Ligand Activation of Overexpressed Epidermal Growth Factor Receptor Results in Loss of Epithelial Phenotype and Impaired RGD-Sensitive Integrin Function in HSC-1 Cells

Various human carcinomas overexpress epidermal growth factor receptor, and the degree of the expression correlates with their malignant phenotype. Because phenotypic transformation of cells involves qualitative and quantitative alteration of integrin function, we compared the effects of exogenous epidermal growth factor on cell-matrix interactions between HSC-1 human cutaneous squamous carcinoma cells overexpressing epidermal growth factor receptor and their revertant cells. Epidermal growth factor impaired RGD-sensitive cell spreading on fibrinogen, fibronectin, or vitronectin in the parent cells in a concentration-dependent manner; 50ng epidermal growth factor per ml treatment for 1–24h reduced cell spreading on these substrata by 75–95%. In the presence of epidermal growth factor, the parent HSC-1 cells lost their epithelial phenotype and did not form coherent colonies. This might involve the impaired RGD-sensitive integrin function, because treatment of the cells with the peptide GRGDS mimicked the effects of epidermal growth factor on cell and colony morphology. The revertant cells expressing about one-tenth the amount of epidermal growth factor receptor did not show reduced RGD-sensitive cell spreading or loss of epithelial phenotype in response to epidermal growth factor. Epidermal growth factor did not downregulate the subunits for the RGD-sensitive integrin receptors for fibrinogen, fibronectin, or vitronectin. Tyrosine phosphorylation of integrin β subunits might be involved in the impairment of integrin function, because EGF tyrosine phosphorylated β1 subunit in the parent, but not in the revertant cells. Our results suggest that the ligand activation of overexpressed epidermal growth factor receptor results in impairment of RGD-sensitive integrin function and loss of epithelial phenotype. This may be advantageous to epithelial tumor cells progressing along malignant pathways