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Expansion of a mutated clone - from stem cell to tumour
  1. Simon Leedham (simon.leedham{at}cancer.org.uk)
  1. Cancer Research UK, United Kingdom
    1. Nicholas Wright (warden{at}qmul.ac.uk)
    1. Cancer Research UK, United Kingdom

      Abstract

      Intestinal stem cells are adult, tissue-based stem cells located at the base of the intestinal crypt and are capable of regenerating all intestinal cell types. The progeny of mutated stem cells can expand to fill an entire crypt as a consequence of genetic drift, selective advantage or hitchhiking - eventually forming a clonal crypt population by a process called 'niche succession'. Cancer is believed to be a disease of stem cells. The digestive tract has a very high cancer prevalence partly due to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes including Famalial Adenomatous Polyposis (FAP) has led to significant advances, including the adenoma-carcinoma sequence. The initial mutation involved in this stepwise progression is in the "gatekeeper" tumour suppressor gene Adenomatous Polyposis Coli (APC). In FAP somatic, second hits in this gene are non-random events, selected for by the position of the germline mutation. The early growth of adenomas is contentious with 2 main theories, the 'top-down' and 'bottom-up' hypotheses attempting to explain the spread of dysplastic tissue in the bowel. Initial X chromosome inactivation studies suggested that colorectal tumours were monoclonal, however work on a rare XO/XY human patient with FAP and chimeric Min mice showed that approximately 76% of adenomas were polyclonal. A reduction in tumour multiplicity in the chimeric mouse model has been achieved by the introduction of a homozygous tumour resistance allele. This model has been used to suggest that short-range interaction between adjacent initiated crypts, not random polyp collision, is responsible for tumour polyclonality.

      • Adenomatous Polyposis Coli (APC)
      • Clonality
      • Niche succession
      • Stem cell

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