How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer.
Based on investigation of the earliest colonic tissue alteration in familial adenomatous polyposis (FAP) patients, we present the hypothesis that initiation of colorectal cancer by adenomatous polyposis coli (APC) mutation is mediated by dysregulation of two cellular mechanisms. One involves differentiation, which normally decreases the proportion (proliferative fraction) of colonic crypt cells that can proliferate; the other is a cell cycle mechanism that simultaneously increases the probability that proliferative cells are in S phase. In normal crypts, stem cells (SC) at the crypt bottom generate rapidly proliferating cells, which undergo differentiation while migrating up the crypt. Our modeling of normal crypts suggests that these transitions are mediated by mechanisms that regulate proliferative fraction and S-phase probability. In FAP crypts, the population of rapidly proliferating cells is shifted upwards, as indicated by the labeling index (LI; i.e., crypt distribution of cells in S phase). Our analysis of FAP indicates that these transitions are delayed because the proliferative fraction and S-phase probability change more slowly as a function of crypt level. This leads to expansion of the proliferative cell population, including a subpopulation that has a low frequency of S-phase cells. We previously reported that crypt SC overpopulation explains the LI shift. Here, we determine that SCs (or cells having high stemness) are proliferative cells with a low probability of being in S phase. Thus, dysregulation of mechanisms that control proliferative fraction and S-phase probability explains how APC mutations induce SC overpopulation at the crypt bottom, shift the rapidly proliferating cell population upwards, and initiate colon tumorigenesis.
Boman
Bruce M
BM
Thomas Jefferson University, Philadelphia, Pennsylvania, USA. BrBoman@ChristianaCare.org
Fields
Jeremy Z
JZ
Cavanaugh
Kenneth L
KL
Guetter
Arthur
A
Runquist
Olaf A
OA
D053687:Adult Stem Cells / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D003106:Colon / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology*; D003198:Computer Simulation; D018450:Disease Progression; D006801:Humans; D007413:Intestinal Mucosa / Q000502:physiology*; D008954:Models, Biological; D013997:Time Factors