Cellular adhesion pathways and metastatic potential of human melanoma

Cellular adhesion molecules of the cadherin, integrin, and immunoglobulin superfamilies are important to both growth and metastasis of many cancers, including malignant melanoma. Malignant melanoma is an excellent model for studying these molecules, due in part to a sequential series of five defineable stages. As the malignant phenotype of melanoma cells changes from the noninvasive radial growth phase to the vertical growth phase, which has high metastatic potential, so does the repertoire of the cellular adhesion molecules expressed on the cells surface. The cellular adhesion molecule MCAM/MUC18 confers metastatic potential and increased tumorgenicity to melanoma cells. MCAM/MUC18 mediates homotypic and heterotypic adhesion between melanoma cells and endothelial cells, respectively. Both types of interaction may promote metastasis at different stages in the metastasis cascade. We developed a fully humanized antibody to MCAM/MUC18 (ABX-MA1) that blocked melanoma metastasis in vivo. Furthermore, ABX-MA1 blocked the homotypic interaction between melanoma cells and endothelial cells as well as the promoter and collagenase activity of MMP-2. During melanoma progression the loss of E-cadherin expression disrupts normal homeostasis in the skin by freeing melanoma cells from structural and functional regulation by keratinocytes. The loss of functional E-cadherin is paralled by a gain in N-cadherin function that mediates homotypic interaction between melanoma cells, facilitates gap-junctional formation with fibroblasts and endothelial cells and promotes melanoma cell migration and survival. In addition, loss of E-cadherin may affect the β-catenin/wnt signaling pathways, resulting in deregulation of genes involved in growth and metastasis. The integrin family member α_vβ₃ is widely expressed on melanoma cells in the vertical growth phase. When α_vβ₃ is expressed in melanoma cells in the radial growth phase, this integrin is associated with increased tumor growth in vivo. α_vβ₃ may also promote melanoma invasion, through an interaction with MMP-2, and transendothelial migration, via a heterotypic melanomaendothelial cell interaction. This review summarizes recent knowledge on how changes in these adhesion molecules contribute to the acquisition of the metastatic phenotype in human melanoma.