Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells

Gastroenterology. 2018 Mar;154(4):839-843.e2. doi: 10.1053/j.gastro.2017.11.278. Epub 2017 Dec 14.


Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a nongenetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM. Based on analyses of molecular and histologic markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells-mainly of chief cells.

Keywords: Cancer; Development; Differentiation; Exocrine Cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology*
  • Adenocarcinoma / surgery
  • Animals
  • Biomarkers, Tumor / metabolism
  • Cell Lineage
  • Cell Proliferation
  • Cell Transdifferentiation* / drug effects
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Chief Cells, Gastric / drug effects
  • Chief Cells, Gastric / metabolism
  • Chief Cells, Gastric / pathology*
  • Fluorouracil / pharmacology
  • Gastrectomy
  • Gastric Mucosa / metabolism
  • Intercellular Signaling Peptides and Proteins
  • Metaplasia
  • Mice
  • Peptides / metabolism
  • Phenotype
  • Precancerous Conditions / metabolism
  • Precancerous Conditions / pathology*
  • Precancerous Conditions / surgery
  • Stomach / drug effects
  • Stomach / pathology*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Stomach Neoplasms / surgery
  • Time Factors


  • Biomarkers, Tumor
  • Intercellular Signaling Peptides and Proteins
  • Peptides
  • spasmolytic polypeptide
  • Fluorouracil