Production of epidermal growth factor related ligands in tumorigenic and benign human lung epithelial cells

We recently demonstrated that human lung epithelial cells, overexpressing ErbB-2, formed tumors in nude mice only when high levels of transforming growth factor alpha (TGF alpha) were produced. Cells transfected with a TGF alpha antisense vector failed to form tumors in nude mice. In order to further evaluate the importance, for tumorigenicity, of TGF alpha and its stimulation of ErbB family signalling, the production of other EGF family growth factors by these human lung epithelial cells was studied. We demonstrate for the first time that both tumorigenic and non-tumorigenic human lung epithelial cells produced, in addition to TGF alpha, amphiregulin, betacellulin, heparin-binding EGF and heregulin. These data suggest that human lung epithelial cells have the potential for multifactorial modulation of ErbB receptor family signalling through control of Ligand as well as receptor production. In this system, the probable importance of TGF alpha-stimulated signaling for tumorigenicity is supported by its 13-fold higher production in tumorigenic as compared with non-tumorigenic cells and the 2-fold or lower differences observed in production of the other epidermal growth factor (EGF) family ligands. (C) 1999 Published by Elsevier Science Ireland Ltd. All rights reserved.