection of cells with the t ransforming growth factor (TGF)-alpha gene induces resistance to TNF. Colon carcinoma cell lines that express elevated levels of TGF-alpha w ere also found to be resistant to this cytokine. Exogenous addition of the growth factor was also effective in decreasing the antiproliferat ive effects of TNF. Transfection of cells with the TGF-alpha gene led to downmodulation of TNF receptors but an increase in intracellular gl utathione levels. Thus, these results support our hypothesis that expr ession of growth factors by certain tumor cells can lead to resistance to antiproliferative agents such as TNF.