Schmidt, Stefanie; Schumacher, Neele; Schwarz, Jeanette; Tangermann, Simone; Kenner, Lukas; Schlederer, Michaela; Sibilia, Maria; Linder, Markus; Altendorf-Hofmann, Annelore; Knoesel, 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 (2018): ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling. In: Journal of Experimental Medicine, Vol. 215, No. 4: pp. 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 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.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
ISSN: | 0022-1007 |
Language: | English |
ID Code: | 65497 |
Deposited On: | 19. Jul 2019 12:17 |
Last Modified: | 19. Jul 2019 12:17 |
- BASE
- Schmidt, Stefanie
- Schumacher, Neele
- Schwarz, Jeanette
- Tangermann, Simone
- Kenner, Lukas
- Schlederer, Michaela
- Sibilia, Maria
- Linder, Markus
- Altendorf-Hofmann, Annelore
- Knoesel, 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
- Google Scholar
- Schmidt, Stefanie
- Schumacher, Neele
- Schwarz, Jeanette
- Tangermann, Simone
- Kenner, Lukas
- Schlederer, Michaela
- Sibilia, Maria
- Linder, Markus
- Altendorf-Hofmann, Annelore
- Knoesel, 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