Alteration of Interendothelial Adherens Junctions Following Tumor Cell–Endothelial Cell Interactionin Vitro (original) (raw)

1997, Experimental Cell Research

mary tumor to distant sites. In order to establish new The integrity of the vascular endothelium is mainly tumor foci, circulating tumor cells must escape from dependent upon the organization of interendothelial the vascular system. The extravasation process can be adherens junctions (AJ). These junctions are formed summarized as a sequence of events which include tuby the homotypic interaction of a transmembrane promor cell adhesion to the vascular endothelium, tumor tein, vascular endothelial cadherin (VE-cadherin), cell-mediated opening of endothelial cell-to-cell juncwhich is complexed to an intracellular protein nettions, adhesion to the underlying basement membrane, work including a-, band nd g-catenin. Additional proand subsequent invasion of the host tissue [1]. teins such as vinculin and a-actinin have been sug-The endothelium forms a continuous permselective gested to link the VE-cadherin/catenin complex to the barrier that regulates the passage of plasma proteins actin-based cytoskeleton. During the process of hemaand circulating cells from blood to tissue. The permetogenous metastasis, circulating tumor cells must disability of the endothelium depends upon specialized rupt these intercellular junctions in order to extravajunctions that are responsible for the lateral plasma sate. In the present study, we have investigated the membrane cohesion between adjacent endothelial cells influence of tumor cell-endothelial cell interaction (EC). On the basis of morphological and functional upon interendothelial AJ. We show that human breast characteristics, at least three types of junctions have adenocarcinoma cells (MCF-7), but not normal human been identified in EC: tight junctions, gap junctions, mammary epithelial cells, induce a rapid endothelial and adherens junctions (AJ). The mechanical resiscell (EC) dissociation which correlates with the loss of tance of interendothelial linkage can be, in a large part, VE-cadherin expression at the site of tumor cell-EC assigned to AJ while tight junctions and gap junctions contact and with profound changes in vinculin distribution and organization. This process could not be have been shown to play a role in the control of the inhibited by metalloproteinase nor serine protease in-permeability to plasma proteins and in the exchange hibitors. Immunoprecipitations and Western blot analof ions and small size molecules between adjacent EC, ysis demonstrate that the overall expression of VErespectively [2]. cadherin and vinculin as well as the composition of Recently, the transmembrane protein involved in enthe VE-cadherin/catenins complex are not affected by dothelial AJ was identified and characterized [3, 4]. tumor cells while the tyrosine phosphorylation status This protein, vascular endothelial cadherin (VE-cadof proteins within the complex is significantly altered. herin) (cadherin 5), belongs to the cadherin family of Our data suggest that tumor cells modulate AJ protein proteins and is selectively expressed in EC from most distribution and phosphorylation in EC and may, types of vessels [3]. As other classical cadherins such thereby, facilitate EC dissociation. ᭧ 1997 Academic Press as E-, Nor or P-cadherins, VE-cadherin is a transmembrane calcium-dependent adhesion molecules that mediate cell-cell interactions through homophilic bind-INTRODUCTION ing. The intracellular domain of VE-cadherin interacts with at least three known cytoplasmic proteins: a-ca-Blood and lymphatic circulations are the major ways tenin, b-catenin, and g-catenin (plakoglobin) [4]. The for metastatic tumor cells to disseminate from the priassociation of VE-cadherin with the catenins and the interaction between the VE-cadherin/catenin complex 1 To whom correspondence and reprint requests should be adand cytoskeletal proteins govern the strength of interdressed at Laboratory of Cellular Biology, Tower of Pathology, B23, endothelial cohesion and the transendothelial perme-CHU,