Qualitative and quantitative relationship between dysplastic aberrant crypt foci and tumorigenesis in the Min/+ mouse colon

The multiple intestinal neoplasia (Min)/+ mouse, which harbors only one fun ctional allele of the Ape gene, is susceptible to environmental factors tha t disrupt this gene and subsequently trigger Ape-driven tumorigenesis in th e colon. Aberrant crypt foci (ACF) are assumed to be preneoplastic lesions in colon carcinogenesis. Recently, we reported the absence of "classical" A CF in the colon of untreated Min/+ mice. Instead we identified flat dysplas tic lesions, which we denoted ACF(Min) (J.E. Paulsen at al., Scand. J Gastr oenterol., 35: 534-539, 2000). In contrast to the classical type, ACF(Min) are not elevated above the surrounding mucosa, and their detection is total ly dependent on methylene blue staining and transillumination, In the prese nt study, we treated Min/+ mice with 5 mg/kg body weight azoxylmethane AOM at weeks 1 and 2 and demonstrated induction of both types of lesions. Howev er, only ACF(Min) appeared to be associated with the development of adenoma s. Monocryptal ACF(Min) large ACF(Min), and adenomas showed a uniform histo pathological picture of dysplasia and cytoplasmic overexpression of beta -c atenin, indicating a qualitative relationship between these lesions. Also a quantitative relationship was suggested because the dramatic decrease in A CF(Min) number from week 7 to II was paralleled by a reciprocal increase in tumor number, indicating fast-crypt multiplication of ACF(Min)., In AOM-tr eated +/+ (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 sh owed normal or hyperplastic crypfs with normal levels of beta -catenin expr ession. In AOM-treated Min/+ mice, the number of classical ACF was virtuall y constant from week 7 to Il, and only a modest increase of crypt multiplic ity mas observed. The number of AOM-induced classical ACF at week II was no t different in Min/+ mice and +/+ mice. Tn conclusion, we identified two di stinct populations of altered crypts in the colon of Min/+ mice after AOM t reatment. The ACF(Min), which resemble the dysplastic ACP described previou sly, clearly showed a continuous development from the monocryptal stage to adenoma, and they were characterized by fast-growing crypts with altered co ntrol of beta -catenin. In contrast, the classical ACF, which resemble the hyperplastic ACF described previously, were characterized by slow-growing c rypts with normal beta -catenin expression, and they were probably not rela ted to tumorigenesis.