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Sequential Analysis of Morphological and Biological Properties of ß-Catenin-accumulated Crypts, Provable Premalignant Lesions Independent of Aberrant Crypt Foci in Rat Colon Carcinogenesis¹

Department of Pathology, Gifu University School of Medicine, Gifu 500-8705, Japan

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

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