On the persistence of tumor initiation in two-stage carcinogenesis on mouse skin

The persistence of the initiated state during two-step carcinogenesis in mouse epidermis is a generally accepted phenomenon, however, conflicting results exist with regard to the degree of irreversibility relative to the age of the animals. Several factors such as age-dependent alterations in the response of the epidermis to the promoter and skin damage following the initiation step have been proposed to account for the observed discrepancies. In the present investigation we have tried to circumvent skin-damaging effects of topically applied 7,12-dimethylbenz[a]anthracene by intragastric administration of the drug. Tumor production by topical promotion with 12-O-tetradecanoylphorbol-13-acetate was subsequently determined in 600 female NMRI mice using intervals of 4, 8, 16, 24, 32 and 40 weeks between initiation and promotion. Independent of the delay between the initiating and promoting step, we observed a similar time course and extent of tumor production in the different experimental groups. This indirectly proves that the promoting capacity of 12-O-tetradecanoylphorbol-13-acetate is age-independent and that during aging no substantial loss of initiated cells occurs in mouse epidermis.