Three stage carcinogenesis in mouse skin--recent results and present status of an advanced model system of chemical carcinogenesis.

In the three stage model of carcinogenesis in mouse skin, to a certain compartment of normal cells new and adverse biological properties are imposed by the initiator DMBA yielding 'potential tumor cells,' or 'initiated cells.' These initiated cells exhibit a selective advantage of growth over surrounding normal cells if exposed to DTE promoters. The new properties may result from a genomic mutation associated with an increase of density, affinity or cooperativity of certain membrane receptors as compared to normal cells. Complete promoters, such as TPA, but not incomplete promoters such as RPA may impose a second additional genomic or epigenomic insult onto initiated cells ('conversion'). As a consequence, initiated cells become ready to respond to unspecific mitogenic stimuli ('propagation'), as provided by hyperplasiogenic agents. The initiation/promotion model of mouse skin presents new and attractive possibilities to apply the oncogene approach for further in-depth analysis of the molecular mechanisms of its stages. It remains to be seen to what extent molecular events demonstrated causative for the stages in the mouse skin model are applicable also to stages in multistage models of chemical carcinogenesis operational in other target tissues.