Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis

Abstract

It is now well established that bile acids act as colon tumor promoters. However, a previous study provided conflicting data showing that dietary exposure of cholic acid (CHA), a primary bile acid, inhibits the carcinogen-induced formation of aberrant crypt foci (ACF), possible preneoplastic lesions, in colonic mucosa of rodents. Recently we found beta-catenin-accumulated crypts (BCAC) in colonic mucosa of rats initiated with azoxymethane (AOM) and provided evidence that BCAC might be preneoplastic lesions independent from ACF. In the present study, we investigated the modifying effects of dietary CHA on the formation of BCAC as well as ACF in male F344 rats after exposure to AOM to determine if the differences in the effect of CHA on these lesions could account for this discrepancy. The results indicate that administration of CHA (0.5%) in the diet during the post-initiation phase significantly reduced the total number, multiplicity and size of ACF (P < 0.00001) in AOM-exposed colonic mucosa as reported previously. The number of ACF even with >4 aberrant crypts/focus was also decreased significantly (P < 0.0002), suggesting that the large ACF are little resistant to continuous feeding of 0.5% CHA diet. Interestingly, the dietary CHA significantly enhanced both the multiplicity (P < 0.002) and size (P < 0.00001), but not the incidence, of AOM-induced BCAC when compared with the control diet group. Importantly, the number of large BCAC with >6 crypts/lesion was increased significantly by the dietary CHA (P < 0.003). Our results support the concept that BCAC are precursors of colon tumors and indicate the usefulness of BCAC as intermediate biomarkers for colon carcinogenesis, although the methodology for their detection requires further improvement.

Gene mutations and altered gene expression in azoxymethane‐induced colon carcinogenesis in rodents

“…NO produced by iNOS causes DNA damage and neovascularization, while activating COX-2. Overexpression of COX-2 produces excess prostaglandins, and causes an increase in cell proliferation and decrease of apoptosis, to some extent mediated by PGE 2 receptor subtypes EP [1][2][3][4] .…”

“…Indeed, administration of PGE 2 enhanced colon carcinogenesis in rats treated with AOM through induction of cell proliferation and reduction of apoptosis. 53) Prostanoids exert their biological actions through binding to their specific membrane receptors and there are four PGE 2 receptor subtypes, EP [1][2][3][4] . Using prostaglandin E receptor subtype-knockout mice, the roles of these receptors in colon carcinogenesis have been investigated in our laboratory.…”

“…1,2) Recently, other pre-neoplastic lesions such as β-catenin-accumulated crypts and mucin-depleted foci have also been reported as specific biomarkers for colon carcinogenesis. [3][4][5] Compounds which appear to be effective in the short-term must then be further examined in longterm experiments focusing on AOM-induced colon cancer development. In order to identify novel prevention approaches, it is very important to take into account the mechanisms underlying colon carcinogenesis in this animal model, and this is the rationale for examining mutations in different genes and changes in expression of proteins.…”

Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers

“…21 However these ACF were unfrequent in Apc D14/ þ mice, and it is the reason why we chose to study the numerous early lesions present in the small intestine.…”

Chemoprevention of 1,2-dimethylhydrazine-induced colonic preneoplastic lesions in Fischer rats by 6-methylsulfinylhexyl isothiocyanate, a wasabi derivative

“…BcAc, another mucosal lesion, was evaluated in the present bioassay as a surrogate biomarker of colon carcinogenesis. our previous results indicated that BcAc are more sensitive and more reliable than AcF as intermediate biomarkers of colon carcinogenesis (31,32). Significantly, ACF and BCAC are considered to be independent and distinct, as they differ in biology, genetics and morphology (31,33,34).…”