Alterations in epidermal functions resulting from exposure to initiators and promoters of carcinogenesis.

Mouse epidermal basal cells can be selectively cultivated in medium with a [Ca++] of 0.02-0.09 mM. Terminal differentiation and sloughing of mature keratinocytes occurs when the [Ca++] is increased to 1.2-1.4 mM. When basal cell cultures are exposed to chemical initiators of carcinogenesis, colonies of cells which resist Ca++ -induced differentiation evolve. Likewise basal cells derived from mouse skin initiated in vivo yield foci which resist terminal differentiation. This defect in the commitment to terminal differentiation appears to be an essential change in initiated cells in skin and is also characteristic of malignant epidermal cells. When normal basal cell cultures are exposed to the potent tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), there is induction of epidermal transglutaminase, an enzyme which is characteristic of terminally differentiating epidermal cells. Morphological differentiation is observed in about 50% of the population, and these cells are lost from the culture. The cells which remain are resistant to induced differentiation by either 1.2 mM Ca++ medium or a second exposure to TPA if the exposure interval is 4 days. These cells are directly stimulated (without an initial inhibition) to proliferate by a second TPA exposure, suggesting that this population is responsive only to the mitogenic effects of the promoter. With a 10-day interval between exposures, responsiveness to both TPA and 1.2 mM Ca++ return to control patterns. These results indicate that exposure to TPA induces differentiation in some basal cells while stimulating proliferation in others. Such responses could lead to clonal expansion of epidermal cells which fail to respond to differentiation signals, such as initiated cells.