Animal Studies of Colon Carcinogenesis and Altered Epithelial Cell Differentiation

Chronic inflammatory bowel disease (IBD) appears to predisposeto subsequent colon cancer. Factors that influence the degree of this risk requiredefinition since the reported incidence of malignant change varies widely.Differing environmental factors such as diet may be critical, and several approacheshave been used to explore the role of specific variables in colon cancerpathogenesis; one has employed the use of animal models. Naturally occurringmodels of colon cancer exist including cotton-topped tamarins with colitis. Beststudied, however, are animal models of colon cancer induced with specificchemical carcinogens. Cycasin and hydrazine derivatives, eg, 1,2-dimethylhydrazine,are most widely used. After parenteral administration of an activecarcinogen, metabolic activation occurs, resulting in colonic adenocarcinomas.Sessile and polypoid neoplasms may be induced, particularly in the distal colon,similar to human colon cancer. Using this model, the effect of differing dietaryand therapeutic variables has been explored. Studies with purified single dietaryfibres, such as microcrystalline cellulose and hemicellulose, but not pectin, havedemonstrated reduced numbers of colonic tumours; these in vivo observationscorrelate with in vitro effects of fibres on rat luminal and fecal mutagenicactivities. Specific therapies used in IBD have also been evaluated - metronidazole,for example, a bacterial mutagen, enhances the development of chemicallyinduced rodent colon cancer. In addition, a significant increase in colonictumour development occurs after intestinal resection or bypass, two proceduresused in the surgical management of IBD. In this setting, surgical sutures, particularlynonabsorbable materials including stainless steel, may play a criticalrole. Although the extent and duration of disease in patients with chronic IBDmay be important in colon cancer pathogenesis, other variables, including dietand treatment, may be critical modulating factors