Transgenic expression of interferon-? in mouse stomach leads to inflammation, metaplasia, and dysplasia.

ABSTRACT: Gastric adenocarcinoma is one of the leading causes of cancer mortality worldwide. It arises through a stepwise process that includes prominent inflammation with expression of interferon-? (IFN-?) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-? under the control of the stomach-specific H(+)/K(+) ATPase ? promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-? transgenic mice exhibited inflammation, expansion of myofibroblasts, loss of parietal and chief cells, spasmolytic polypeptide expressing metaplasia, and dysplasia. Proliferation was elevated in undifferentiated and metaplastic epithelial cells in H/K-IFN-? transgenic mice, and there was increased apoptosis. H/K-IFN-? mice had elevated levels of mRNA for IFN-? target genes and the pro-inflammatory cytokines IL-6, IL-1?, and tumor necrosis factor-?. Intracellular mediators of IFN-? and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K-IFN-? mice developed dysplasia as early as 3 months of age, and 4 of 39 mice over 1 year of age developed antral polyps or tumors, including one adenoma and one adenocarcinoma, which expressed high levels of nuclear ?-catenin. Our data identified IFN-? as a pivotal secreted factor that orchestrates complex changes in inflammatory, epithelial, and mesenchymal cell populations to drive pre-neoplastic progression in stomach; however, additional alterations appear to be required for malignant conversion.

SUBMITTER: Syu LJ 

PROVIDER: S-EPMC3509761 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature