Gastrointestinal stem cells and cancer: bridging the molecular gap.

Cancer is believed to be a disease involving stem cells. The digestive tract has a very high cancer prevalence partly owing to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes including familial 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" tumor suppressor gene adenomatous polyposis coli (APC). In FAP somatic, second hits in this gene are nonrandom events, selected for by the position of the germ-line mutation. Extensive work in both the mouse and human has shown that crypts are clonal units and mutated stem cells may develop a selective advantage, eventually forming a clonal crypt population by a process called "niche succession." Aberrant crypt foci are then formed by the longitudinal division of crypts into two daughter units--crypt fission. The early growth of adenomas is contentious with two 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 tumors were monoclonal; however, work on a rare XO/XY human patient with FAP and chimeric Min mice showed that 76% of adenomas were polyclonal. A reduction in tumor multiplicity in the chimeric mouse model has been achieved by the introduction of a homozygous tumor resistance allele. This model has been used to suggest that short-range interaction between adjacent initiated crypts, not random polyp collision, is responsible for tumor polyclonality

From gene mutations to tumours--stem cells in gastrointestinal carcinogenesis.

Stem cells share many properties with malignant cells, such as the ability to self-renew and proliferate. Cancer is believed to be a disease of stem cells. The gastrointestinal tract has high cancer prevalence partly because of rapid epithelial cell turnover and exposure to dietary toxins. The molecular pathways of carcinogenesis differ according to the tissue. Work on hereditary cancer syndromes including familial adenomatous polyposis (FAP) has led to advances in our understanding of the events that occur in tumour development from a gastrointestinal stem cell. The initial mutation involved in the adenoma-carcinoma sequence is in the 'gatekeeper' tumour-suppressor gene adenomatous polyposis coli (APC). Somatic hits in this gene are non-random in FAP, with the type of mutation selected for by the position of the germline mutation. In the stomach, a metaplasia-dysplasia sequence occurs and is often related to Helicobacter pylori infection. Clonal expansion of mutated cells occurs by niche succession. Further expansion of the aberrant clone then occurs by the longitudinal division of crypts into two daughter units--crypt fission. Two theories seek to explain the early development of adenomas--the 'top down' and 'bottom up' hypotheses. Initial studies suggested that colorectal tumours were monoclonal; however, later work on chimeric mice and a sex chromosome mixoploid patient with FAP suggested that up to 76% of early adenomas were polyclonal. Introduction of a homozygous resistance allele has reduced tumour multiplicity in the mouse and has been used to rule out random collision of polyps as the cause of these observations. It is likely that short-range interaction between adjacent initiated crypts is responsible for polyclonality