ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling
AuthorSchmidt, S; Schumacher, N; Schwarz, J; Tangermann, S; Kenner, L; Schlederer, M; Sibilia, M; Linder, M; Altendorf-Hofmann, A; Knoesel, T; ...
Source TitleJournal of Experimental Medicine
PublisherROCKEFELLER UNIV PRESS
Document TypeJournal Article
CitationsSchmidt, S., Schumacher, N., Schwarz, J., Tangermann, S., Kenner, L., Schlederer, M., Sibilia, M., Linder, M., Altendorf-Hofmann, A., Knoesel, T., Gruber, E. S., Oberhuber, G., Bolik, J., Rehman, A., Sinha, A., Lokau, J., Arnold, P., Cabron, A. -S., Zunke, F. ,... Rose-John, S. (2018). ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling. JOURNAL OF EXPERIMENTAL MEDICINE, 215 (4), pp.1205-1225. https://doi.org/10.1084/jem.20171696.
Access StatusOpen Access
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.
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