| First Author | Schmidt S | Year | 2018 |
| Journal | J Exp Med | Volume | 215 |
| Issue | 4 | Pages | 1205-1225 |
| PubMed ID | 29472497 | Mgi Jnum | J:258845 |
| Mgi Id | MGI:6120650 | Doi | 10.1084/jem.20171696 |
| Citation | Schmidt S, et al. (2018) ADAM17 is required for EGF-R-induced intestinal tumors via IL-6 trans-signaling. J Exp Med 215(4):1205-1225 |
| abstractText | 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 beta-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. |
