The transepithelial transport processes which occur in the gastrointestinal and urinary tract are responsible for the reabsorption and retention of nutrients, salt and water, processes which are the hallmark of all higher forms of life. The epithelial cells performing this work have tow key characteristics: 1) they are all polar, possessing distinct """"""""front"""""""" (luminal) and """"""""back"""""""" (anti-luminal) membranes containing completely different sets of proteins; and 2) the spaces between individual cells are selectively seal4ed by a network of protein strands called the tight junction (TJ). Taken together these properties allow an epithelial cell sheet to form a selective barrier between two compartments, the primary function of all epithelial. Any receptor-mediated process which can increase TF permeability, and thereby decrease epithelial barrier function, will profoundly affect homeostasis of a tissue and organism. Our earlier findings that activation of protein kinase C causes severe increases in TJ permeability portends dramatic alternatives of not only physiological but also development and neoplastic processes. Although moist clinicians and researcher are aware for example the salt and water gradients across epithelia, only very few would be aware that this extends to proteins as well. One result is that the luminal fluid compartments of epithelial tissues contain extremely high concentrations of specific growth factors. Because the receptors for these growth factors are on the opposite (anti-luminal) cell surface, any processes which make TJ's leaky to these proteins will profoundly alter cell growth within that tissue by simply allowing ligands to access receptors. We have shown that TJ's can be made leaky by phorbol ester tumor promoters (PKC activation) and area leaky in epithelial tumors. It is well known that the cancers accounting for most deaths worldwide are all epithelial in origin, and that the incidence of these cancers increases with age. Because of our hypothesis that TJ leakiness plays a causal role in epithelial tumor development we therefore wish to test our hypothesis that the age-relationship of many epithelial cancers drives from an age- related breakdown of epithelial barrier function at the level of the TJ.
| Mullin, J M; Valenzano, M C; Verrecchio, J J et al. (2002) Age- and diet-related increase in transepithelial colon permeability of Fischer 344 rats. Dig Dis Sci 47:2262-70 |
