ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling Academic Article uri icon

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.

authors

  • Schmidt, S
  • Schumacher, N
  • Schwarz, J
  • Tangermann, S
  • Kenner, L
  • Schlederer, M
  • Sibilia, M
  • Linder, M
  • Altendorf-Hofmann, A
  • Knösel, 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, Jennifer
  • Afshar-Sterle, Shoukat
  • Chand, Ashwini L
  • Westermann, J
  • Dempsey, PJ
  • Garbers, C
  • Schmidt-Arras, D
  • Rosenstiel, P
  • Putoczki, T
  • Ernst, Matthias
  • Rose-John, S

publication date

  • 2018

has subject area