IKKß acts as a tumor suppressor in cancer-associated fibroblasts during intestinal tumorigenesis.
J Exp Med
; 212(13): 2253-66, 2015 Dec 14.
Article
em En
| MEDLINE
| ID: mdl-26621452
ABSTRACT
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 IKKß/NF-κB in CAFs. Fibroblast-restricted deletion of Ikkß 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 Ikkß-deficient fibroblasts, transcription of negative regulators of TGFß signaling, including Smad7 and Smurf1, is impaired, causing up-regulation of a TGFß gene signature and elevated hepatocyte growth factor (HGF) secretion. Overexpression of Smad7 in Ikkß-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 Ikkß-mutant animals. Collectively, these results highlight an unexpected tumor suppressive function of IKKß/NF-κB in CAFs linked to HGF release and raise potential concerns about the use of IKK inhibitors in colorectal cancer patients.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Supressoras de Tumor
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Quinase I-kappa B
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Fibroblastos
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Carcinogênese
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Neoplasias Intestinais
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article