CARCINOMA FORMATION IN NMRI MOUSE SKIN PAINTING STUDIES IS A PROCESS SUGGESTING GREATER-THAN-2 STAGES

The two-stage model of carcinogenesis, which incorporates clonal growt h of intermediate cells, has gained increasing attention in recent yea rs. It was formulated to match tumor incidence data and expanded to en compass observations made in initiation - promotion carcinogenicity ex periments. Mouse skin experiments are perceived as supporting this mod el, with papillomas representing the intermediate cells and carcinomas representing the malignant cells. In this manuscript, the two-stage m odel is applied to data concerning papilloma and carcinoma formation f rom an initiation-promotion NMRI mouse skin painting experiment which included stop-promotion. It is shown that the model is not compatible with these data if all papillomas are considered premalignant lesions. The model was modified to allow for a heterogeneous population of pap illomas. In this case, unless one assumes that premalignant and termin ally benign papillomas are morphologically different in the sense that both types of papillomas at detection limit contain distinct numbers of actively dividing initiated cells, the model predicts larger number s of papillomas at the end of the experiment than were actually observ ed. The best explanation is that the model is not in accordance with t hese data and that the data indicate the need for stages between initi ated and malignant cells.