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, Knoesel 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 (2018)
Publication Type: Journal article
Publication year: 2018
Journal
Book Volume: 215
Pages Range: 1205-1225
Journal Issue: 4
DOI: 10.1084/jem.20171696
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 downregulation 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.
Authors with CRIS profile
Involved external institutions
Christian-Albrechts-Universität zu Kiel
Germany (DE)
Olivia Newton-John Cancer Research Institute
Australia (AU)
Walter and Eliza Hall Institute of Medical Research (WEHI)
Australia (AU)
Stiftung Tierärztliche Hochschule Hannover (TiHo)
Germany (DE)
Universität zu Lübeck
Germany (DE)
University of Colorado System
United States (USA) (US)
Medizinische Universität Wien
Austria (AT)
Ludwig-Maximilians-Universität (LMU)
Germany (DE)
Universitätsklinikum Jena
Germany (DE)
Germany (DE)
Olivia Newton-John Cancer Research Institute
Australia (AU)
Walter and Eliza Hall Institute of Medical Research (WEHI)
Australia (AU)
Stiftung Tierärztliche Hochschule Hannover (TiHo)
Germany (DE)
Universität zu Lübeck
Germany (DE)
University of Colorado System
United States (USA) (US)
Medizinische Universität Wien
Austria (AT)
Ludwig-Maximilians-Universität (LMU)
Germany (DE)
Universitätsklinikum Jena
Germany (DE)
How to cite
APA:
Schmidt, S., Schumacher, N., Schwarz, J., Tangermann, S., Kenner, L., Schlederer, M.,... Rose-John, S. (2018). ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling. Journal of Experimental Medicine, 215(4), 1205-1225. https://doi.org/10.1084/jem.20171696
MLA:
Schmidt, Stefanie, et al. "ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling." Journal of Experimental Medicine 215.4 (2018): 1205-1225.
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