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Gewählte Publikation:

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Publikationstyp: Zeitschriftenaufsatz
Dokumenttyp: Originalarbeit

Jahr: 2018

AutorInnen: 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, J; Afshar-Sterle, S; Chand, AL; Westermann, J; Dempsey, PJ; Garbers, C; Schmidt-Arras, D; Rosenstiel, P; Putoczki, T; Ernst, M; Rose-John, S

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

Quelle: J Exp Med. 2018; 215(4):1205-1225



Autor/innen der Vetmeduni Vienna:

Kenner Lukas
Tangermann Simone

Beteiligte Vetmed-Organisationseinheiten
Institut für Pathologie, Abteilung für Labortierpathologie


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.© 2018 Crown copyright. The government of Australia, Canada, or the UK ("the Crown") owns the copyright interests of authors who are government employees. The Crown Copyright is not transferable.

Keywords Pubmed: ADAM17 Proteindeficiencymetabolism
Adenomatous Polyposis Colimetabolism
Animals
Carcinogenesismetabolismpathology
Cell Line, Tumor
Cell Nucleusmetabolism
Colorectal Neoplasmsgeneticsmetabolismpathology
Disease Models, Animal
ErbB Receptorsmetabolism
Gastrointestinal Microbiome
Gene Expression Regulation, Neoplastic
Humans
Interleukin-6metabolism
Intestinal Neoplasmsgeneticsmetabolismpathology
Intestine, Smallpathology
Ki-67 Antigenmetabolism
Mice, Inbred C57BL
Neoplasm Metastasis
Neoplasm Staging
Organoidspathology
Prognosis
RNA, Messengergeneticsmetabolism
STAT3 Transcription Factormetabolism
Signal Transduction
Tumor Burden
beta Cateninmetabolism

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