Increased tight junctional permeability is associated with the developmentof colon cancer

Epithelial tissues act as barriers between two fluid compartments, and the epithelial barrier function is provided by the epithelial cells and the tig ht junctions (TJs) that connect them. We have shown previously that chronic treatment of a cultured epithelial monolayer with phorbol ester tumor prom oters induces an increase in transepithelial paracellular permeability and produces tumor-like polyps, suggesting an association between TJ permeabili ty and tumor formation. In this study, we analyzed the association between TJ permeability and formation of tumors in vivo. The permeability of the TJ s was assessed in normal human and rat colon epithelia and in colon tumors by measuring the transepithelial electrical resistance, the paracellular fl ux rate of D-[C-14]mannitol and the electron microscopic evaluation of the penetration of the electron dense dye ruthenium red across the TJs, By thes e criteria, the TJs of human colon tumors, including carcinomas and adenoma tous polyps, and the TJs of 1,2-dimethylhydrazine (DMH)-induced rat colon t umors were leakier than the TJs of normal colon. Treatment of rats with the carcinogen DMH induced a progressive increase in the number of aberrant co lonic crypts, considered the putative pre-neoplastic colonic phenotype whil e increasing TJ permeability of the colon epithelium prior to the developme nt of tumors. These results showed that increased TJ permeability of the co lon epithelium and consequently a decrease in epithelial barrier function p recede the development of colon tumors.