Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus

Gastroenterology. 2021 Dec;161(6):1907-1923.e26. doi: 10.1053/j.gastro.2021.08.013. Epub 2021 Aug 12.

Abstract

Background & aims: Metaplasia and dysplasia in the corpus are reportedly derived from de-differentiation of chief cells. However, the cellular origin of metaplasia and cancer remained uncertain. Therefore, we investigated whether pepsinogen C (PGC) transcript-expressing cells represent the cellular origin of metaplasia and cancer using a novel Pgc-specific CreERT2 recombinase mouse model.

Methods: We generated a Pgc-mCherry-IRES-CreERT2 (Pgc-CreERT2) knock-in mouse model. Pgc-CreERT2/+ and Rosa-EYFP mice were crossed to generate Pgc-CreERT2/Rosa-EYFP (Pgc-CreERT2/YFP) mice. Gastric tissues were collected, followed by lineage-tracing experiments and histologic and immunofluorescence staining. We further established Pgc-CreERT2;KrasG12D/+ mice and investigated whether PGC transcript-expressing cells are responsible for the precancerous state in gastric glands. To investigate cancer development from PGC transcript-expressing cells with activated Kras, inactivated Apc, and Trp53 signaling pathways, we crossed Pgc-CreERT2/+ mice with conditional KrasG12D, Apcflox, Trp53flox mice.

Results: Expectedly, mCherry mainly labeled chief cells in the Pgc-CreERT2 mice. However, mCherry was also detected throughout the neck cell and isthmal stem/progenitor regions, albeit at lower levels. In the Pgc-CreERT2;KrasG12D/+ mice, PGC transcript-expressing cells with KrasG12D/+ mutation presented pseudopyloric metaplasia. The early induction of proliferation at the isthmus may reflect the ability of isthmal progenitors to react rapidly to Pgc-driven KrasG12D/+ oncogenic mutation. Furthermore, Pgc-CreERT2;KrasG12D/+;Apcflox/flox mice presented intramucosal dysplasia/carcinoma and Pgc-CreERT2;KrasG12D/+;Apcflox/flox;Trp53flox/flox mice presented invasive and metastatic gastric carcinoma.

Conclusions: The Pgc-CreERT2 knock-in mouse is an invaluable tool to study the effects of successive oncogenic activation in the mouse corpus. Time-course observations can be made regarding the responses of isthmal and chief cells to oncogenic insults. We can observe stomach-specific tumorigenesis from the beginning to metastatic development.

Keywords: Gastric Carcinogenesis; Intramucosal Dysplasia; Invasive and Metastatic Gastric Cancer; Metaplasia; Mouse Model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Dedifferentiation
  • Cell Lineage
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chief Cells, Gastric / enzymology*
  • Chief Cells, Gastric / pathology
  • Gene Expression Regulation, Neoplastic
  • Genes, APC
  • Genetic Predisposition to Disease
  • Integrases / genetics*
  • Integrases / metabolism
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Metaplasia
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation
  • Pepsinogen C / genetics*
  • Pepsinogen C / metabolism
  • Phenotype
  • Precancerous Conditions / enzymology
  • Precancerous Conditions / genetics*
  • Precancerous Conditions / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Red Fluorescent Protein
  • Stomach Neoplasms / enzymology
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Transcriptional Activation*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Luminescent Proteins
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Pepsinogen C
  • Cre recombinase
  • Integrases
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)