Metastatic potential of mouse skin carcinomas produced by different protocols of chemical carcinogenesis.

Squamous cell carcinomas (SCC) of the mouse skin were produced by three different protocols of chemical carcinogenesis, i.e., complete carcinogenesis with 7,12-dimethylbenz(a)anthracene (DMBA) two-stage carcinogenesis with DMBA as initiator, 12-O-tetradecanoyl-phorbol-13-acetate (TPA) as promoter and three stage carcinogenesis with DMBA, TPA and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) as third-stage agent or progressor. Tumors were sequentially studied at weeks 38-52 of treatment. Although no significant differences in the rate of appearance of gamma-glutamyl transpeptidase (GGT) could be seen, a larger number of SCC produced by complete carcinogenesis protocols were GGT-negative. This coincided with the higher grade of malignancy of these tumors as evaluated by histopathology. In general terms high-grade tumors were seen more frequently in the complete carcinogenesis experiment than in the other two protocols. SCC produced by complete carcinogenesis also exhibited a markedly higher DNA index than the SCC from the other experimental groups. All three protocols were very effective in producing late metastasizing tumors, and no significant differences could be established in the incidence of spontaneous lung metastasis. This shows that, contrary to general knowledge, if adequately observed for more than 40 weeks, SCC of the murine skin is able to metastasize in the lung in approximately 30% of cases. Nevertheless, complete carcinogenesis-induced SCC were usually of higher histological grade, a proportion of these were GGT-negative and produced more multiple or diffuse metastases than the tumors induced by the multistage protocols.