ADAM17 is required for EGF-R induced intestinal tumors via IL-6 trans-signaling

Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R) but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited and the few remaining tumors were of low grade dysplasia. RNA-Seq analysis demonstrated downregulation of STAT3 and Wnt pathway components. Since EGF-R on myeloid cells, but not on intestinal epithelial cells is required for intestinal cancer and IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally inhibited in IL-6-/- and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R-mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces ?-catenin dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer, which could circumvent intrinsic and acquired resistance to EGF-R blockade.