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Title: ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling.
Austin Authors: Schmidt, Stefanie;Schumacher, Neele;Schwarz, Jeanette;Tangermann, Simone;Kenner, Lukas;Schlederer, Michaela;Sibilia, Maria;Linder, Markus;Altendorf-Hofmann, Annelore;Knösel, Thomas;Gruber, Elisabeth S;Oberhuber, Georg;Bolik, Julia;Rehman, Ateequr;Sinha, Anupam;Lokau, Juliane;Arnold, Philipp;Cabron, Anne-Sophie;Zunke, Friederike;Becker-Pauly, Christoph;Preaudet, Adele;Nguyen, Paul;Huynh, Jennifer;Afshar-Sterle, Shoukat ;Chand, Ashwini L ;Westermann, Jürgen;Dempsey, Peter J;Garbers, Christoph;Schmidt-Arras, Dirk;Rosenstiel, Philip;Putoczki, Tracy;Ernst, Matthias ;Rose-John, Stefan
Affiliation: Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany
Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria
Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
Department of Experimental and Laboratory Animal Pathology, Medical University Vienna, Vienna, Austria
Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria
Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany
Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany
Department of General Surgery, Division of Surgery and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria
Institute of Clinical Molecular Biology, Christian Albrechts Universität Kiel, Kiel, Germany
Anatomisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Institut für Anatomie, Universität zu Lübeck, Lübeck, Germany
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
School of Cancer Medicine, La Trobe University, Melbourne, Victoria, Australia
Issue Date: 22-Feb-2018 2018
Publication information: The Journal of experimental medicine 2018; 215(4): 1205-1225
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 β-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.
DOI: 10.1084/jem.20171696
ORCID: 0000-0002-6471-5473
PubMed URL: 29472497
Type: Journal Article
Appears in Collections:Journal articles

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