Stem Cells in Intraepithelial Neoplasia
Tumours are thought to contain a subpopulation of self-renewing stem cells, the so-called cancer stem cells, which maintain the tumour. Moreover, tumours themselves are thought to arise from organ-specific stem cells. In epithelia, transformation of these cells leads to spread of a mutated stem cell clone through the epithelial sheet, leading to the development of a pre-invasive lesion. Barrett’s oesophagus is used as an example of the role of stem cells in the development of such a pre-invasive lesion. This is an intriguing condition where the stratified squamous epithelium of the lower oesophagus is replaced with a metaplastic epithelium, which usually shows goblet cell-containing crypts. A similar metaplasia occurs in the stomach in chronic atrophic gastritis. In both cases these epithelial fields can becomes genetically unstable and develop a considerable mutation burden, including mutations in important tumour-suppressor genes, setting in motion the so-called metaplasia/dysplasia/carcinoma sequence. There has long been argument about the nature of this metaplasia, but in the stomach we have shown that it represents a clonal proliferation and arises through a process of monoclonal conversion from gastric stem cells to the intestinal phenotype in individual gastric glands. We have further shown clonal spread of the metaplastic process within the epithelium, mediated through the mechanism of crypt fission. In Barrett’s mucosa however, we have shown that the mucosa is composed of numbers of discrete mutated clones, all of which may compete, providing a stimulus for clonal progression and thus malignant change. We also propose that the origin of these multiple clones is from stem cells in the ducts of the oesophageal glands found in the lower oesophagus.
KeywordsIntestinal Metaplasia Stem Cell Niche Metaplastic Epithelium Oesophageal Gland Crypt Fission
I thank Malcolm Alison, Stuart McDonald, Lydia Gutierrez-Gonzalez, Simon Leedham and Trevor Graham for much help with this work, and Cancer Research UK for funding.
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