CELL-CELL INTERACTIONS DURING TRANSENDOTHELIAL MIGRATION OF TUMOR-CELLS

A key event in cancer metastasis is the transendothelial migration of tumor cells. This process involves multiple adhesive interactions betw een tumor cells and the endothelium. After adhering to the surface of endothelial cells, tumor cells must penetrate the endothelial junction , which contains high concentrations of the cell adhesion molecules VE -cadherin and PECAM-1. Studies using an in vitro model system, consist ing of melanoma cells which are seeded onto a monolayer of endothelial cells cultured on Matrigel, have revealed reorganization of the cytos keleton and dynamic changes in the cell shape of both tumor and endoth elial cells. The initial stages of transmigration are characterized by numerous membrane blebs protruding from the basolateral surfaces of t he melanoma cells. Contact regions also show an abundance of microfila ments arising from the underlying endothelial cells. These adhesive in teractions lead to the redistribution of both VE-cadherin and PECAM-1 and, consequently, a localized dissolution of the endothelial junction . The penetration of the endothelial junction is initiated by melanoma pseudopods. Despite the disappearance of VE-cadherin from the retract ing endothelial junction, heterotypic contacts between the tumor cell and its surrounding endothelial cells show a high concentration of pan -cadherin staining, suggesting that transmigration of melanoma cells m ight yet be facilitated by interactions with another member of the cad herin family. Upon adhesion to the Matrigel, melanoma cells begin to s pread and invade the matrix material, while the endothelial cells exte nd processes over the melanoma cells to reform the monolayer. Interest ingly, the leading margins of these endothelial processes contain a hi gh concentration of N-cadherin. VE-cadherin and PECAM-1 reappear only when the advancing endothelial processes meet to reform the endothelia l junction. Together, these observations suggest that endothelial cell s actively participate in the transmigration of tumor cells and specif ic cadherins are involved in different steps of this complex process. (C) 1998 Wiley-Liss, Inc.