TGF-β Suppresses Tumor Progression in Colon Cancer by Inhibition of IL-6 trans-Signaling
Open accessAbstract
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.
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TGF-β is a powerful anti-inflammatory cytokine that acts on many target cells and tones down the inflammatory effects of TNF, IL-1β, IL-2, and IL-12.
“Together with IL-10, TGF-β is another powerful anti-inflammatory cytokine that acts on many target cells and tones down the inflammatory effects of TNF, IL-1β, IL-2, and IL-12, etc. (61, 67, 68).”
From Macrophage Cytokines: Involvement in Immunity and Infectious Diseases (2014) · cites this paper as [68]
IL-6 binds to gp130 on target cells to activate STAT3 in tumour cells and tumour-associated inflammatory cells.
“IL-6 binds to gp130 on target cells to activate the signal transducer and activator of transcription 3 [STAT3] in tumour cells and tumour-associated inflammatory cells 12, 15.”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [15]
The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.
“The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.12,15,46,48,49”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [15]
IL-6 has been previously identified as a key cytokine that directly induces tumour growth in CRC via STAT3 activation in IECs.
“IL-6 has been previously identified as a key cytokine that directly induces tumuor growth in CRC via STAT3 activation in IECs.12,15,46,47.”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [15]
Tumour cells in experimental CRC lose IL-6R expression and become susceptible to IL-6 trans-signalling via the soluble IL-6R.
“As tumour cells in experimental CRC lose IL-6R expression and become susceptible to IL-6 trans-signalling via the soluble IL-6R,15 our findings underlined that Th9 cells may regulate tumour growth via IL-6 trans-signalling.”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [15]
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- Authors
- Becker, C., Fantini, M. C., Schramm, C., Lehr, H. A., Wirtz, S., Nikolaev, A., Burg, J., Strand, S., Kiesslich, R., Huber, S., Ito, H., Nishimoto, N., Yoshizaki, K., Kishimoto, T., Galle, P. R., Blessing, M., Rose-John, S., & Neurath, M. F.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- The University of Osaka (JP)
- Leipzig University (DE)
- Corresponding author
- Neurath, Markus F.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 21
- Issue
- 4
- Pages
- 491-501
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2007606465
- Cited by
- 726
- References
- 1
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 22 · 2023: 20 · 2022: 30 · 2021: 33 · 2020: 26 · 2019: 24 · 2018: 27 · 2017: 26 · 2016: 36 · 2015: 57 · 2014: 35 · 2013: 49 · 2012: 54
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- TGF-beta signaling, colorectal cancer, IL-6 trans-signaling, soluble IL-6 receptor, STAT3 activation, tumor-infiltrating T cells, TGF-βRII, tumor progression, chromoendoscopy
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Colonic Neoplasms, Disease Models, Animal, DNA-Binding Proteins, Enzyme-Linked Immunosorbent Assay, Humans, Immunohistochemistry, Intestinal Mucosa, Mice, Transgenic, Recombinant Fusion Proteins, T-Lymphocytes, Blotting, Western, Signal Transduction, Trans-Activators, Interleukin-6, Endoscopy, Digestive System, Transforming Growth Factor beta, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Mice, Knockout, Disease Progression, Receptors, Interleukin-6, Reverse Transcriptase Polymerase Chain Reaction, STAT3 Transcription Factor, Mice
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