Endothelial cell-expressed Tim-3 facilitates metastasis of melanoma cells by activating the NF-kappaB pathway

T cell immunoglobulin and mucin domain-3 (Tim-3) is originally recognized as a receptor of Th1 cells. We found that Tim-3 could be expressed in endothelial cells after stimulation with tumor cell-released TLR4 ligand. Tim-3 expressed by endothelial cells does not function as the receptor of galectin-9, but mediates the interaction of endothelial cells with tumor cells. The engagement of endothelial cell-expressed Tim-3 with a non-galectin 9 putative receptor on B16 melanoma cells could trigger the NF-kappaB signaling pathway in B16 cells. The activated NF-kappaB not only promoted the proliferation of B16 cells, but also enhanced apoptosis resistance of B16 cells by up-regulating Bcl-2 and Bcl-xL and down-regulating Bax. Consistently, Tim-3 facilitated the survival of B16 cells in the blood stream, arrested in the lung and following invasion, resulted in more metastatic nodules in the lung. These findings suggest that endothelial cell-expressed Tim-3 increases tumor cell metastatic potential by facilitating tumor cell intravasation, survival in blood stream and extravasation. Thus, anti-inflammation or blockade of Tim-3 may contribute to the prevention of metastasis.