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

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.

• Authors: Christoph Becker, Massimo C Fantini, Christoph Schramm, Hans A Lehr, Stefan Wirtz, Alexei Nikolaev, Jürgen Burg, Susanne Strand, Ralf Kiesslich, Samuel Huber, Hiroaki Ito, Norihiro Nishimoto, Kazuyuki Yoshizaki, Tadamitsu Kishimoto, Peter R Galle, Manfred Blessing, Stefan Rose-John, Markus F Neurath
• Journal: Immunity (Immunity) Vol. 21 Issue 4 Pg. 491-501 (Oct 2004) ISSN: 1074-7613 [Print] United States
• PMID: 15485627 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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