APC mutation and the crypt cycle in murine and human intestine.
Dysplastic colon adenomas are thought to arise from growth of clones of APC -/- colonic epithelial cells. Isolated clusters of dysplastic crypts are often observed in patients with familial adenomatous polyposis. These patients have genotype APC +/-, and the clusters of dysplastic crypts (called microadenoma or aberrant crypt foci) are thought to represent an early stage in the expansion of a mutant clone of APC -/- cells. It is thought that the growth of these clusters of mutant crypts results from crypt replication through a process similar to what occurs in the normal crypt cycle. We measured the relative replication rate of mutant crypts by analyzing the size of clusters of mutant crypts in APC +/- individuals and found that mutant APC -/- crypts replicate more rapidly than do normal APC +/- (i.e., nonneoplastic) crypts. In contrast, the replication rate of mutant crypts in Apc +/- mice is not significantly different from that of normal crypts, thus supporting previous findings that aberrant crypt foci do not contribute significantly to the colon adenoma population in adult Apc +/- mice. Intriguingly, we found an effect of Apc heterozygosity on the frequency of branching crypts in young mice.
Bjerknes
M
M
Department of Anatomy and Cell Biology, University of Toronto, Ontario, Canada.
Cheng
H
H
Hay
K
K
Gallinger
S
S
D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology; D000375:Aging / Q000473:pathology; D000818:Animals; D003106:Colon / Q000254:growth & development* / Q000473:pathology; D003108:Colonic Diseases / Q000235:genetics / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D017491:Genes, APC / Q000235:genetics*; D006801:Humans; D007583:Jejunum / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D013045:Species Specificity