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

ABSTRACT: Cancer-associated fibroblasts (CAFs) comprise one of the most important cell types in the tumor microenvironment. A proinflammatory NF-?B 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 IKK?/NF-?B in CAFs. Fibroblast-restricted deletion of Ikk? 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 Ikk?-deficient fibroblasts, transcription of negative regulators of TGF? signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGF? gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikk?-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 Ikk?-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKK?/NF-?B in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.

SUBMITTER: Pallangyo CK 

PROVIDER: S-EPMC4689166 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature