Journal Article

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

Alejandro Peralta Soler, R.Daniel Miller, Kathleen V. Laughlin, Ned Z. Carp, David M. Klurfeld and James M. Mullin

in Carcinogenesis

Volume 20, issue 8, pages 1425-1432
Published in print August 1999 | ISSN: 0143-3334
Published online August 1999 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/20.8.1425
Increased tight junctional permeability is associated with the development of colon cancer

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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.

Keywords: DMH, 1,2-dimethylhydrazine; EM, Electron microscopy; RR, ruthenium red; Rt, transepithelial electrical resistance; TJ, tight junction

Journal Article.  5375 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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