MODULATION OF HUMAN EPIDERMAL-CELL RESPONSE TO 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN BY EPIDERMAL GROWTH-FACTOR

Cultured human epidermal cells were treated with 2,3,7,8-tetrachlorodi benzo-p-dioxin (TCDD) in the presence or absence of epidermal growth f actor (EGF). In both normal keratinocytes and a spontaneously immortal ized keratinocyte (SIK) line, TCDD treatment in the absence of EGF ind uced a marked reduction in colony size and cell number, and it perturb ed colony morphology. These effects were largely prevented by EGF, ind icating that growth factor action in the cellular microenvironment may considerably modify TCDD action in target cells. Both TCDD and EGF su bstantially reduced expression of the differentiation markers keratin 1 and keratin 10 in the normal and immortalized cells, and did so in a n additive fashion. The cells did not display a general loss of differ entiated function, since several other markers, including involucrin, were little affected. EGF dramatically stimulated telomerase activity in SIK cultures, and TCDD prevented this action but not by reducing ce ll growth. However, EGF did not stimulate telomerase activity in norma l human epidermal cells despite an evident increase in their growth. T he growth factor stimulation of telomerase in the minimally deviated S IK line suggests that derepression of enzyme activity in normal cells may occur in a stepwise fashion during neoplastic progression. TCDD co uld act as a late stage tumor promoter by selecting for variants in wh ich telomerase is constitutively active.