Surgery (RMH) - Research Publications

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Author: Ernst, Matthias × Author: Putoczki, Tracy × Author: Nguyen, Paul × Start date: 2010 × End date: 2019 ×

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    STAT3-Activating Cytokines: A Therapeutic Opportunity for Inflammatory Bowel Disease?
    Nguyen, PM ; Putoczki, TL ; Ernst, M (MARY ANN LIEBERT, INC, 2015-05-01)
    The gastrointestinal tract is lined by a single layer of epithelial cells that secrete mucus toward the lumen, which collectively separates the immune sentinels in the underlying lamina propria from the intestinal microflora to prevent aberrant immune responses. Inflammatory bowel disease (IBD) describes a group of autoimmune diseases that arise from defects in epithelial barrier function and, as a consequence, aberrant production of inflammatory cytokines. Among these, interleukin (IL)-6, IL-11, and IL-22 are elevated in human IBD patients and corresponding mouse models and, through activation of the JAK/STAT3 pathway, can both propagate and ameliorate disease. In particular, cytokine-mediated activation of STAT3 in the epithelial lining cells affords cellular protection, survival, and proliferation, thereby affording therapeutic opportunities for the prevention and treatment of colitis. In this review, we focus on recent insights gained from therapeutic modulation of the activities of IL-6, IL-11, and IL-22 in models of IBD and advocate a cautionary approach with these cytokines to minimize their tumor-promoting activities on neoplastic epithelium.
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    ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling
    Schmidt, S ; Schumacher, N ; Schwarz, J ; Tangermann, S ; Kenner, L ; Schlederer, M ; Sibilia, M ; Linder, M ; Altendorf-Hofmann, A ; Knoesel, T ; Gruber, ES ; Oberhuber, G ; Bolik, J ; Rehman, A ; Sinha, A ; Lokau, J ; Arnold, P ; Cabron, A-S ; 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 (ROCKEFELLER UNIV PRESS, 2018-04)
    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.