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

Schmidt, S; Schumacher, N; Schwarz, J; Tangermann, S; Kenner, L; Schlederer, M; Sibilia, M; Linder, M; Altendorf-Hofmann, A; Knosel, T; Gruber, ES; Oberhuber, G; Bolik, J; Rehman, A; Sinha, A; Lokau, J; Arnold, P; Cabron, AS; Zunke, F; Becker-Pauly, C; Preaudet, A; Nguyen, P; Huynh, J; Afshar-Sterle, S; Chand, AL; Westermann, J; DEMPSEY, PJ; Garbers, C; Schmidt-Arras, D; Rosenstiel, P; Putoczki, T; Ernst, M; Rose-John, S

Author(s): Schmidt, S; Schumacher, N; Schwarz, J; Tangermann, S; Kenner, L; Schlederer, M; Sibilia, M; Linder, M; Altendorf-Hofmann, A; Knosel, T; Gruber, ES; Oberhuber, G; Bolik, J; Rehman, A; Sinha, A; Lokau, J; Arnold, P; Cabron, AS; Zunke, F; Becker-Pauly, C; Preaudet, A; Nguyen, P; Huynh, J; Afshar-Sterle, S; Chand, AL; Westermann, J; DEMPSEY, PJ; Garbers, C; Schmidt-Arras, D; Rosenstiel, P; Putoczki, T; Ernst, M; Rose-John, S;
Details: Publication Year 2018-04-02,Volume 215,Issue #4,Page 1205-1225
Journal Title: Journal of Experimental Medicine
Publication Type: Journal Article
Abstract: 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 sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6(-/-) mice 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 beta-catenin-dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.
Publisher: Rockefeller Press
Research Division(s): Inflammation
PubMed ID: 29472497
Publisher's Version: https://doi.org/10.1084/jem.20171696
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-05-18 09:33:24

Last Modified: 2018-06-27 09:45:24