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

Abstract

Chronic inflammation and intestinal metaplasia are strongly associated with gastric carcinogenesis. Kras activation and Pten deletion are observed in intestinal-type gastric cancer, and Cdh1 mutation is associated with diffuse-type gastric cancer. Although various mouse models of gastric carcinogenesis have been reported, few mouse lines enable gene manipulation selectively in the stomach. Here we established a Tff1-Cre bacterial artificial chromosome transgenic mouse line in an attempt to induce gene modification specifically in the gastric pit lineage. In the stomach, Tff1-Cre-mediated recombination was most evident in the pit lineage in the corpus and in entire antral glands; recombination was also observed in a few gastric chief and parietal cells. Outside the stomach, recombination was patchy throughout the intestines, and particularly frequently in the duodenum (Brunner glands), cecum, and proximal colon. In the stomachs of Tff1-Cre;LSL-Kras mice, proliferating cell clusters expanded throughout the corpus glands, with foveolar cell expansion with ectopic Alcian blue-positive mucins, oxyntic atrophy, and pseudopyloric changes with spasmolytic polypeptide-expressing metaplasia; however, gastric cancer was not observed even at 12 months of age. Corpus-derived organoids from Tff1-Cre;LSL-Kras mice exhibited accelerated growth and abnormal differentiation with a loss of chief and parietal cell markers. Tff1-Cre;Pten mice displayed similar changes to those seen in Tff1-Cre;LSL-Kras mice, both with aberrant ERK activation within 3 months. In contrast, Tff1-Cre;Cdh1 mice initially showed signet ring-like cells that were rapidly lost with disruption of the mucosal surface, and later developed gastric epithelial shedding with hyperproliferation and loss of normal gastric lineages. Eventually, the glandular epithelium in Tff1-Cre;Cdh1 mice was completely replaced by squamous epithelium which expanded from the forestomach. Tff1-Cre mice offer an additional useful tool for studying gastric carcinogenesis both in vivo and in vitro. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Tumor microenvironment in gastric cancers

“…In mouse models of gastritis and gastric cancers, there is a marked infiltration of macrophages. These macrophages are recruited by epithelium‐derived chemokines and cytokines 41‐46 . They produce pro‐inflammatory cytokines such as TNF‐α, and stimulate tumor growth, in part through Wnt activation 45,47 .…”

Gastric Stem Cell and Cellular Origin of Cancer

“…However, given that metaplastic cells arise in Mist1 -CreERT; LSL- Kras G12D ; Lgr5 -DTR mice even after the ablation of Lgr5 + chief cells, most of the metaplastic cells are likely to be derived from Mist1 + isthmus stem cells, or at least from Lgr5 -negative Mist1 + cells [22]. The induction of mutant Kras in the upper isthmus region of K19 -CreERT or Tff1 -Cre mice results in the development of a similar metaplasia and supports the notion that isthmus stem/progenitors are the predominant source of metaplasia [22,47,48]. Although the research group using Lgr5 -2A-CreERT mice claimed that Lgr5 + chief cells gave rise to cancer following high-dose-tamoxifen-induced injury and mutant Kras expression, Kras activation alone does not cause histological cancer, but instead metaplasia, as in other Kras models.…”

“…Although we have a different opinion and interpretation of their results [45]. However, all mice with mutant Kras eventually develop SPEM at the base of the metaplastic glands and glands in the Kras -mutated stomach predominantly contain aberrant MUC4+ cells with Alcian blue-positive ectopic mucins [47]. Distinguishing between SPEM and other types of metaplasia could be an interesting experimental approach, but it is unlikely to be relevant to a determination of the cellular origin of metaplasia or pathogenesis in humans [49] given that the ultimate phenotypes in all Kras models are essentially indistinguishable.…”

Hypergastrinemia Expands Gastric ECL Cells Through CCK2R+ Progenitor Cells via ERK Activation

“…On the other hand, differentiation into the endocrine-like tuft cell lineage is enhanced by activation of EGFR/ERK signaling both in the stomach and intestine. 52 , 53 , 54 Therefore, it appears that regulatory mechanisms of cellular differentiation and proliferation are likely to be cell type–dependent and/or organ-dependent.…”