TY  - JOUR
AU  - Schmidt, S
AU  - Schumacher, N
AU  - Schwarz, J
AU  - Tangermann, S
AU  - Kenner, L
AU  - Schlederer, M
AU  - Sibilia, M
AU  - Linder, M
AU  - Altendorf-Hofmann, A
AU  - Knoesel, T
AU  - Gruber, ES
AU  - Oberhuber, G
AU  - Bolik, J
AU  - Rehman, A
AU  - Sinha, A
AU  - Lokau, J
AU  - Arnold, P
AU  - Cabron, A-S
AU  - Zunke, F
AU  - Becker-Pauly, C
AU  - Preaudet, A
AU  - Nguyen, P
AU  - Huynh, J
AU  - Afshar-Sterle, S
AU  - Chand, AL
AU  - Westermann, J
AU  - Dempsey, PJ
AU  - Garbers, C
AU  - Schmidt-Arras, D
AU  - Rosenstiel, P
AU  - Putoczki, T
AU  - Ernst, M
AU  - Rose-John, S
Y2  - 2020/12/17
Y1  - 2018/04/01
SN  - 0022-1007
UR  - http://hdl.handle.net/11343/254793
AB  - 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.
LA  - English
PB  - ROCKEFELLER UNIV PRESS
T1  - ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling
DO  - 10.1084/jem.20171696
IS  - Journal of Experimental Medicine
VL  - 215
IS  - 4
SP  - 1205-1225
L1  - /bitstream/handle/11343/254793/PMC5881468.pdf?sequence=1&isAllowed=y
ER  -