Cell-cell contacts in melanoma and the tumor microenvironment

Cell-contacts are essential for intercellular communication and are involved in proliferation, differentiation, and homeostasis. Melanocytes establish multiple contacts with keratinocytes, which in turn control melanocyte growth and expression of cell surface receptors. Most melanoma arise within the epidermis (melanoma in situ) and then invade across the basement membrane. These melanoma cells escape from control by keratinocytes through five major mechanisms: (1) downregulation of receptors important for communication with keratinocytes such as E-cadherin, P-cadherin, desmoglein, and connexins; (2) upregulation of receptors and signaling molecules important for interactions between melanoma cells and other melanoma cells, fibroblasts, or endothelial cells, such as N-cadherin, Mel-CAM, and zonula occludens protein-1 (ZO-1); (3) deregulation of morphogens such as Notch receptors and their ligands; (4) loss of anchorage to the basement membrane due to altered expression of cell-matrix adhesion molecules; (5) increased expression of metalloproteinases. Melanoma depends on, interacts with and reacts to its stroma, including extracellular matrix, growth factors, cytokines, fibroblasts, endothelial cells, and immune cells. In turn, melanoma is known to produce factors that influence its environment, and may force it to alter cell-cell communication. In this chapter, we describe the alterations in cell-cell contacts in melanoma and the tumor microenvironment associated with melanoma development and progression.