Early Stages of 1,2-Dimethylhydrazine-induced Colon Carcinogenesis Suppress Immune-regulated Ion Transport of Mouse Distal Colon

Genetic events, such as gene deletion, mutation, and amplification, are involved in the development and progression of colonic neoplasia. The importance of interactions between immune cells and neoplastic cells in influencing the pathogenesis of colon cancer is suggested by the clinical efficacy of levamisole, an immunostimulant, in the treatment of colon cancer and by the association of local lymphocytic infiltration with improved prognosis. Thus, the immune cell-neoplastic cell interaction can be viewed as being analogous to various host-parasite relationships that involve the immune system attempting to contain the intruding parasite on the one hand and the parasite attempting to escape detection and rejection on the other. This study is an attempt to gain a better understanding of such interactions by examining possible effects of a developing tumor on the immune system. Colon cancer was experimentally induced in mice to examine potential effects of carcinogenesis in the colon on local mucosal immune function in situ, using the expression of type I hypersensitivity as an index of immune function. Antigen-induced changes in net ion transport, a quantifiable correlate of type I hypersensitivity, were measured in the colon of mice following the administration of the procarcinogen 1,2-dimethylhydrazine (DMH). Segments of colon and small intestine from mice immunized by infection with Trichinella spiralis secrete ions, manifested as a rise in transmural short-circuit current, when challenged with T. spiralis antigen in Ussing chambers. Antigen-induced rise in transmural short-circuit current is mast cell dependent and occurs only in immunized mice. To determine the effects of early stages of colon carcinogenesis on this mucosal immune response, mice were immunized with T. spiralis prior to and after 6 weekly injections of DMH. Responsiveness to antigenic challenge was suppressed in the distal colon 4-6 weeks after the final injection of DMH. Although responsiveness to antigen was suppressed, the colonic epithelium remained sensitive to direct stimulation by exogenous secretagogues. Decreased antigen responsiveness observed in the distal colon was not due to generalized immune suppression by DMH, because the proximal colon and the jejunum retained their responsiveness to antigen, and immune rejection of a secondary T. spiralis infection from the small intestine was not altered. Visible tumors eventually developed 30 weeks after the final injection of DMH only in the distal portions of the colon. These results suggest that early stages of DMH-induced carcinogenesis are associated with the suppression of mucosal immune function, as measured by immune-regulated ion secretion, in the distal colon but not in the proximal colon or jejunum. Future elucidation of the mechanisms by which this localized immunosuppression occurs may provide clues to the microenvironmental changes necessary for tumor progression in the distal colon.