Regulation of transendothelial migration of colon cancer cells by E‐selectin‐mediated activation of MAP kinases in endothelial cells

Abstract

Cancer cells invasive properties depend on their intrinsic motile potential and their ability to breach the endothelial barrier. In the present work, we investigated mechanisms by which adhesion of colon cancer cells to E-selectin expressed by endothelial cells regulates the endothelial barrier function and modulates cancer cells transmigration. We found that stimulation of E-selectin by the adhesion of HT-29 cells, in a static or a dynamic fashion, results in increased activity of ERK and p38 MAP kinases. In turn, activation of p38 and ERK enhanced transendothelial permeability and migration of HT-29 cells. We also obtained evidence suggesting that p38-mediated increase in transendothelial permeability and cancer cells migration depends on a myosin light chain phosphorylation-mediated formation of stress fibers. On the other hand, the activation of ERK by E-selectin modulated the opening of interendothelial spaces by initiating the activation of Src kinase activities and the dissociation of the VE-cadherin/b-catenin complex. Thus, we conclude that activation of E-selectin by adhering cancer cells is an important process that regulates the extravasation of colon cancer cells by initiating p38- and ERK-dependent mechanisms that both contribute to the regulation of the integrity of the endothelial layer.