Malignant conversion, the first stage in progression, is distinct from phorbol ester promotion in mouse skin

Papillomas induced by DMBA initiation-TPA promotion protocols are necessary precursor lesions of squamous cell carcinomas. The papillomas are heterogeneous in their potential for progression to carcinomas, a property apparently induced at the time of initiation. The probability of conversion to malignancy is highest for the papillomas most easily promoted, by either the first few TPA treatments or by "weak" promoters such as mezerein or chrysarobin. The conversion frequency is lowest for TPA-dependent papillomas and those papillomas which appear late in a TPA promotion protocol. The spontaneous rate of malignant conversion is not altered by continued TPA treatment; TPA promotion may simply expand clones of initiated cells which are already programmed with a given probability of conversion. Treatment of papilloma-bearing mice with a genotoxic agent, such as 4-NQO, urethane or cisplatin, increases the rate of malignant conversion. The properties of active converting agents differ markedly from those of the phorbol ester promoting agents, suggesting differences in the mechanisms of action of these two classes of compounds. A genetic mechanism appears likely to explain conversion. The differences between the two stages are further emphasized by the finding that inhibitors of tumor promotion are not inhibitory when given during malignant conversion. The converting agent urethane also affects the subsequent discrete stage in tumor progression, tumor metastasis. Differences in metastatic potential have been found between carcinomas which progress spontaneously after TPA promotion and carcinomas induced in TPA-promoted papillomas by urethane. The multistage nature of experimental epidermal carcinogenesis is well established. The mouse skin model will continue to be valuable for mechanistic studies since similar stages have been described in other tissues as well as in man.