Metastatic melanoma account for most skin cancer deaths. When diagnosed early, primary, non-disseminated, tumors are successfully eliminated through excision. However, in about 20% of the cases, dissemination of tumor cells leads to aggressive forms of cancers highly refractory to chemotherapy, with a median survival rate of 6 months . Uncovering molecules required for melanoma metastasis is therefore essential.
Hematogenous metastasis of cancer consists of several steps enabling cancer cells to intravasate, to survive in the blood circulation and to adhere to the vessels, eventually extravasating and establishing new metastatic lesions. Extravasation of most cancer cells largely mimics leukocyte transendothelial migration from the blood flow into sites of tissue inflammation . This controlled process involves the multistep action of traffic signals and adhesion molecules that mediate rolling, adhesion and transendothelial migration of lymphocytes .
The role of cell adhesion molecules (CAMs), such as intercellular cell adhesion molecule-1 (ICAM-1), vascular endothelial cell adhesion molecule-1 (VCAM-1), E-selectin, and P-selectin, has been studied extensively in the process of inflammation . Indeed, leukocyte adhesion during inflammation is thought to proceed in a cascade-like fashion, in which selectins are responsible for leukocyte capture and rolling, and integrins for mediating firm adhesion and transmigration [5, 6]. Among these integrins, Leukocyte Function-Associated antigen-1 (LFA-1; αLβ2) composed of two chains, CD11a and CD18, has been extensively described for its essential role in leukocyte extravasation [2, 7]. It functions as a receptor for ICAM-1 (CD54) [8–10]. Besides its role in the firm adhesion of leukocytes to the endothelium, it appears dominant in transendothelial migration [7, 11]. In addition numerous studies have shown that complete inhibition of CD18, or genetic mutations in CD18 profoundly reduce leukocyte transmigration at sites of inflammation .
Junctional Adhesion Molecules A (JAM-A) can also interact with LFA-1 via its second membrane-proximal Ig domain [13, 14]. During leukocyte transendothelial migration, the homophilic transendothelial interactions between two molecules of JAM-A must be disrupted to enable a migrating leukocyte to pass through junctions  and it has been evidenced that LFA-1 binding to JAM-A destabilizes the JAM-A homophilic interaction, thus allowing transendothelial migration to proceed .
LFA-1 has been studied in different tumors, for instance myelomas and gastrointestinal carcinomas. It has been shown that expression of LFA-1 correlates with the aggressiveness of myeloma  and is present in metastatic gastrointestinal carcinomas .
In melanoma cell lines, LFA-1 cell-surface expression is not detected. Towards a molecular explanation to the high capacity of melanoma tumor cells to metastase, two groups proposed that melanoma cells interact with neutrophils, thereby suggesting that neutrophils might be used as carriers by the tumor cells [19–21]. Liang et al. have notably demonstrated that under IL-8 signaling, melanoma interact with polymorphonuclear neutrophils (PMNs) through the binding between ICAM-1 on melanoma cells and β2 integrins on PMNs. The authors also showed that this interaction facilitates melanoma cell adhesion to the endothelial cells and subsequent extravasation by a shear-rate dependent mechanism .
However during our studies of melanoma metastasis, we observed that melanoma cell lines have the capacity to transmigrate through endothelial monolayers in the absence of PMNs. We therefore hypothesized that melanoma-endothelial cell co-culture might induce the ICAM-1/LFA-1 ligand-receptor interaction. In this manuscript we studied three human melanoma cell lines with differential transmigration capacities. We provide evidence that melanoma supernatants induce ICAM-1 expression on HUVEC cells, and that LFA-1 can be detected on melanoma cell lines when using HUVEC-conditioned medium. Further confirmation was obtained through the use of either ICAM-1 or LFA-1 blocking antibodies introduced during the co-culture and show that they strongly impair melanoma transmigration.