title: Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model.
abstract: About 5% to 10% of human gastric tumors harbor oncogenic mutations in the KRAS pathway, but their presence alone is often insufficient for inducing gastric tumorigenesis, suggesting a requirement for additional mutagenic events or microenvironmental stimuli, including inflammation. Assessing the contribution of such events in preclinical mouse models requires Cre recombinase-mediated conditional gene expression in stem or progenitor cells of normal and transformed gastric epithelium. We therefore constructed a bacterial artificial chromosome containing transgene (Tg), comprising the regulatory elements of the trefoil factor 1 (Tff1) gene and the tamoxifen-inducible Cre recombinase (CreERT2)-coding sequence. The resulting Tg(Tff1-CreERT2) mice were crossed with mice harboring conditional oncogenic mutations in Kras or Braf The administration of tamoxifen to the resulting adult Tg(Tff1-CreERT2);Kras(LSL-G12D/+) and Tg(Tff1-CreERT2);Braf(LSL-V600E/+) mice resulted in gastric metaplasia, inflammation, and adenoma development, characterized by excessive STAT3 activity. To assess the contribution of STAT3 to the spontaneously developing gastric adenomas in gp130(F/F) mice, which carry a knockin mutation in the Il6 signal transducer (Il6st), we generated Tg(Tff1-CreERT2);Stat3(fl/fl);gp130(F/F) mice that also harbor a conditional Stat3 knockout allele and found that tamoxifen administration conferred a significant reduction in their tumor burden. Conversely, excessive Kras activity in Tg(Tff1-CreERT2);Kras(LSL-G12D/+);gp130(F/F) mice promoted more extensive gastric inflammation, metaplastic transformation, and tumorigenesis than observed in Tg(Tff1-CreERT2);Kras(LSL-G12D/+) mice. Collectively, our findings demonstrate that advanced gastric tumorigenesis requires oncogenic KRAS or BRAF in concert with aberrant STAT3 activation in epithelial precursor cells of the glandular stomach, providing a new conditional model of gastric cancer in which to investigate candidate therapeutic targets and treatment strategies. Cancer Res; 76(8); 2277-87. ©2016 AACR.
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia.
authors.forename: Stefan
authors.initials: S
authors.lastname: Thiem
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia.
authors.forename: Moritz F
authors.initials: MF
authors.lastname: Eissmann
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia.
authors.forename: Joachim
authors.initials: J
authors.lastname: Elzer
authors.affiliation: Department of Multiple Sclerosis, The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Jonas
authors.affiliation: Inflammation Division, The Walter & Eliza Hall Institute of Medical Research and Department of Medical Biology University of Melbourne, Melbourne, Australia.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Putoczki
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia. Inflammation Division, The Walter & Eliza Hall Institute of Medical Research and Department of Medical Biology University of Melbourne, Melbourne, Australia.
authors.forename: Ashleigh
authors.initials: A
authors.lastname: Poh
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia. Inflammation Division, The Walter & Eliza Hall Institute of Medical Research and Department of Medical Biology University of Melbourne, Melbourne, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Nguyen
authors.affiliation: Inflammation Division, The Walter & Eliza Hall Institute of Medical Research and Department of Medical Biology University of Melbourne, Melbourne, Australia.
authors.forename: Adele
authors.initials: A
authors.lastname: Preaudet
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia.
authors.forename: Dustin
authors.initials: D
authors.lastname: Flanagan
authors.affiliation: Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Vincan
authors.affiliation: Department of Pathology, University of Melbourne, Melbourne, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Waring
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Buchert
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia. School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jarnicki
authors.affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute and School of Cancer Medicine La Trobe University, Heidelberg, Australia. matthias.ernst@onjcri.org.au.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ernst
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D011905:Genes, ras; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009857:Oncogenes; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse