PRESENCE OF WELL-DIFFERENTIATED DISTAL, BUT NOT POORLY DIFFERENTIATEDPROXIMAL, RAT COLON CARCINOMAS IS CORRELATED WITH INCREASED CELL-PROLIFERATION IN AND LENGTHENING OF COLON CRYPTS

To determine whether colon crypt proliferative parameters were signifi cantly altered by the stage of colon carcinogenesis or the type or loc ation of colon tumors in rats, male Sprague-Dawley rats received an in jection of the carcinogen 1,2-dimethylhydrazine (12 mg DMH base/kg bod y weight) or DMH vehicle once a week for 8 weeks, then were killed 24 weeks later. Three hours before sacrifice, rats were injected with I m g/kg body weight colchicine to arrest mitotic cells at metaphase, Tran sverse sections of the colon mucosa were taken 6 cm from the anus and at least 3 cm from any tumor, fixed in formalin, then stained with hem atoxylin & eosin (H&E) for analyses of proliferative parameters. Only complete, mid-axial crypts were scored for mitotic count (MC), crypt p roliferative zone (PZ) height and crypt height (CH), Serial tumor sect ions were stained with H&E for histological evaluation or used in immu nohistochemical detection of transforming growth factor alpha (TGF alp ha). DMH treatment significantly increased MC, PZ and CH regardless of tumor status. The PZ and CH of rats with a carcinoma located in the d istal colon were significantly increased compared with DMH-treated rat s without an adenocarcinoma (AC) or with rats which had a tumor locate d in the proximal colon. Distal colon ACs were found to be well differ entiated and to have greater TGF alpha immunoreactivity than the gener ally less differentiated proximal colon carcinomas. Distal colon AC pr oduction and systemic circulation of a soluble colon crypt stimulating factor such as TGF alpha may explain the significant increase in PZ a nd CH in histologically normal colonic mucosa located away from the tu mor. (C) 1999 Wiley-Liss, Inc.