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Of mice and men: a critical reappraisal of the two-stage theory of carcinogenesis.

The two-stage theory of carcinogenesis attempts to reduce a very complex set of data to simple terms: it defines a carcinogen as "an agent that causes a neoplasm by a two-step process involving initiation and promotion". The theory has achieved the status of a paradigm, and all new experiments carried out by two-stage supporters are designed according to its premises and therefore will eo ipso tend to confirm it. Popper's dictum that any scientific hypothesis should be put to the strongest test, namely, by trying to refute it, has rarely (or never) been observed. The two-stage theory was originally based on standard mouse skin-painting experiments. All the original work is grounded on classic skin carcinogenesis, and only later was it extended to also comprise carcinogenesis in other organs, thereby becoming a general theory. On the basis of the same standard skin painting experiments and in accordance with Popper's dictum, the present review shows how the following generally accepted corollaries of the two-stage theory have been refuted: initiation must come first in time; in previously initiated mouse skin promotion always leads to a synergistic increase in tumor crop, whereas complete carcinogens at subthreshold does (regarded as merely initiating) have only an additive effect; the reverse experiment is innocuous; there is a qualitative difference between the effect of initiators and that of promoters; initiators only initiate at low dose levels, but abruptly become rather complete carcinogens at higher doses, promotion must take place over a long period, and repeated exposure without prolonged intervals is essential; pure initiators exist, for example, urethane for the epidermis; pure promoters exist, e.g., TPA; skin inflammation and persistent hyperplasia are essential parts of promotion; increased levels of the enzyme ODC followed by increasing levels of polyamines are casually involved in promotion; the appearance of many dark epidermal cells is a sign of promotion and the dark cells are stem cells from which tumors arise. Carcinogenesis is a very complicated process characterized not only by disturbances in cell cycle control, cell differentiation and/or maturation, but also by changes in the normal ability of cells to respect organ and tissue boundaries. Infiltrative growth and metastases are the most dangerous properties of cancer, and the two-stage theory does not provide an explanation for these two most serious aspects of the disease.