Review article: the stages of gastrointestinal carcinogenesis - application of rodent models to human disease

The development of gastrointestinal cancer in humans and animals occurs thr ough a consecutive series of stages termed initiation, promotion and progre ssion. The characterization of each of these stages has been elucidated in several model systems as well as in human neoplasms. Both single, putatively initiated cells and preneoplastic foci have been id entified by marker protein differences as well as by mutational changes. The promotion stage involves the clonal expansion of single initiated cells . Such expansion can be rapidly reversed by a variety of means, of which ac ute fasting (as exemplified in rat hepatocarcinogenesis) is among the most rapid and efficient. This reversal involves a selective apoptosis of preneo plastic cells and preneoplastic lesions, associated with a marked increase in expression of the proto-oncogene c-myc. Transition of cells from the stage of promotion to that of progression init ially involves specific karyotypic alterations, as noted in both the rat li ver model and human colon carcinogenesis. In the former, the transition app ears to be associated with enhanced expression of the H119 imprinted putati ve tumour suppressor gene. Thus, the use of model systems may be applied directly to the human circums tance, increasing the potential both for rational prevention of gastrointes tinal neoplasia and for new approaches to the therapy of neoplastic disease in the progression stage.