title: IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.
abstract: Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKβ/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkβ stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4(+)Foxp3(+) regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkβ-deficient fibroblasts, transcription of negative regulators of TGFβ signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFβ gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkβ-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF-Met signaling in mucosa of Ikkβ-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKβ/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
authors.forename: Charles K
authors.initials: CK
authors.lastname: Pallangyo
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
authors.forename: Paul K
authors.initials: PK
authors.lastname: Ziegler
authors.affiliation: Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany German Cancer Consortium (DKTK), 69120 Heidelberg, Germany German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany greten@gsh.uni-frankfurt.de.
authors.forename: Florian R
authors.initials: FR
authors.lastname: Greten
mesh_terms: D000208:Acute Disease; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D019070:Cell Lineage; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D051858:Forkhead Transcription Factors / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000172:deficiency / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D051906:Smad7 Protein; D025521:Tumor Suppressor Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D051550:I-kappa B Kinase; C045073:Cre recombinase; D019426:Integrases