TY  - JOUR
A1  - Pallangyo, Charles
A1  - Ziegler, Paul K.
A1  - Greten, Florian
T1  - IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis
T2  - Journal of experimental medicine
N2  - 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.
Y1  - 2015
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/50604
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-506049
SN  - 1540-9538
SN  - 1540-9358
SN  - 0022-1007
N1  - 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/).
VL  - 212
IS  - 13
SP  - 2253
EP  - 2266
PB  - Rockefeller Univ. Press
CY  - New York, NY
ER  -