EPIDERMAL GROWTH-FACTOR INDUCES TERMINAL DIFFERENTIATION IN HUMAN EPIDERMOID CARCINOMA-CELLS

Previous studies have reported that the proliferation of A431 cells, a human squamous cell carcinoma cell line, was stimulated by picomolar epidermal growth factor (EGF) but inhibited by nanomolar EGF. This bip hasic dose-response phenomenon is not observed in normal human epithel ial cells where nanomolar EGF is usually mitogenic. We have examined t he effects of inhibitory and stimulatory concentrations of EGF on the growth and differentiation of A431 cells. In the presence of 100 pM EG F, A431 cells showed a mild increase in growth rate (129% of control) compared to cells grown in the absence of EGF. At 10 nM EGF, growth in hibition to 63% of control was observed. EGF at 10 nM stimulates a two fold increase both in cornified envelope formation and in epidermal tr ansglutaminase activity, suggesting that high concentrations of EGF in duce terminal differentiation in A431 cells. Mitogenic concentrations of EGF (100 pM) had no significant effect on these differentiation mar kers. Chronic exposure of A431 cells to 20 or 50 nM EGF resulted in EG F-resistant A431 variants that are neither growth arrested nor induced to terminally differentiate by 10 nM EGF. Removal of EGF from the gro wth medium of the EGF-resistant cells resulted in the reversion of the se cells back to the wild-type A431 biphasic response pattern within 2 weeks. Our results suggest that A431 cells have the capacity to non-m utatively alter their response pattern to EGF in vitro to maintain the mselves in a state of optimum proliferation and away from terminal dif ferentiation. (C) 1993 Wiley-Liss, Inc.