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E-Cadherin Expression in Melanoma Cells Restores Keratinocyte-Mediated Growth Control and Down-Regulates Expression of Invasion-Related Adhesion Receptors

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In human epidermis, functional symbiosis requires homeostatic balance between keratinocytes and melanocytes. Compelling evidence from co-culture studies demonstrated a sophisticated, multileveled regulation of normal melanocytic phenotype orchestrated by undifferentiated, basal-type keratinocytes. Keratinocytes control cell growth and dendricity, as well as expression of melanoma-associated cell surface molecules of normal melanocytes. In contrast, melanoma cells are refractory to the keratinocyte-mediated regulation. The loss of regulatory dominance by keratinocytes occurs in concert with down-regulation of E-cadherin expression in melanoma cells. To investigate the potential role of E-cadherin in melanoma-keratinocyte interaction, we transduced E-cadherin-negative melanoma cells with full-length E-cadherin cDNA using an adenoviral vector. Our results show that functional E-cadherin expression in melanoma cells leads to cell adhesion to keratinocytes rendering them susceptible for keratinocyte-mediated control. In a skin reconstruction model, ectopic E-cadherin expression inhibits invasion of melanoma cells into dermis by down-regulating invasion-related adhesion receptors, MelCAM/MUC18 and β3 integrin subunit, and by induction of apoptosis. Thus, disruption of the E-cadherin-mediated, normal regulatory control from keratinocytes may represent one of the mechanisms accounting for melanocyte transformation.

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Supported by National Institutes of Health grants CA-76674, CA-25874, and CA-15479, by the Wistar Cancer Center Core Grant (CA-10815), and NASA grant NAG-9–832.

M.-Y. Hsu's current address: Department of Pathology, Thomas Jefferson University, Philadelphia, PA 19107.

F. E. Meier's current address: Department of Dermatology, University of Tübingen, Tübingen, Germany.

J.-Y. Hsu's current address: Sidney Kimmel Cancer Center, San Diego, CA 92121.