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
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Colonic Neoplasms / immunology
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Colonic Neoplasms / metabolism*
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Colonic Neoplasms / pathology
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DNA-Binding Proteins / immunology
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DNA-Binding Proteins / metabolism
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Disease Models, Animal
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Disease Progression
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Endoscopy, Digestive System
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Enzyme-Linked Immunosorbent Assay
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Humans
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Immunohistochemistry
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Interleukin-6 / immunology
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Interleukin-6 / metabolism*
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II
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Receptors, Interleukin-6 / immunology
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Receptors, Interleukin-6 / metabolism
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / immunology
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Receptors, Transforming Growth Factor beta / metabolism
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Recombinant Fusion Proteins / immunology
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Recombinant Fusion Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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STAT3 Transcription Factor
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Signal Transduction / physiology*
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T-Lymphocytes / immunology*
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Trans-Activators / immunology
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Trans-Activators / metabolism
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / immunology
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Transforming Growth Factor beta / metabolism*
Substances
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DNA-Binding Proteins
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Interleukin-6
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Receptors, Interleukin-6
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Receptors, Transforming Growth Factor beta
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Recombinant Fusion Proteins
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STAT3 Transcription Factor
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STAT3 protein, human
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Stat3 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type II