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Hormonal Suppression of Stem Cells Inhibits Symmetric Cell Division and Gastric Tumorigenesis

Wenju Chang1, Hongshan Wang2, Woosook Kim3

  • 1Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Colorectal Cancer Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China; Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA.

Cell Stem Cell
|March 7, 2020
PubMed

Insights

Gastric stem cells divide asymmetrically to prevent mutations. Gastrin signaling suppresses symmetric division, reducing cancer risk and mutational load in the stomach.

Area of Science:

  • Gastroenterology
  • Stem Cell Biology
  • Cancer Research

Background:

  • Cancer is thought to originate from stem cells, but the mechanisms controlling mutation acquisition and tumor formation are not fully understood.
  • Gastric stem cells play a crucial role in maintaining stomach tissue homeostasis and are implicated in gastric tumorigenesis.

Purpose of the Study:

  • To investigate the role of specific gastric stem cell populations in tumor development.
  • To elucidate the mechanisms by which stem cell division patterns influence mutation accumulation and gastric cancer progression.
  • To explore the potential of gastrin signaling as a therapeutic strategy to suppress gastric tumorigenesis.

Main Methods:

  • Identification and characterization of a specific +4 stem cell population in the gastric antrum using markers like Cck2r and Delta-like ligand 1 (DLL1).
  • Analysis of stem cell division patterns (asymmetric vs. symmetric) in normal and chemically induced gastric cancer models.
  • Assessment of the impact of gastrin signaling on stem cell division, glandular structure, and mutational load using exomic sequencing.

Main Results:

  • A distinct +4 stem cell in the gastric antrum, expressing Cck2r and DLL1, was identified as a label-retaining cell undergoing predominantly asymmetric division.
  • This stem cell population is characterized by Notch1 low/Numb+ expression and is normally repressed by signaling from gastrin-expressing endocrine (G) cells.
  • Chemical carcinogenesis led to a loss of G cells, increased symmetric stem cell division, glandular fission, and accelerated stem cell lineage tracing.
  • Exogenous gastrin treatment suppressed these carcinogenic processes and significantly reduced the mutational load in gastric cancer.

Conclusions:

  • Gastric tumorigenesis is linked to an increase in symmetric stem cell division, which promotes mutation accumulation.
  • Gastrin signaling, acting through G protein-coupled receptors (GPCRs), plays a protective role by suppressing symmetric stem cell division and reducing mutational burden.
  • Targeting GPCR signaling, specifically via gastrin, offers a potential therapeutic avenue for preventing and treating gastric cancer by controlling stem cell behavior.
Keywords:
Cck2rasymmetric divisioncarcinogenesisgastric neoplasmgastringene mutationnotch signalingstem cellsymmetric division

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