Basic–Alimentary TractMechanisms of Field Cancerization in the Human Stomach: The Expansion and Spread of Mutated Gastric Stem Cells
Section snippets
Patients
Patients undergoing gastrectomy or gastroesophagectomy for adenocarcinoma were used in this study (n = 15). Morphologically normal gastric mucosa was taken from outside the tumor margins from each specimen (these specimens are histologically normal but because they are taken from cancer patients we cannot exclude the possibility of influence by the tumor), and frozen epithelial surface–side down on a microscope slide in liquid nitrogen–cooled isopentane. In one case, the presence of a mild
Multiple Stem Cells Are Present in the Human Gastric Unit
Gastric units containing mtDNA mutations were identified by finding units that were deficient in histocytochemical cytochrome c oxidase activity and by using this as a marker of stem cell clonal expansion.10 Cytochrome c oxidase–deficient units were highlighted by the activity of nuclear-encoded SDH.14 We observed gastric units that were partially mutated to varying degrees. Figure 1A shows a cross-section of a gastric body–type unit with a single cytochrome c oxidase–deficient cell within the
Discussion
We conclude that human gastric units contain multiple multipotential stem cells, one of which, once mutated, can colonize the entire unit, resulting in a new clonal unit by monoclonal conversion (Figure 7A). The simplest model for stem cell architecture suggested by our data is that the multiple stem cells are housed in a niche in the isthmus/neck of the gastric unit, above where several glands enter (Figure 7A) and that these cells give rise to all lineages in the gland and in the foveolus.
References (27)
- et al.
Lineage and clonal development of gastric glands
Dev Biol
(1998) - et al.
Clonal analysis of isolated single fundic and pyloric gland of stomach using X-linked polymorphism
Biochem Biophys Res Commun
(1996) - et al.
Methylation of multiple genes in gastric glands with intestinal metaplasia: a disorder with polyclonal origins
Am J Pathol
(2006) - et al.
Clonal analysis of mouse intestinal epithelial progenitors
Gastroenterology
(1999) - et al.
Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age
Am J Hum Genet
(2001) - et al.
Natural selection in neoplastic progression of Barrett’s esophagus
Semin Cancer Biol
(2005) Mutation selection and the natural history of cancer
Nature
(1975)- et al.
Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog
Nat Med
(1999) - et al.
Gastric stem cells: an update
Keio J Med
(2003) Gastrointestinal and Oesophageal Pathology
Multipotential stem cells in adult mouse gastric epithelium
Am J Physiol
Intestinal metaplasia of human stomach displays distinct patterns of mucin (MUC1, MUC2, MUC5AC, and MUC6) expression
Cancer Res
Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract
Gut
Cited by (209)
Hallmarks of stemness in mammalian tissues
2024, Cell Stem CellModulating mitochondrial DNA mutations: factors shaping heteroplasmy in the germ line and somatic cells
2022, Pharmacological ResearchCitation Excerpt :As a result, the POLG mutator mice present a premature aging phenotype that is attributed to defective tissue regeneration [92,115–117]. In humans, stem cell populations of the colorectal epithelium and bone marrow also display mitochondrial dysfunction associated with clonal expansion of mtDNA mutations, suggesting that the link between mtDNA mutations and aging is, at least in part, explained by decreased tissue regeneration [105,118–124]. In addition to this, the clonal expansion of mtDNA deletions and point mutations in substantia nigra neurons have been shown to cause mitochondrial defects associated with aging and Parkinson disease [83–86,125].
Big Data on Gastric Dysplasia Support Gastric Cancer Prevention
2022, Clinical Gastroenterology and HepatologyClonal Transitions and Phenotypic Evolution in Barrett's Esophagus
2022, GastroenterologyGastritis: The clinico-pathological spectrum
2021, Digestive and Liver Disease
Supported by Oxford University and Cancer Research UK (S.A.C.M. and J.A.Z.J.), and supported in part by The Wellcome Trust (L.C.G. and D.M.T.). None of our sponsors were involved in the design of this study.