Mel-CAM-specific genetic suppressor elements inhibit melanoma growth and invasion through loss of gap junctional communication

Normal human melanocytes are interspersed singly among keratinocytes along the basement membrane of the epidermis, whereas melanoma cells readily adhe re to each other during invasion of the dermis or distant organs. The tumor igenic and metastatic phenotype of melanoma cells often correlates with inc reased expression of cell-cell and cell-matrix adhesion receptors. Mel-CAM (MCAM, MUC 18, CD146) is a cell-cell adhesion receptor highly expressed by melanoma cells but not normal melanocytes. We show here that inhibition of Mel-CAM expression in metastatic melanoma cells using genetic suppressor el ements of Mel-CAM cDNA leads to inhibition of adhesion between melanoma cel ls and to downregulation of the tumorigenic phenotype. Growth was not inhib ited in genetic suppressor elements-transduced melanoma cells cultured in m onolayers but was inhibited when cells were maintained anchorage-independen tly in soft agar and greatly reduced in immunodeficient mice. A three-dimen sional epidermal skin equivalent model demonstrated that Mel-CANT allows me lanoma cells to separate from the epidermis and invade the basement membran e zone and dermis. However, melanoma cells with little or no Mel-CAM were p oorly invasive, possibly due to their loss of gap junctional communication. These results suggest the multifunctional role of a melanoma-associated ce ll-cell adhesion receptor in tumor progression.