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/þ and Tg(Tff1-CreERT2);Braf LSL-V600E/þ 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

Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer

“…In addition, STAT3 promotes cancer development by promoting the self-renewal and differentiation of cancer stem cells (CSCs), which play crucial roles in tumorigenesis [38]. STAT3 has been identified as a key regulator in epithelial and gastric carcinogenesis [39, 40]. In pancreatic cancer, STAT3 was observed during all stages of pancreatic oncogenesis, and inhibition or loss of STAT3 reduced oncogenic KRAS-induced ADM and PanIN formation [8].…”

Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium

“…Compared with the recently reported Tff1 ‐CreERT2 mouse line , our constitutive Tff1 ‐Cre transgenic line has several unique features. First, it does not require administration of tamoxifen, which is reported to induce inflammation and metaplastic change in the stomach and may affect the phenotype.…”

“…Many Cre driver lines show gene recombination in organs other than the stomach, such as the pancreas or lung, and most are not suitable for long‐term observation. A Tff1 ‐CreERT2 mouse line was recently reported; however, it appears that Cre recombination in the antrum of this mouse was not restricted to pit cells, and recombination in the corpus was quite rare and insufficient for analysis of metaplasia and cancer development in the corpus .…”

Mouse models for gastric cancer: Matching models to biological questions

“…This, however, will require the identification of promoter sequences that restrict transgene expression to the specific gastric epithelial cells. For example, drivers such as K19:Cre and Foxa3:Cre are also expressed in the colon and intestine, while a Tff1:CreERT2 driver confers recombination to the glandular epithelium of the stomach . A number of studies have identified potential stem‐cell markers for gastrointestinal tissues.…”