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.
Leedham
S J
SJ
Histopathology Unit, Cancer Research UK, London, UK. simon.leedham@cancer.org.uk
Schier
S
S
Thliveris
A T
AT
Halberg
R B
RB
Newton
M A
MA
Wright
N A
NA
D000818:Animals; D005770:Gastrointestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D041981:Gastrointestinal Tract / Q000166:cytology* / Q000502:physiology; D052138:Genes, Neoplasm; D006801:Humans; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000473:pathology*