The functional role of integrins during intra- and extravasation within the metastatic cascade.

Formation of distant metastases is by far the most common cause of cancer-related deaths. The process of metastasis formation is complex, and within this complex process the formation of migratory cells, the so called epithelial mesenchymal transition (EMT), which enables cancer cells to break loose from the primary tumor mass and to enter the bloodstream, is of particular importance. To break loose from the primary cancer, cancer cells have to down-regulate the cell-to-cell adhesion molecuIes (CAMs) which keep them attached to neighboring cancer cells. In contrast to this downregulation of CAMS in the primary tumor, cancer cells up-regulate other types of CAMs, that enable them to attach to the endothelium in the organ of the future metastasis. During EMT, the expression of cell-to-cell and cell-to-matrix adhesion molecules and their down- and upregulation is therefore critical for metastasis formation. Tumor cells mimic leukocytes to enable transmigration of the endothelial barrier at the metastatic site. The attachment of leukocytes/cancer cells to the endothelium are mediated by several CAMs different from those at the site of the primary tumor. These CAMs and their ligands are organized in a sequential row, the leukocyte adhesion cascade. In this adhesion process, integrins and their ligands are centrally involved in the molecular interactions governing the transmigration. This review discusses the integrin expression patterns found on primary tumor cells and studies whether their expression correlates with tumor progression, metastatic capacity and prognosis. Simultaneously, further possible, but so far unclearly characterized, alternative adhesion molecules and/or ligands, will be considered and emerging therapeutic possibilities reviewed.