DIFFERENTIAL-EFFECTS OF EGF AND AMPHIREGULIN ON ADHESION MOLECULE EXPRESSION AND MIGRATION OF COLON-CARCINOMA CELLS

Epidermal growth factor (EGF) is a potent morphogen affecting cell sha pe and motility through regulation of adhesive interactions, We have c haracterized the morphological effects of EGF on GP2d and GP5d colon c arcinoma cell lines and have compared the ability of the heparin-bindi ng EGF receptor ligand amphiregulin (AR) to elicit the same effects. E GF induced a marked epithelial-mesenchymal transition in both cell lin es, This effect was evident at 7 pM EGF and was associated with a redu ction in cellular adherens junctions and diminished cell-cell contact; it was also associated with an increase in expression of alpha 2-inte grin as well. as enhanced adhesion to the substratum and cell spreadin g, These changes in adhesion molecule expression were accompanied by e nhanced migration on collagen. Blockade of cell growth with mitomycin C did not prevent the EGF-induced morphological change, showing that t he mitogenic and morphogenic responses of the GP cells were separable. The phosphatidyl inositol (PI) 3-kinase inhibitor wortmannin inhibite d basal proliferation but had no effect on the EG;F-induced morphologi cal change, further suggesting that the PI 3-kinase pathway was not in volved in the morphogenic response of these cells. Amphiregulin stimul ated proliferation of both cell lines, but could only elicit a modest morphological change if used at considerably higher doses or if growth was blocked with mitomycin C, In cells treated with 55 nM AR, alpha(2 )-integrin expression was slightly increased; however, unlike the EGF case, adherens junctions remained intact, These differences in the abi lity of EGF and amphiregulin to affect cellular adhesion and migration may be significant factors influencing normal and tumor cell behavior . (C) 1997 Academic Press.