Mechanisms of Field Cancerization in the Human Stomach: The Expansion and Spread of Mutated Gastric Stem Cells
Open accessAbstract
Background & aims How mutations are established and spread through the human stomach is unclear because the clonal structure of gastric mucosal units is unknown. Here we investigate, using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion, the clonality of the gastric unit and show how mutations expand in normal mucosa and gastric mucosa showing intestinal metaplasia. This has important implications in gastric carcinogenesis.Methods Mutated units were identified by a histochemical method to detect activity of cytochrome c oxidase. Negative units were laser-capture microdissected, and mutations were identified by polymerase chain reaction sequencing. Differentiated epithelial cells were identified by immunohistochemistry for lineage markers.Results We show that mtDNA mutations establish themselves in stem cells within normal human gastric body units, and are passed on to all their differentiated progeny, thereby providing evidence for clonal conversion to a new stem cell-derived unit-monoclonal conversion, encompassing all gastric epithelial lineages. The presence of partially mutated units indicates that more than one stem cell is present in each unit. Mutated units can divide by fission to form patches, with each unit sharing an indentical, mutant mtDNA genotype. Furthermore, we show that intestinal metaplastic crypts are clonal, possess multiple stem cells, and that fission is a mechanism by which intestinal metaplasia spreads.Conclusions These data show that human gastric body units are clonal, contain multiple multipotential stem cells, and provide definitive evidence for how mutations spread within the human stomach, and show how field cancerization develops.
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Several studies relate mtDNA defects to human stem cell aging.
“several studies have related mtDNA defects to human stem cell aging100–102.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [101]
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- Authors
- McDonald, S. A. C., Greaves, L. C., Gutierrez–Gonzalez, L., Rodriguez–Justo, M., Deheragoda, M., Leedham, S. J., Taylor, R. W., Lee, C. Y., Preston, S. L., Lovell, M., Hunt, T., Elia, G., Oukrif, D., Harrison, R., Novelli, M. R., Mitchell, I., Stoker, D. L., Turnbull, D. M., Jankowski, J. A. Z., & Wright, N. A.
- Affiliations
- Cancer Research UK (GB)
- Newcastle University (GB)
- University College London (GB)
- University Hospitals of Leicester NHS Trust (GB)
- University College Hospital (GB)
- University of London (GB)
- Corresponding author
- McDonald, Stuart A.C.
- ORCID
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 134
- Issue
- 2
- Pages
- 500-510
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2096969440
- Cited by
- 242
- References
- 30
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 3 · 2023: 9 · 2022: 9 · 2021: 11 · 2020: 13 · 2019: 6 · 2018: 13 · 2017: 18 · 2016: 17 · 2015: 14 · 2014: 16 · 2013: 16 · 2012: 14
- FWCI
- 13.98
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- CLOK (University of Central Lancashire) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity)
- Funders
- Wellcome Trust
- Cancer Research UK
- Medical Research Council
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- field cancerization, gastric stem cells, clonal expansion, mitochondrial DNA mutations, cytochrome c oxidase, intestinal metaplasia, gastric carcinogenesis, gastric mucosa, multipotent stem cells
- MeSH terms
- Cell Transformation, Neoplastic, Electron Transport Complex IV, DNA, Mitochondrial, Epithelium, Gastric Mucosa, Genotype, Humans, Metaplasia, Mutation, Precancerous Conditions, Stomach, Stomach Neoplasms, Multipotent Stem Cells
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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