Putting melanoma in context: Regulation and function of intercellular communications in melanocytic homeostasis

Melanoma development not only involves genetic and epigenetic changes that take place within the transformed cells, but also involves processes that are determined collectively by contextual factors including intercellular adhesions and communications. My studies have been focused on cadherin-mediated intercellular communications, and growth factor/cytokine-mediated paracrine/autocrine communications during melanoma development. E-cadherin expressed in normal melanocytes mediates growth and invasion control by keratinocytes. However melanoma cells do not express E-cadherin. The first study investigated the regulation of cell adhesion molecules E-cadherin and Desmoglein 1 by hepatocyte growth factor (HGF) in melanoma. In contrast to melanocytes, which do not produce HGF, most melanoma cells express HGF. When autocrine activation was induced with HGF-expressing adenovirus, E-cadherin and Desmoglein 1 were decreased in melanocytes. c-Met (HGF receptor) was coimmunoprecipitated with E-cadherin, Desmoglein 1 and Plakoglobin, suggesting that they form a complex(es) that acts to regulate intercellular adhesion. The results indicate that autocrine HGF decouples melanomas from keratinocytes by downregulating E-cadherin and Desmoglein. During melanoma development, loss of functional E-cadherin accompanies gain of expression of N-cadherin. The second study investigated the functional significance of N-cadherin in melanoma cells. N-cadherin mediated homotypic aggregation among melanoma cells as well as heterotypic adhesion of melanoma cells to dermal fibroblasts and vascular endothelial cells. Antibody blocking of N-cadherin-mediated intercellular interaction increased the number of cells undergoing apoptosis. N-cadherin-mediated cell adhesion activated anti-apoptotic protein Akt/PKB and subsequently increased β-catenin and inactivated the pro-apoptosic factor Bad. N-cadherin promoted migration of melanocytic cells on dermal fibroblasts. The results suggest that N-cadherin may also play a role in melanoma cell survival and migration. Melanocytic cells also interact with their microenvironment through growth factors and cytokines. Fibroblasts, upon stimulation by melanoma-derived growth factors, secrete insulin-like growth factor-I (IGF-I), which stimulates melanoma cells to grow, survive and migrate. The third study shows that IGF-I exerts its pro-migratory effect through IL-8 induction. The study identifies IL-8 as a new target of IGF-I in melanoma and suggests that some of the biological functions of IGF-I are mediated by IL-8