ALTERATION OF INTERENDOTHELIAL ADHERENS JUNCTIONS FOLLOWING TUMOR CELL-ENDOTHELIAL CELL-INTERACTION IN-VITRO

The integrity of the vascular endothelium is mainly dependent upon the organization of interendothelial adherens junctions (AJ). These junct ions are formed by the homotypic interaction of a transmembrane protei n, vascular endothelial cadherin (VE cadherin), which is complexed to an intracellular protein network including alpha-, beta-, and gamma-ca tenin. Additional proteins such as vinculin and alpha-actinin have bee n suggested to link the VE-cadherin/catenin complex to the actin-based cytoskeleton. During the process of hematogenous metastasis, circulat ing tumor cells must disrupt these intercellular junctions in order to extravasate. In the present study, we have investigated the influence of tumor cell-endothelial cell interaction upon interendothelial AJ. We show that human breast adenocarcinoma cells (MCF-7), but not normal human mammary epithelial cells, induce a rapid endothelial cell (EC) dissociation which correlates with the loss of VE-cadherin expression at the site of tumor cell-EC contact and with profound changes in vinc ulin distribution and organization. This process could not be inhibite d by metalloproteinase nor serine protease inhibitors. Immunoprecipita tions and Western blot analysis demonstrate that the overall expressio n of VE-cadherin and vinculin as well as the composition of the VE-cad herin/catenins complex are not affected by tumor cells while the tyros ine phosphorylation status of proteins within the complex is significa ntly altered. Our data suggest that tumor cells modulate AJ protein di stribution and phosphorylation in EC and may, thereby, facilitate EC d issociation. (C) 1997 Academic Press.