Increased tight junctional permeability is associated with the development of colon cancer

• Published in: Carcinogenesis (New York) Vol. 20; no. 8; pp. 1425 - 1432
• Main Authors: Soler, Alejandro Peralta, Miller, R.Daniel, Laughlin, Kathleen V., Carp, Ned Z., Klurfeld, David M., Mullin, James M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.08.1999; Oxford Publishing Limited (England)
• Subjects: 1,2-Dimethylhydrazine; 2-dimethylhydrazine; Animals; Biological and medical sciences; Carcinogens; Cell Membrane Permeability - drug effects; Cell Membrane Permeability - physiology; Colon - drug effects; Colon - physiopathology; Colon - ultrastructure; Colonic Neoplasms - chemically induced; Colonic Neoplasms - physiopathology; DMH; Electric Impedance; Electron microscopy; Epithelial Cells - drug effects; Epithelial Cells - physiology; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Intestinal Mucosa - drug effects; Intestinal Mucosa - physiopathology; Male; Medical sciences; Microscopy, Electron; Precancerous Conditions - chemically induced; Precancerous Conditions - physiopathology; Rats; Rats, Sprague-Dawley; ruthenium red; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; tight junction; Tight Junctions - drug effects; Tight Junctions - physiology; transepithelial electrical resistance; Tumors; Human; Animal model; Rat; Tumoral tissue; Rodentia; Permeability; Malignant tumor; Colonic disease; Carcinogen; Vertebrata; Mammalia; Animal; Tumor progression; Digestive diseases; Intestinal disease; Tight junction; Colon
• ISSN: 0143-3334; 1460-2180; 1460-2180
• DOI: 10.1093/carcin/20.8.1425

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