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 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 beta3 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.
Hsu
M Y
MY
Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Meier
F E
FE
Nesbit
M
M
Hsu
J Y
JY
Van Belle
P
P
Elder
D E
DE
Herlyn
M
M
D000256:Adenoviridae / Q000235:genetics; D015703:Antigens, CD / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D017209:Apoptosis; D015153:Blotting, Western; D051929:CD146 Antigen; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002455:Cell Division; D002460:Cell Line; D018920:Coculture Techniques; D004274:DNA, Recombinant / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D039661:Integrin beta3; D015603:Keratinocytes / Q000166:cytology*; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins; D009361:Neoplasm Invasiveness; D019006:Neural Cell Adhesion Molecules; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D017768:Skin, Artificial; D014162:Transfection; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D000954:Antigens, Surface; D051929:CD146 Antigen; D015820:Cadherins; D004274:DNA, Recombinant; D039661:Integrin beta3; C497902:MCAM protein, human; D008562:Membrane Glycoproteins; D019006:Neural Cell Adhesion Molecules; D010980:Platelet Membrane Glycoproteins