Humphries, A.; (2012) Stem cell biology and clonal expansion in normal and adenomatous human intestinal crypts. Doctoral thesis , UCL (University College London).

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Abstract

Gastrointestinal cancer is thought to be primarily a disease of stem cells, whereby a tumorigenic stem cell clone can expand within an individual colonic crypt and then within the epithelium to form an adenoma - the pre-malignant lesion of the colon. However, data demonstrating stem cell populations and the dynamics of clonal expansion in human intestinal crypts is lacking. Naturally occurring, somatic clonal mutations in mitochondrial DNA were used to identify the progeny of a putative single stem cell lineage within crypts; this allowed the visualization of putative stem cell clones arising and expanding within human colon and small bowel crypts. Immunohistochemistry for lineage specific markers, to confirm multi-potentiality, and in-situ hybridisation for stem cell markers was then performed to phenotype clones further and to demonstrate a single stem cell lineage and their direct progeny within the human crypt. By combining clonal somatic mutations in mitochondrial DNA with methylation signatures, the dynamics of clonal expansion within normal colon crypts and the epithelium was studied, and using mathematical modeling the time course of these events was able to be estimated. By applying the same techniques, in addition to studying genomic mutations, the dynamics of human adenoma growth was investigated; this suggested that adenomas appear to grow in a punctuated manner, with episodes of rapid clonal expansion being followed by periods of relative quiescence.

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