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

DOI PDF 被引用文献2件
  • Stefanie Schmidt
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Neele Schumacher
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Jeanette Schwarz
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Simone Tangermann
    Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria 2
  • Lukas Kenner
    Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria 2
  • Michaela Schlederer
    Department of Experimental and Laboratory Animal Pathology, Medical University Vienna, Vienna, Austria 4
  • Maria Sibilia
    Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria 5
  • Markus Linder
    Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria 5
  • Annelore Altendorf-Hofmann
    Department of General, Visceral and Vascular Surgery, Jena University Hospital, Jena, Germany 6
  • Thomas Knösel
    Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany 7
  • Elisabeth S. Gruber
    Department of General Surgery, Division of Surgery and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria 8
  • Georg Oberhuber
    Department of Experimental and Laboratory Animal Pathology, Medical University Vienna, Vienna, Austria 4
  • Julia Bolik
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Ateequr Rehman
    Institute of Clinical Molecular Biology, Christian Albrechts Universität Kiel, Kiel, Germany 9
  • Anupam Sinha
    Institute of Clinical Molecular Biology, Christian Albrechts Universität Kiel, Kiel, Germany 9
  • Juliane Lokau
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Philipp Arnold
    Anatomisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 10
  • Anne-Sophie Cabron
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Friederike Zunke
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Christoph Becker-Pauly
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Adele Preaudet
    The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia 11
  • Paul Nguyen
    The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia 11
  • Jennifer Huynh
    Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia 13
  • Shoukat Afshar-Sterle
    Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia 13
  • Ashwini L. Chand
    Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia 13
  • Jürgen Westermann
    Institut für Anatomie, Universität zu Lübeck, Lübeck, Germany 14
  • Peter J. Dempsey
    Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 15
  • Christoph Garbers
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Dirk Schmidt-Arras
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1
  • Philip Rosenstiel
    Institute of Clinical Molecular Biology, Christian Albrechts Universität Kiel, Kiel, Germany 9
  • Tracy Putoczki
    The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia 11
  • Matthias Ernst
    Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia 13
  • Stefan Rose-John
    Biochemisches Institut, Christian Albrechts Universität Kiel, Kiel, Germany 1

書誌事項

公開日
2018-02-22
権利情報
  • http://www.rupress.org/terms/
  • https://creativecommons.org/licenses/by-nc-sa/4.0/
DOI
  • 10.1084/jem.20171696
公開者
Rockefeller University Press

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説明

<jats:p>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.</jats:p>

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