Studies of skin tumorigenesis in PGK mosaic mice: many promoter-independent papillomas and carcinomas do not develop from pre-existing promoter-dependent papillomas.

The induction of mouse skin papillomas in two stages by initiation-promotion protocols has been studied extensively. On the basis of kinetics of induction and morphological observations of apparent progression to carcinomas, it has been argued that the papillomas sequentially advance to carcinomas through promoter-dependent and promoter-independent premalignant stages. Although this hypothesis has been widely accepted, the step-wise development of the same cell population from papilloma to carcinoma has not been established at the cellular level. We show here that some carcinomas which morphologically appear to result from progression of promoter-dependent papillomas do not develop from sequential progression of the same cell population as was found in the original papillomas. Other initiated cells also participate during the growth of these tumors and may replace the original papilloma cells. We also present evidence that some tumors develop directly as promoter-independent papillomas without going through an apparent promoter-dependent papilloma stage.