IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis

J Exp Med. 2015 Dec 14;212(13):2253-66. doi: 10.1084/jem.20150576. Epub 2015 Nov 30.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Cell Lineage
  • Colitis / metabolism
  • Colitis / pathology
  • Disease Models, Animal
  • Down-Regulation
  • Fibroblasts / metabolism
  • Fibroblasts / pathology*
  • Forkhead Transcription Factors / metabolism
  • Hepatocyte Growth Factor / genetics
  • Hepatocyte Growth Factor / metabolism
  • I-kappa B Kinase / deficiency
  • I-kappa B Kinase / metabolism*
  • Inflammation / pathology
  • Integrases / metabolism
  • Intestinal Neoplasms / metabolism*
  • Intestinal Neoplasms / pathology*
  • Mice
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / metabolism
  • Recombination, Genetic / genetics
  • Signal Transduction
  • Smad7 Protein / metabolism
  • Tumor Burden
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation

Substances

  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Smad7 Protein
  • Tumor Suppressor Proteins
  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • I-kappa B Kinase
  • Cre recombinase
  • Integrases