Gastroenterology

Gastroenterology

Volume 134, Issue 2, February 2008, Pages 500-510
Gastroenterology

Basic–Alimentary Tract
Mechanisms of Field Cancerization in the Human Stomach: The Expansion and Spread of Mutated Gastric Stem Cells

https://doi.org/10.1053/j.gastro.2007.11.035Get rights and content

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.

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.

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  • Cited by (0)

    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.

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