Liang S, Dong C. Integrin VLA-4 enhances sialyl-Lewis x/a -negative melanoma adhesion to and extravasation through the endothelium under low flow conditions. Am J Physiol Cell Physiol 295: C701-C707, 2008. First published July 16, 2008 doi:10.1152/ajpcell.00245.2008.-During their passage through the circulatory system, tumor cells undergo extensive interactions with various host cells including endothelial cells. The capacity of tumor cells to form metastasis is related to their ability to interact with and extravasate through endothelial cell layers, which involves multiple adhesive interactions between tumor cells and endothelium (EC). Thus it is essential to identify the adhesive receptors on the endothelial and melanoma surface that mediate those specific adhesive interactions. P-selectin and E-selectin have been reported as adhesion molecules that mediate the cell-cell interaction of endothelial cells and melanoma cells. However, not all melanoma cells express ligands for selectins. In this study, we elucidated the molecular constituents involved in the endothelial adhesion and extravasation of sialyl-Lewis x/a -negative melanoma cell lines under flow in the presence and absence of polymorphonuclear neutrophils (PMNs). Results show the interactions of ␣41 (VLA-4) on sialylLewis x/a -negative melanoma cells and vascular adhesion molecule (VCAM-1) on inflamed EC supported melanoma adhesion to and subsequent extravasation through the EC in low shear flow. These findings provide clear evidence for a direct role of the VLA-4/ VCAM-1 pathway in melanoma cell adhesion to and extravasation through the vascular endothelium in a shear flow. PMNs facilitated melanoma cell extravasation under both low and high shear conditions via the involvement of distinct molecular mechanisms. In the low shear regime, 2-integrins were sufficient to enhance melanoma cell extravasation, whereas in the high shear regime, selectin ligands and  2-integrins on PMNs were necessary for facilitating the melanoma extravasation process. tumor cell extravasation; vascular adhesion molecule-1; leukocytes; inflammation MALIGNANT MELANOMA has a high propensity for metastatic spread making it the most deadly form of skin cancer. An important step in the metastatic process is the arrest of melanoma cells in the venous or capillary bed of the target organ and subsequent extravasation (3, 5). Therefore, it is important to identify and characterize adhesive receptors on the endothelial and melanoma surfaces that mediate their specific adhesive interactions. P-selectin and E-selectin have been reported as adhesion molecules that mediate the cell-cell interaction of endothelial cells (EC) and melanoma cells (35,36). Members of the selectin family are structurally related, containing a lectin-binding domain that recognizes specific carbohydrates (30). However, not all melanoma cells express ligands for selectins (29, 37), which raised the question as to whether selectin-mediated binding of melanoma cell to the EC is necessary for initiating the adhesi...