Sorting out roles for EGF receptor and its ligands in colonic neoplasia

ED09-01

We previously reported that there is iterative use of EGF receptor (EGFR) signaling in colonic neoplasia, both at a post-initiation, establishment phase and again later during tumor progression (Proc Natl Acad Sci USA 99:1521-1526, 2002). Recent studies have examined trafficking of EGFR ligands in the context of polarizing epithelial cells, including a battery of human colorectal cell lines developed from well-differentiated cancers. Two EGFR ligands, TGF-α and amphiregulin, are delivered preferentially to the basolateral surface where they are cleaved by TACE/ADAM17 whereupon soluble ligand binds to basolaterally restricted EGFRs. Thus, the EGFR axis (which we define as the proximal events in activation of the EGFR) is compartmentalized to the basolateral surface of polarized epithelial cells. Combined blockade of the EGFR axis (ligand cleavage, ligand uptake and EGFR tyrosine kinase activity) results in cooperative growth inhibition in colorectal cancer cell lines in vitro. We will present recent data demonstrating that Naked2, an inducible negative regulator of canonical WNT signaling, is a critical regulator of delivery of TGF-α to the basolateral surface of polarized epithelial cells and is downregulated as a late event in colorectal neoplasia.