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Heterogeneity in mouse spasmolytic polypeptide-expressing metaplasia lineages identifies markers of metaplastic progression
  1. Victoria G Weis1,
  2. Josane F Sousa1,
  3. Bonnie J LaFleur2,
  4. Ki Taek Nam1,
  5. Jared A Weis3,
  6. Paul E Finke4,
  7. Nadia A Ameen5,
  8. James G Fox6,
  9. James R Goldenring1
  1. 1Nashville VA Medical Center and the Departments of Surgery and Cell and Developmental Biology, Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
  2. 2Division of Epidemiology and Biostatistics, University of Arizona, Tuscon, Arizona, USA
  3. 3Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee, USA
  4. 4Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey, USA
  5. 5Departments of Pediatrics/Gastroenterology and Hepatology, Yale University School of Medicine, New Haven, Connecticut, USA
  6. 6Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  1. Correspondence to Dr James R Goldenring, Vanderbilt University School of Medicine, Epithelial Biology Center, 10435G MRBIV, 2213 Garland Avenue, Nashville, TN 37232-2733, USA; jim.goldenring{at}vanderbilt.edu

Abstract

Objectives Spasmolytic polypeptide-expressing metaplasia (SPEM) develops as a preneoplastic lesion in the stomachs of mice and humans after parietal cell loss. To identify the commonalities and differences between phenotypic SPEM lineages, SPEM were studied from three different mouse models of parietal cell loss: with chronic inflammation with Helicobacter felis infection; with acute inflammation with L635 treatment; and without inflammation following DMP-777 treatment.

Design RNA transcripts from laser capture microdissected normal chief cells and SPEM lineages were compared using gene microarray. Alterations in transcripts were validated by quantitative real-time PCR. Clusterin and cystic fibrosis transmembrane conductance regulator (CFTR) were selected for immunohistochemical analysis in all mouse models as well as in human SPEM, intestinal metaplasia and gastric cancer.

Results Transcript expression patterns demonstrated differences among the phenotypic SPEM models. Clusterin expression was significantly upregulated in all three mouse SPEM models as well as in human SPEM. The highest clusterin expression in human gastric cancers correlated with poor survival. Conversely, CFTR expression was upregulated only in SPEM with inflammation in mice. In humans, intestinal metaplasia, but not SPEM, expressed CFTR.

Conclusions While markers such as clusterin are expressed in all phenotypic SPEM lineages, distinct patterns of upregulated genes including CFTR are present in murine metaplasia associated with inflammation, indicative of progression of metaplasia towards a more intestinalised metaplastic phenotype.

  • CFTR
  • cholera
  • clusterin
  • cystic fibrosis
  • diarrhoeal disease
  • DMP-777
  • gastric cancer
  • gastrointestinal cancer
  • Helicobacter felis
  • H pylori-pathogenesis
  • molecular pathology
  • spasmolytic polypeptide-expressing metaplasia
  • stem cells
  • trefoil peptides

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Footnotes

  • Funding These studies were supported by grants from a Department of Veterans Affairs merit review award, NIH grant RO1 DK071590, and an ARRA supplement (DK071590-S1) (to JRG); NIH grants RO1 AI037750 and P30 ES02109 (to JGF); R01 DK 077065 (to NAA); P50 CA95060 (to BJL). This work was supported by core resources of the Vanderbilt Digestive Disease Center (P30 DK058404) and the Vanderbilt–Ingram Cancer Center, and imaging was supported by both the Vanderbilt combined imaging shared resource and the shared imaging resource of the Vanderbilt Epithelial Biology Center.

  • Competing interests None.

  • Ethics approval Ethics approval was provided by Vanderbilt institutional review board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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