Edwin F. Spangler

Malignant conversion of mouse skin tumours is increased by tumour initiators and unaffected by tumour promoters.

Multi-stage carcinogenesis (initiation–promotion) was first demonstrated in mouse skin1,2. The first stage, initiation, is accomplished by a low dose of carcinogen that causes no tumours. Promotion by repeated treatment of initiated mice with certain non-carcinogenic hyperplastic agents results in the rapid production of numerous benign papillomas, a few of which progress to squamous cell carcinomas. Although this model system produces mostly benign tumours, many of the concepts concerning carcinogenesis in epithelial tissues have been derived from mouse skin studies. The permanent change in growth potential accomplished by tumour initiators is generally considered to be a mutagenic event3; cell selection and clonal expansion of initiated cells may be involved in promotion4. In initiation–promotion experiments, more than 90% of the squamous cell carcinomas develop from papillomas5,6, but the conversion rate is low. The factors necessary for this conversion of benign to malignant tumours have not been defined but tumour promoters have been assumed to be involved. However, we report here that the tumour promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) is ineffective in the conversion of papillomas to carcinomas whereas three initiators, urethane, N-methyl-N′-nitro-N-nitrosoguanidine ((MNNG) and 4-nitroquinoline-N-oxide (4-NQO) are effective. This suggests that malignant conversion may result from a further genetic change in papilloma cells and that the ineffectiveness of TPA may be due to its inactivity as a mutagen.