IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis
- Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-κB gene signature in CAFs has been suggested to promote tumorigenesis in models of pancreatic and mammary skin cancer. Using an autochthonous model of colitis-associated cancer (CAC) and sporadic cancer, we now provide evidence for a tumor-suppressive function of IKKβ/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkβ stimulates intestinal epithelial cell proliferation, suppresses tumor cell death, enhances accumulation of CD4+Foxp3+ regulatory T cells, and induces angiogenesis, ultimately promoting colonic tumor growth. In Ikkβ-deficient fibroblasts, transcription of negative regulators of TGFβ signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFβ gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkβ-deficient fibroblasts prevents HGF secretion, and pharmacological inhibition of Met during the CAC model confirms that enhanced tumor promotion is dependent on HGF–Met signaling in mucosa of Ikkβ-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKβ/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.
Author: | Charles Pallangyo, Paul K. Ziegler, Florian GretenORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-506049 |
DOI: | https://doi.org/10.1084/jem.20150576 |
ISSN: | 1540-9538 |
ISSN: | 1540-9358 |
ISSN: | 0022-1007 |
Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/26621452 |
Parent Title (English): | Journal of experimental medicine |
Publisher: | Rockefeller Univ. Press |
Place of publication: | New York, NY |
Document Type: | Article |
Language: | English |
Year of Completion: | 2015 |
Date of first Publication: | 2015/11/30 |
Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Release Date: | 2019/07/04 |
Volume: | 212 |
Issue: | 13 |
Page Number: | 14 |
First Page: | 2253 |
Last Page: | 2266 |
Note: | Copyright & Usage: © 2015 Pallangyo et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
HeBIS-PPN: | 452214149 |
Institutes: | Medizin / Medizin |
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus | |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Licence (German): | Creative Commons - Namensnennung-Keine kommerzielle Nutzung-Weitergabe unter gleichen Bedingungen |