APC mutation, niche succession and colon cancer initiation
Niche succession is a phenomenon by which a single stem cell lineage comes to dominate the stem cell niche periodically. Normally niche succession occurs not by selection but by a random process in which an occasional symmetric division of a stem cell produces two differentiated daughters that leave the niche while another stem cell divides symmetrically to produce two stem cell daughters that stay in the niche. Tumorigenic mutations that cannot by themselves give a proliferative advantage to the cells can ‘hitchhike’ on niche succession and dominate the niche even before tumor progression begins. Homozygous mutations of the Adenomatous Polyposis Coli (APC) gene are found in majority of colorectal cancers and are known to cause constitutive activation of; proliferative pathways but heterozygous mutations of the APC gene are considered incapable of giving any proliferative advantage to the cell. However there are indications that heterozygous APC mutations increase stem cell number, somatic mutation rates and speed of transformation to cancer but the mechanism of these effects is unclear. Using an agent based model of colon crypt dynamics, a hypothesis that heterozygous APC mutation increases symmetric division as well as biases the division in favor of stem cell progeny was computationally investigated. The simulations based on this hypothesis demonstrate how the mutation can cooperate with the phenomenon of niche succession to produce some of the observed changes in precancerous colon crypts and to speed up the onset of cancer.
This work suggests that the molecular mechanism by which APC mutation could increase and bias symmetric division in favor of stem cell progeny may be worth investigating from the point of view of preventing the onset of colorectal cancer.