Chemoprevention of colon cancer: systematic review of preclinical studies in rats & mice.
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Min mouse, and other mutant mice and rats: colon cancer models.
A mutant mouse, Min, was found with multiple intestinal neoplasia in 1990 by Moser, Pitot & Dove
. It was shown to have a mutated Apc gene, similar to that in patients with familial adenomatous polyposis (FAP), and in many sporadic cancers. This promising animal model mimics the rapid development of adenomatous polyps that affect humans with germline inactivation of one Apc gene.
However, adenocarcinomas are seldom observed in this model, and no typical aberrant crypt foci (ACF) arise above the intestinal mucosa. Consequently, the ACF to carcinoma progression is not established in this model. Moreover, the K-ras mutations observed in many human tumors were not detected in Min mice polyps, and p53 inactivation, frequent in human cancers, does not raise tumor number in Min mice.
Following the Min mouse discovery with truncated Apc in position 850, other mice have been genetically modified so that one or more oncogenes hold a germline mutation (e.g., truncated Apc in positions 716, 1309, or 1638, and mutated Msh2 or Mlh1). A mutation on Msh2 or Mlh1 genes leads to mismatch repair defect, which makes these mice a model for human hereditary nonpolyposis colorectal cancers.
Like in humans, different mutations lead to different phenotypes: for instance, more adenomas are found in the gut of Apc716 mutant mice (250 polyps ± 95) than in classical Min mice (40 ± 20), or in Apc1309 and 1638 (30 and 3 polyps, respectively). Compared to Min mice, the number of polyps is higher in mice bearing both Apc850 and Msh2 mutations (160 ± 140 /small intestine, and 5 ± 5 /colon).
These mutant mouse models have increased our understanding of carcinogenesis. They have also provided a model to evaluate the effect of diets and chemopreventive agents. The model avoids the hazard of carcinogen handling, leads to shorter assay, but is more expensive than the AOM rat model.
Dietary treatments are typically begun for the mice by the age of 4-5 weeks, when tumors may be already present. A few studies have exposed the animals in utero, when neoplastic foci are already present. The timing mimics that of clinical intervention trials. Dietary interventions are given to adults that likely bear minute polyps, remaining after the visible ones have been removed. In most mouse studies it is the number of tumors in the small intestine that is the primary endpoint although some authors have split the small intestine between proximal and distal parts and shown that some agents afford a protection limited to the distal part. The major drawback of these mutants as models of human colon cancer is that their tumors occur predominantly in the small intestine, not the colon.
J.M. Amos-Landgraf et al. 2007 built a rat model carrying a knockout allele in the gatekeeper gene Adenomatous polyposis coli (Apc). They showed these so-called PIRC rats develop multiple neoplasms with a distribution between the colon and small intestine that simulates that found in human familial adenomatous polyposis patients much better than Min mice.
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Corpet DE & Taché S, 2002, Nutrition & Cancer - & - DE Corpet & F Pierre, 2003, Cancer Epidemiol. Biomarkers Prevention - http://www.inra.fr/reseau-nacre/sci-memb/corpet/indexan.html & Mirror site