| First Author | Pallangyo CK | Year | 2015 |
| Journal | J Exp Med | Volume | 212 |
| Issue | 13 | Pages | 2253-66 |
| PubMed ID | 26621452 | Mgi Jnum | J:229017 |
| Mgi Id | MGI:5750241 | Doi | 10.1084/jem.20150576 |
| Citation | Pallangyo CK, et al. (2015) IKKbeta acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis. J Exp Med 212(13):2253-66 |
| abstractText | Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-kappaB 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 IKKbeta/NF-kappaB in CAFs. Fibroblast-restricted deletion of Ikkbeta 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 Ikkbeta-deficient fibroblasts, transcription of negative regulators of TGFbeta signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFbeta gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkbeta-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 Ikkbeta-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKbeta/NF-kappaB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients. |
