TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling

Immunity. 2004 Oct;21(4):491-501. doi: 10.1016/j.immuni.2004.07.020.

Abstract

Alterations of TGF-beta signaling have been described in colorectal cancer, although the molecular consequences are largely unknown. By using transgenic mice overexpressing TGF-beta or a dominant-negative TGF-betaRII, we demonstrate that TGF-beta signaling in tumor infiltrating T lymphocytes controls the growth of dysplastic epithelial cells in experimental colorectal cancer, as determined by histology and a novel system for high-resolution chromoendoscopy. At the molecular level, TGF-beta signaling in T cells regulated STAT-3 activation in tumor cells via IL-6. IL-6 signaling required tumor cell-derived soluble IL-6R rather than membrane bound IL-6R and suppression of such TGF-beta-dependent IL-6 trans-signaling prevented tumor progression in vivo. Taken together, our data provide novel insights into TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on inhibition of TGF-beta-dependent IL-6 trans-signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • DNA-Binding Proteins / immunology
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Endoscopy, Digestive System
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Immunohistochemistry
  • Interleukin-6 / immunology
  • Interleukin-6 / metabolism*
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Interleukin-6 / immunology
  • Receptors, Interleukin-6 / metabolism
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / immunology
  • Receptors, Transforming Growth Factor beta / metabolism
  • Recombinant Fusion Proteins / immunology
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor
  • Signal Transduction / physiology*
  • T-Lymphocytes / immunology*
  • Trans-Activators / immunology
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / metabolism*

Substances

  • DNA-Binding Proteins
  • Interleukin-6
  • Receptors, Interleukin-6
  • Receptors, Transforming Growth Factor beta
  • Recombinant Fusion Proteins
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Stat3 protein, mouse
  • Trans-Activators
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II