Use of animal models in colorectal cancer prevention.

CS01-03 Considerable progress has been made in developing relevant animal models for studies of the mechanisms of colorectal tumorigenesis and for colorectal cancer prevention investigations. Early rat and mouse models were based on the administration of carcinogens (primarily azoxymethane and 1,2-dimethylhydrazine) to induce the development of precursor colorectal aberrant crypt foci (ACF), polyps, and invasive tumors. More recently, genetically modified mice (such as the multiple intestinal neoplasia, Min, mouse with a truncating germline Apc mutation) have become popular for studies of chemopreventive and dietary factors in colorectal cancer. In addition, genetic crosses of Min mice with other knockout mouse models (such as mismatch repair deficient mice, Igf-2, EphB2, and many others) are important in understanding genetic modifiers of bowel neoplasia and gene x environment interactions. Models that mimic our 9bad Western diet9 (eg. the NWD diet in C57BL/6 mice) are attractive alternatives to carcinogen-induced models or genetically manipulated mice, however long periods of observation are necessary to induce phenotypic changes in the colonic mucosa. In general, it is fair to state that almost all popular human colorectal cancer prevention strategies, from dietary manipulations (such as folate or calcium supplementation), to both old (eg. aspirin) and new (COX-2 inhibitors) drugs, have been evaluated in both carcinogen-induced and genetically modified animal models. In most cases, simple enumeration of polyps has demonstrated the preventive effects of these strategies, and in some cases, investigators have been able to dissect pathways where these agents block the development of ACF or polyps. Not surprisingly, the preventive effects of almost all of these agents are exaggerated in rodent models, compared to more 9blunted9 effects in humans. The reasons for the differential responses of mice compared to humans are multifactorial including; genetic homogeneity of mice compared to genetic heterogeneity of humans, physiologic differences in gut motility, hormones, and immune surveillance, and differences in somatic genetic events during the ACF-to-adenoma-to-carcinoma sequence in mouse compared to human colorectal neoplasia. For example, the Min mouse, which is the 9mainstay9 of many colorectal cancer prevention studies develops primarily small bowel polyps as opposed to large bowel adenomas or cancer. Despite the aforementioned limitations, small animal models provide an efficient, inexpensive and safe surrogate for rapidly testing colorectal cancer prevention strategies. Moreover, approaches that are seemingly effective in preventing the early stages of colorectal tumorigenesis (such as folate supplementation), have been shown to actually promote tumor growth in later stages of the polyp-cancer sequence. This type of observation in mice is important in polyp prevention studies in humans where folate supplementation may actually be harmful in subjects already predisposed to colorectal neoplasia. Future advances in model development will require combinations of dietary and genetic manipulation of rodents or other inexpensive animals to more accurately mimic the various factors that contribute to colorectal neoplasia in humans. As epidemiologic and molecular studies demonstrate the heterogeneity of tumor development in different populations (eg the microsatellite instability or CIMP pathways), it is likely that a single model will not suffice. Moreover, larger animal models (eg. rats vs mice) are needed to provide investigators with the opportunity to survey and monitor polyp development in vivo using mini-endoscopic strategies.

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