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J Exp Med. 2015 Dec 14;212(13):2253-66. doi: 10.1084/jem.20150576. Epub 2015 Nov 30.

IKKβ acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.

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Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany.
Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, 60596 Frankfurt am Main, Germany German Cancer Consortium (DKTK), 69120 Heidelberg, Germany German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany


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.

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