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Qualitative and Quantitative Relationship between Dysplastic Aberrant Crypt Foci and Tumorigenesis in the Min/+ Mouse Colon

Department of Environmental Medicine, National Institute of Public Health, 0403 Oslo [J. E. P., I-L. S., T. H., E. N., J. A.], and Department of Pathology, Ullevål University Hospital, N-0407 Oslo [E. M. L.], Norway

The multiple intestinal neoplasia (Min)/+ mouse, which harbors only one functional allele of the Apc gene, is susceptible to environmental factors that disrupt this gene and subsequently trigger Apc-driven tumorigenesis in the colon. Aberrant crypt foci (ACF) are assumed to be preneoplastic lesions in colon carcinogenesis. Recently, we reported the absence of "classical" ACF in the colon of untreated Min/+ mice. Instead we identified flat dysplastic lesions, which we denoted ACF_Min (J. E. Paulsen et al., Scand. J. Gastroenterol., 35: 534–539, 2000). In contrast to the classical type, ACF_Min are not elevated above the surrounding mucosa, and their detection is totally dependent on methylene blue staining and transillumination. In the present study, we treated Min/+ mice with 5 mg/kg body weight azoxymethane (AOM) at weeks 1 and 2 and demonstrated induction of both types of lesions. However, only ACF_Min appeared to be associated with the development of adenomas. Monocryptal ACF_Min, large ACF_Min, and adenomas showed a uniform histopathological picture of dysplasia and cytoplasmic overexpression of ß-catenin, indicating a qualitative relationship between these lesions. Also a quantitative relationship was suggested because the dramatic decrease in ACF_Min number from week 7 to 11 was paralleled by a reciprocal increase in tumor number, indicating fast-crypt multiplication of ACF_Min. In AOM-treated +/+ (wild-type) littermates, a low number of ACF_Min and tumors with the same characteristics as in Min/+ mice was seen. In contrast to ACF_Min, histopathological and immunohistochemical examination of classical ACF showed normal or hyperplastic crypts with normal levels of ß-catenin expression. In AOM-treated Min/+ mice, the number of classical ACF was virtually constant from week 7 to 11, and only a modest increase of crypt multiplicity was observed. The number of AOM-induced classical ACF at week 11 was not different in Min/+ mice and +/+ mice. In conclusion, we identified two distinct populations of altered crypts in the colon of Min/+ mice after AOM treatment. The ACF_Min, which resemble the dysplastic ACF described previously, clearly showed a continuous development from the monocryptal stage to adenoma, and they were characterized by fast-growing crypts with altered control of ß-catenin. In contrast, the classical ACF, which resemble the hyperplastic ACF described previously, were characterized by slow-growing crypts with normal ß-catenin expression, and they were probably not related to tumorigenesis.

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