A rat colon cancer model induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, PhIP.
2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is one of the most abundant heterocyclic amines contained in cooked meat and fish, and induces aberrant crypt foci (ACF), putative preneoplastic lesions of the colon, and colon cancers in male rats when administered orally. As has been reported previously, F344 rats are susceptible to induction of ACF by PhIP, while ACI rats being relatively resistant. Approximately one-fourth of ACF induced by PhIP in F344 rats are dysplastic; exhibiting lesions with structural distortion of the crypt, decrease of goblet cells, nuclear stratification and enlargement of nuclei. Dysplastic ACF demonstrate beta-catenin accumulation, mainly in the cytoplasm, and increased cell proliferation in crypts. These dysplastic ACF are, therefore, strongly considered to be putative preneoplastic lesions of the colon.A genetic trait affecting the susceptibility to colon carcinogenesis in F344 rats was mapped to chromosome 16, between D16Rat17 and D16Wox3, using the number of ACF as a surrogate biomarker for colon carcinogenesis. Since the number of dysplastic lesions is well correlated with the total number of ACF, being approximately one-fourth of the total ACF as described above in F344 rats and will be described elsewhere in ACI rats, the gene involved in the susceptibility to ACF induction may possibly be partly responsible for the susceptibility to colon carcinogenesis by PhIP. We, thus, tentatively referred the name of the candidate susceptibility gene on rat chromosome 16 as susceptibility to colon tumor (Sct). In the present study, the colonic lesions induced by PhIP were well refined histologically and genetically, and the multi-step profiles of colon cancer development by PhIP were well characterized and revealed to be similar to the multi-step model of colon carcinogenesis in humans. The PhIP-induced colon cancer model in rats, thus contributes as a relevant tool to elucidate genetic factors responsible for susceptibility to colon carcinogenesis in human. Other unknown genetic or epigenetic alterations, which are essential for the development of early lesions of colon carcinogenesis, could also be clarified using this system.
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002875:Chromosomes / Q000235:genetics; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005819:Genetic Markers / Q000502:physiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D051381:Rats; D011912:Rats, Inbred ACI; D011916:Rats, Inbred F344
D002273:Carcinogens; D005819:Genetic Markers; D007093:Imidazoles; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine