title: Transgenic expression of interferon-γ 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-γ (IFN-γ) and multiple other pro-inflammatory cytokines. We engineered mice expressing IFN-γ under the control of the stomach-specific H(+)/K(+) ATPase β promoter to test the potential role of this cytokine in gastric tumorigenesis. Stomachs of H/K-IFN-γ 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-γ transgenic mice, and there was increased apoptosis. H/K-IFN-γ mice had elevated levels of mRNA for IFN-γ target genes and the pro-inflammatory cytokines IL-6, IL-1β, and tumor necrosis factor-α. Intracellular mediators of IFN-γ and IL-6 signaling, pSTAT1 and pSTAT3, respectively, were detected in multiple cell types within stomach. H/K-IFN-γ 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 β-catenin. Our data identified IFN-γ 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.
authors.affiliation: Department of Dermatology, School of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Li-Jyun
authors.initials: LJ
authors.lastname: Syu
authors.forename: Mohamad
authors.initials: M
authors.lastname: El-Zaatari
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Eaton
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.forename: Manas
authors.initials: M
authors.lastname: Tetarbe
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Keeley
authors.forename: Joanna
authors.initials: J
authors.lastname: Pero
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferris
authors.forename: Dawn
authors.initials: D
authors.lastname: Wilbert
authors.forename: Ashley
authors.initials: A
authors.lastname: Kaatz
authors.forename: Xinlei
authors.initials: X
authors.lastname: Zheng
authors.forename: Xiotan
authors.initials: X
authors.lastname: Qiao
authors.forename: Marina
authors.initials: M
authors.lastname: Grachtchouk
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Gumucio
authors.forename: Juanita L
authors.initials: JL
authors.lastname: Merchant
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Dlugosz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001284:Atrophy; D019070:Cell Lineage / Q000235:genetics; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism*; D017506:H(+)-K(+)-Exchanging ATPase / Q000235:genetics; D053823:Hedgehog Proteins / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009929:Organ Size; D010295:Parietal Cells, Gastric / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D011230:Precancerous Conditions / Q000473:pathology; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013270:Stomach / Q000473:pathology*; D013274:Stomach Neoplasms / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics
chemical_list: D053823:Hedgehog Proteins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; D050791:STAT Transcription Factors; C451060:spasmolytic polypeptide; D007371:Interferon-gamma; D017506:H(+)-K(+)-Exchanging ATPase