Are Corrupted Non-dysplastic Colonic Crypts the First Histological Event in Experimental Colonic Carcinogenesis?

Background: The colonic crypts in rats replicate by symmetric fission at the base of the crypts, and proceeds upwards, to generate two separate identical crypts. Recently, anomalous crypts (called corrupted colonic crypts, CCCs) were found in the colonic mucosa of Sprague-Dawley rats treated with the carcinogen dimethylhydrazine. Here it was investigated whether CCCs develop in the colonic mucosa of another rat strain, treated with a different carcinogen. Materials and Methods: Archived Swiss-roll colon sections from 25 male Fisher-344 rats treated with the mutagen 2-amino-6-methyldipyrido imidazole (GLU1) were reviewed. Non-dysplastic and dysplastic CCCs were regarded as those exhibiting asymmetric fission, asymmetric lateral sprouting/lateral fission, basal dilatations, or spatial aberrations of the normal (vertical) axis. Colonic adenomas were found in three out of the 25 specimens. Results: In the entire colonic mucosa of the 25 GLU1-treated rats, 130 non-dysplastic CCCs were recorded amongst 357 non-dysplastic crypts with fission (36.4%). The mean number of non-dysplastic CCCs per animal was 5.2 (range=2-12). These numbers only mirror events taking place at a particular time (i.e. at sacrifice). Considering the high cell production rate of the colonic crypts, the actual number of CCCs/rat occurring during the usual mucosal turnover time of 72 hours might be substantial. In the three adenoma specimens, non-dysplastic CCCs were found underneath CCCs with dysplasia. Discussion and Conclusion: For many years, the development of crypt dysplasia and adenoma have been considered the initial histological events in colonic carcinogenesis. This study demonstrates that non-dysplastic CCCs also develop in GLU 1-treated Fisher-344 rats. Non-dysplastic CCCs were found underneath CCCs with dysplasia. Non-dysplastic CCCs might act as scaffolds at the time of top-down cell replacement/transformation of the crypts by dysplastic cells. It is submitted that non-dysplastic CCCs might be the initial histological recordable event in experimental colonic carcinogenesis.

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