Azoxymethane-induced beta-catenin-accumulated crypts in colonic mucosa of rodents as an intermediate biomarker for colon carcinogenesis.
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.
Hirose
Yoshinobu
Y
Department of Tumor Pathology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan. yhirose@cc.gifu-u.ac.jp
Kuno
Toshiya
T
Yamada
Yasuhiro
Y
Sakata
Keiko
K
Katayama
Masaki
M
Yoshida
Koujiro
K
Qiao
Zheng
Z
Hata
Kazuya
K
Yoshimi
Naoki
N
Mori
Hideki
H
D000818:Animals; D001397:Azoxymethane / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D003106:Colon / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051381:Rats; D018570:Risk Assessment; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
D014408:Biomarkers, Tumor; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D001397:Azoxymethane