IL-6 signaling promotes tumor growth in colorectal cancer

Cell Cycle. 2005 Feb;4(2):217-20. Epub 2005 Feb 3.

Abstract

Recent investigations support an important role for TGF-beta in the development of colorectal cancer. However, the molecular consequences of TGF-beta signaling in the colon remains incompletely understood. In a recent study in Immunity, we analyzed the role of TGF-beta in a murine model of colon cancer. Using transgenic mice overexpressing TGF-beta or a dominant negative TGF-beta receptor II under control of the CD2 minigene, we show that TGF-beta signaling in tumor infiltrating T lymphocytes regulates the growth of dysplastic colon epithelial cells, as determined by histology and a novel system for high resolution chromoendoscopy in vivo. 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. Similar to these observations in mice, here we show that human colon cancer tissue expressed only low amounts of membrane bound IL-6R. In contrast, expression and activity of the matrix metalloproteinase TACE were increased. In summary, our data provide novel insights into the role of TGF-beta signaling in colorectal cancer and suggest novel therapeutic approaches for colorectal cancer based on an inhibition of TGF-beta-dependent IL-6 trans-signaling.

MeSH terms

  • ADAM Proteins / genetics
  • ADAM Proteins / metabolism
  • ADAM17 Protein
  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • CD2 Antigens / genetics
  • CD2 Antigens / physiology
  • Cell Proliferation
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • Colorectal Neoplasms / physiopathology*
  • Gene Expression Regulation / physiology
  • Gene Expression Regulation, Neoplastic
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / genetics
  • Interleukin-6 / physiology*
  • Mice
  • Mice, Transgenic
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / physiology
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / physiology
  • Signal Transduction* / drug effects
  • Signal Transduction* / genetics
  • T-Lymphocytes / pathology
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / physiology*

Substances

  • Antineoplastic Agents
  • CD2 Antigens
  • Interleukin-6
  • Receptors, Interleukin-6
  • Receptors, Transforming Growth Factor beta
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transforming Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse