Abstract
The classical nuclear factor-kappaB (NF-κB) signaling pathway has been shown to be important in a number of models of inflammation-associated cancer. In a mouse model of Helicobacter-induced gastric cancer, impairment of classical NF-κB signaling in the gastric epithelium led to the development of increased preneoplastic pathology, however the role of specific NF-κB proteins in Helicobacter-associated gastric cancer development remains poorly understood. To investigate this C57BL/6, Nfkb1−/−, Nfkb2−/− and c-Rel−/− mice were infected with Helicobacter felis for 6 weeks or 12 months. Bacterial colonization, gastric atrophy and preneoplastic changes were assessed histologically and cytokine expression was assessed by qPCR. Nfkb1−/− mice developed spontaneous gastric atrophy when maintained for 12 months in conventional animal house conditions. They also developed more pronounced gastric atrophy after short-term H. felis colonization with a similar extent of preneoplasia to wild-type (WT) mice after 12 months. c-Rel−/− mice developed a similar degree of gastric atrophy to WT mice; 3 of 6 of these animals also developed lymphoproliferative lesions after 12 months of infection. Nfkb2−/− mice developed minimal gastric epithelial pathology even 12 months after H. felis infection. These findings demonstrate that NF-κB1- and NF-κB2-mediated signaling pathways differentially regulate the epithelial consequences of H. felis infection in the stomach, while c-Rel-mediated signaling also appears to modulate the risk of lymphomagenesis in gastric mucosa-associated lymphoid tissue.
Highlights
In many malignancies, changes in the tissue microenvironment, influenced by immune responses, create a niche that promotes selection of malignant clones.[1]
Despite a worldwide prevalence of H. pylori infection of at least 50%,4 gastric cancer remains relatively rare. This demonstrates that factors other than H. pylori infection contribute to the development of gastric cancer, and several lines of evidence have suggested that immune responses are important regulators of Helicobacterinduced disease progression
NF-kB1 deletion leads to spontaneous gastric inflammation and increased cellular turnover
Summary
Changes in the tissue microenvironment, influenced by immune responses, create a niche that promotes selection of malignant clones.[1]. Despite a worldwide prevalence of H. pylori infection of at least 50%,4 gastric cancer remains relatively rare (peak incidence, in men from Eastern Asia, 42.4 per 100 0005). This demonstrates that factors other than H. pylori infection contribute to the development of gastric cancer, and several lines of evidence have suggested that immune responses are important regulators of Helicobacterinduced disease progression. A pro-inflammatory genotype appears to enhance an individual’s risk of developing gastric cancer when infected with H. pylori.[6] Transgenic animal studies have revealed complex associations between Th1 cytokines and gastric carcinogenesis. Overexpression of interleukin-1b (IL-1b) was sufficient to promote murine carcinogenesis in the absence of Helicobacter infection,[7] while overexpression of interferon-g (IFN-g) in parietal cells inhibited progression of Helicobacter felis-induced gastric carcinogenesis.[8]
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