E-cadherin expression in melanoma cells restores keratinocyte-mediated growth control and down-regulates expression of invasion-related adhesion receptors

In human epidermis, functional symbiosis requires homeostatic balance betwe en keratinocytes and melanocytes, Compelling evidence from co-culture studi es demonstrated a sophisticated, multileveled regulation of normal melanocy tic phenotype orchestrated by undifferentiated, basal-type keratinocytes. K eratinocytes control cell growth and dendricity, as well as expression of m elanoma-associated cell surface molecules of normal melanocytes, In contras t, melanoma cells are refractory to the keratinocyte-mediated regulation. T he loss of regulatory dominance by keratinocytes occurs in concert with dow n-regulation of E-cadherin expression in melanoma cells. To investigate the potential role of E-cadherin in melanomakeratinocyte interaction, we trans duced E-cadherin-negative melanoma cells with full-length E-cadherin cDNA u sing an adenoviral vector. Our results show that functional E-cadherin expr ession in melanoma cells leads to cell adhesion to keratinocytes rendering them susceptible for keratinocyte-mediated control. In a skin reconstructio n model, ectopic E-cadherin expression inhibits invasion of melanoma cells into dermis by down-regulating invasion-related adhesion receptors, Me1CAM/ MUC18 and beta 3 integrin subunit, and by induction of apoptosis. Thus, dis ruption of the E-cadherin-mediated, normal regulatory control from keratino cytes may represent one of the mechanisms accounting for melanocyte transfo rmation.