Sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis

Our previous study (Cancer Res., 60: 3323-3327, 2000) showed that frequent beta -catenin gene mutations are present in beta -catenin-accumulated crypt s, which occur early in rodent colonic carcinogenesis, with a lack of the a ppearance of aberrant crypt foci (ACF), To clarify the nature of such lesio ns, we performed a sequential analysis of the morphological and biological properties of beta -catenin-accumulated crypts, Azoxymethane was administer ed s.c. to male F344 rats (15 mg/kg body weight) once a week for 3 weeks, a nd the animals were sacrificed at 5, 10, and 20 weeks after the carcinogen treatment. Both the number of crypts/lesion and the diameter of beta -caten in-accumulated crypts were significantly increased with time courses of 5, 10, and 20 weeks from carcinogen exposure (P < 0.01). Likewise, the histolo gical abnormality in those crypts, assessed by semiquantitative analyses, w as also increased with time (P < 0.01). Conversely, ACF did not show any in crease in histological abnormality during the time course and maintained a monotonous histology throughout the experiment. The histological abnormalit y score fur beta -catenin-accumulated crypts was significantly higher than for ACF at every time point (P < 0.001). The number of AgNOR/nucleus in <be ta>-catenin-accumulated crypts was significantly higher than in ACF (P < 0. 001). <beta>-Catenin-accumulated crypts were accompanied frequently by Pane th cells and had decreased hexosaminidase activity. such data, together wit h the results in our previous report, strongly suggest that beta -catenin-a ccumulated crypts, which are independent of ACF, are truly premalignant les ions for colon cancer.