title: IKKβ in intestinal mesenchymal cells promotes initiation of colitis-associated cancer.
abstract: The importance of mesenchymal cells in inflammation and/or neoplastic transformation is well recognized, but their role in the initiation of these processes, particularly in the intestine, remains elusive. Using mouse models of colorectal cancer, we show that IKKβ in intestinal mesenchymal cells (IMCs) is critically involved in colitis-associated, but not spontaneous tumorigenesis. We further demonstrate that IMC-specific IKKβ is involved in the initiation of colitis-associated cancer (CAC), as in its absence mice develop reduced immune cell infiltration, epithelial cell proliferation, and dysplasia at the early stages of the disease. At the molecular level, these effects are associated with decreased early production of proinflammatory and protumorigenic mediators, including IL-6, and reduced STAT3 activation. Ex vivo IKKβ-deficient IMCs show defective responses to innate immune stimuli such as LPS, as shown by decreased NF-κB signaling and reduced expression of important NF-κB target genes. Collectively, our results reveal a hitherto unknown role of mesenchymal IKKβ in driving inflammation and enabling carcinogenesis in the intestine.
authors.affiliation: Biomedical Sciences Research Center "Alexander Fleming", 16672 Vari, Greece koliaraki@fleming.gr kollias@fleming.gr.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Koliaraki
authors.affiliation: Institute for Genetics, University of Cologne, D-50674 Cologne, Germany.
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.affiliation: Biomedical Sciences Research Center "Alexander Fleming", 16672 Vari, Greece Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece koliaraki@fleming.gr kollias@fleming.gr.
authors.forename: George
authors.initials: G
authors.lastname: Kollias
mesh_terms: D000818:Animals; D017209:Apoptosis; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D019070:Cell Lineage; D049109:Cell Proliferation; D003092:Colitis / Q000473:pathology*; D024142:Collagen Type VI / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000378:metabolism; D017353:Gene Deletion; D051550:I-kappa B Kinase / Q000378:metabolism*; D007113:Immunity, Innate; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007422:Intestines / Q000473:pathology*; D008648:Mesoderm / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D019899:Paracrine Communication; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D012995:Solubility
chemical_list: D024142:Collagen Type VI; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D016264:Dextran Sulfate; D051550:I-kappa B Kinase