High affinity interaction of integrin α4β1 (VLA-4) and vascular cell adhesion molecule 1 (VCAM-1) enhances migration of human melanoma cells across activated endothelial cell layers

The capacity of tumor cells to form metastatic foci correlates with their ability to interact with and migrate through endothelial cel I layers. This process involves multiple adhesive interactions between tumor cells and the endothelium. Only little is known about the molecular nature of these interactions during extravasation of tumor cells. In human melanoma cells, the integrin alpha v beta 3 is involved in transendothelial migration and its expression correlates with metastasis. However, many human melanoma cells do not express beta 3 integrins. Therefore, it remained unclear how these cells undergo transendothelial migration. In this study we show that human melanoma cells with different metastatic potency, which do not express beta 2 or beta 3 integrins, express the VCAM-I receptor alpha 4 beta 1. VCAM-I is up-regulated on activated endothelial cells and is known to promote transendothelial migration of leukocytes. Interestingly, despite comparable cell surface levels of alpha 4 beta 1, only the highly metastatic melanoma cell lines MV3 and BLM, but not the low metastatic cell lines IF6 and 530, bind VCAM-I with high affinity without further stimulation, and are therefore able to adhere to and migrate on isolated VCAM-1. Moreover, we demonstrate that function-blocking antibodies against the integrin alpha 4 beta 1, as well as siRNA-mediated knock-down of the alpha 4 subunit in these highly metastatic human melanoma cells reduce their transendothelial migration. These data imply that only high affinity interactions between the integrin alpha 4 beta 1 on melanoma cells and VCAM-I on activated endothelial cells may enhance the metastatic capacity of human beta 2/beta 3-negative melanoma cells.