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Title: Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model.
Austin Authors: Thiem, Stefan;Eissmann, Moritz F ;Elzer, Joachim;Jonas, Anna;Putoczki, Tracy L;Poh, Ashleigh;Nguyen, Paul;Preaudet, Adele;Flanagan, Dustin;Vincan, Elizabeth;Waring, Paul;Buchert, Michael;Jarnicki, Andrew;Ernst, Matthias 
Affiliation: Cancer and Inflammation, Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Inflammation Division, The Walter & Eliza Hall Institute of Medical Research and Department of Medical Biology University of Melbourne, Melbourne, Australia
Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia
Department of Pathology, University of Melbourne, Melbourne, Australia
School of Cancer Medicine La Trobe University, Heidelberg, Australia
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, Australia
Department of Multiple Sclerosis, The Florey Institute of Neuroscience and Mental Health, Melbourne, Australia
Issue Date: 15-Apr-2016 2016-02-02
Publication information: Cancer research 2016; 76(8): 2277-87
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.
DOI: 10.1158/0008-5472.CAN-15-3089
ORCID: 0000-0002-6399-1177
PubMed URL: 26837764
Type: Journal Article
Appears in Collections:Journal articles

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