Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus

Daisuke Douchi, Akihiro Yamamura, Junichi Matsuo, Yi Hui Melissa Lim, Napat Nuttonmanit, Mitsuhiro Shimura, Kazuto Suda, Sabirah Chen, Shu Chin Pang, Kazuyoshi Kohu, Takaya Abe, Go Shioi, Guowei Kim, Asim Shabbir, Supriya Srivastava, Michiaki Unno, Jimmy Bok-Yan So, Ming Teh, Khay Guan Yeoh, Linda Shyue Huey ChuangYoshiaki Ito

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1907-1923.e26
JournalGastroenterology
Volume161
Issue number6
DOIs
Publication statusPublished - 2021 Dec
Externally publishedYes

Keywords

  • Gastric Carcinogenesis
  • Intramucosal Dysplasia
  • Invasive and Metastatic Gastric Cancer
  • Metaplasia
  • Mouse Model

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Fingerprint

Dive into the research topics of 'Induction of Gastric Cancer by Successive Oncogenic Activation in the Corpus'. Together they form a unique fingerprint.

Cite this