Article: article from journal or magazin.
TGF-beta suppresses tumor progression in colon cancer by inhibition of IL-6 trans-signaling.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Animals, Blotting, Western, Colonic Neoplasms/immunology, Colonic Neoplasms/metabolism, 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, Receptors, Interleukin-6/immunology, Receptors, Interleukin-6/metabolism, Receptors, Transforming Growth Factor beta/genetics, Receptors, Transforming Growth Factor beta/immunology, 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
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