Journal article

ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling

Stefanie Schmidt, Neele Schumacher, Jeanette Schwarz, Simone Tangermann, Lukas Kenner, Michaela Schlederer, Maria Sibilia, Markus Linder, Annelore Altendorf-Hofmann, Thomas Knoesel, Elisabeth S Gruber, Georg Oberhuber, Julia Bolik, Ateequr Rehman, Anupam Sinha, Juliane Lokau, Philipp Arnold, Anne-Sophie Cabron, Friederike Zunke, Christoph Becker-Pauly Show all

JOURNAL OF EXPERIMENTAL MEDICINE | ROCKEFELLER UNIV PRESS | Published : 2018

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-..

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Grants

Awarded by Deutsche Forschungsgemeinschaft, Bonn


Awarded by Austrian Science Fund


Awarded by European Research Council


Awarded by National Breast Cancer Foundation


Awarded by Austrian Science Fund (FWF)


Funding Acknowledgements

This work was supported by the Deutsche Forschungsgemeinschaft, Bonn (CRC841, project C1 to D. Schmidt-Arras and S. Rose-John; CRC877, project A1 to S. Rose-John; SFB877, project A9 to C. Becker-Pauly; project A10 to C. Garbers; SFB877, project B9 to P. Rosenstiel; and the Cluster of Excellence "Inflammation at Interfaces"). The research of M. Sibilia was supported by Austrian Science Fund grant DK W1212 and the European Research Council Advanced Grant 694883.