TGF-α-Driven Tumor Growth Is Inhibited by an EGF Receptor Tyrosine Kinase Inhibitor

Abstract

The simultaneous presence of the EGFR and its ligand TGF-α in human tumor tissues suggests that autocrine TGF-α stimulation drives tumor growth. Here we show that autocrine TGF-α stimulation does cause increased tumor growth in vivo, an effect that was proven to be mediated via EGFR activation, and that this TGF-α/EGFR autocrine loop was accessible to an EGFR specific tyrosine kinase inhibitor. Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-α cDNA using a tetracycline-inhibitory system for gene expression. TGF-α expression was inhibited by the presence of tetracycline, and subcutaneous tumors forming from cell lines injected into nude mice could be inhibited by feeding mice tetracycline. We confirmed that TGF-α mRNA and protein were present in these tumors and that, subsequently, the endogenous EGFR was activated. Tumor growth could be inhibited by an EGFR specific tyrosine kinase inhibitor of the type 4-(3-chloroanilino)-6,7-dimethoxy-quinazoline, administered daily by intraperitoneal injection, thereby interrupting the autocrine loop.