COLONIC CRYPTS LOCATED OVER LYMPHOID NODULES OF 1,2-DIMETHYLHYDRAZINE-TREATED RATS ARE HYPERPLASTIC AND AT HIGH-RISK OF FORMING ADENOCARCINOMAS

Male, Sprague-Dawley rats were injected subcutaneously with the colon carcinogen 1,2-dimethylhydrazine (DMH) at a dosage of 9.5 mg DMH base/per kg rat body weight once weekly for 8 weeks; control rats received an equivalent volume of the vehicle. Analyses of variance showed that in carcinogen-treated as well as in non-carcinogen-treated rats, the proliferative zone height and the crypt height in colonic crypts located over the aggregates of lymphoid nodules (ALN) were significantly higher than in colonic crypts located away from the ALN. Immunohistochemical localization of transforming growth factor a (TGF alpha) showed that this mitogenic factor was found in cells in the proliferative zone of colonic crypts located over the ALN, but TGF alpha was not detectable in cells in the proliferative zone of colonic crypts located away from the ALN. Examination of histological sections of the colon taken through the ALN of DMH-treated rats revealed that eight out of 25 DMH-treated rats had microscopic adenocarcinomas (AC) within the ALN, but in the same rats no microscopic AC were seen in histological sections taken away from the ALN. Furthermore, there was no evidence of an adenomatous precursor to these microscopic, endophytic AC, suggesting that the endophytic AC arose de novo. Therefore, because of (i) the significantly higher proliferative activity in colonic crypts located over the ALN, (ii) the localization of TGF alpha in the proliferative zone of the colonic crypts associated with ALN and (iii) the high incidence of endophytic AC associated with ALN, it seems likely that factors emanating from the ALN are promotional to carcinogenesis in the colonic epithelium that is located in close proximity to the ALN.