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.
Highlights
Despite a recent decline in mortality and incidence, gastric cancer still accounts for one of the largest cancer-related mortal-Note: Supplementary data for this article are available at Cancer Research Online.S
High concentrations of tamoxifen (>3 mg/20 g mouse) can induce transient mucosal damage and parietal cell atrophy 3 days after the first tamoxifen administration; these cytotoxic side effects fully resolve within 1 to 3 weeks through increased gastric stem cell proliferation [24].Our data suggest an involvement of trefoil factor 1 (Tff1)-expressing, possibly Lgr5-positive, stem cells in this process, because we observe a maximal number of traced antral glands 10 days after tamoxifen administration
High tamoxifen concentrations could induce transient metaplastic changes [23, 24], this is less likely to interfere in situations of "long latency phenotypes" (i.e., KrasG12D and BrafV600E–induced tumorigenesis) than with short-term lineage tracing experiments reported by Huh and colleagues [24]
Summary
Despite a recent decline in mortality and incidence, gastric cancer still accounts for one of the largest cancer-related mortal-. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). S. Thiem and M.F. Eissmann contributed to this article. The most prevalent form of gastric cancer is intestinaltype gastric adenocarcinoma, which progresses from superficial gastritis through stages of chronic gastritis, atrophic gastritis, metaplastic transformation, and dysplasia to invasive adenocarcinoma [2]. Chronic infection with Helicobacter pylori (H. pylori) remains the main risk factor for intestinal-type gastric cancer, others include high-salt diet and viral infections [2]
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