4 research outputs found
Role of Heterozygous APC Mutation in Niche Succession and Initiation of Colorectal Cancer – A Computational Study
Mutations in the adenomatous polyposis coli (APC) gene are found in most colorectal cancers. They cause constitutive activation of proliferative pathways when both alleles of the gene are mutated. However studies on individuals with familial adenomatous polyposis (FAP) have shown that a single mutated APC allele can also create changes in the precancerous colon crypt, like increased number of stem cells, increased crypt fission, greater variability of DNA methylation patterns, and higher somatic mutation rates. In this paper, using a computational model of colon crypt dynamics, we evolve and investigate a hypothesis on the effect of heterozygous APC mutation that explains these different observations. Based on previous reports and the results from the computational model we propose the hypothesis that heterozygous APC mutation has the effect of increasing the chances for a stem cell to divide symmetrically, producing two stem cell daughters. We incorporate this hypothesis into the model and perform simulation experiments to investigate the consequences of the hypothesis. Simulations show that this hypothesis links together the changes in FAP crypts observed in previous studies. The simulations also show that an APC+/− stem cell gets selective advantages for dominating the crypt and progressing to cancer. This explains why most colon cancers are initiated by APC mutation. The results could have implications for preventing or retarding the onset of colon cancer in people with inherited or acquired mutation of one APC allele. Experimental validation of the hypothesis as well as investigation into the molecular mechanisms of this effect may therefore be worth undertaking
Development of a crypt from stem cells.
<p>States of the cells are represented by different colors : Purple – “Quiescent” , Red –“ G1”, Brown “S+G2”, Dark Brown – “Mitosis”, Black shows the gaps where there are no cells.</p
Variation of the total number of cells from each stem cell lineage with time.
<p>Stem cell number and Niche Succession Period for different values of symmetric division probability and the biasing factor.</p
Time variation of stem cell number with: (a) Bias factor = 1, (b) Bias factor = 0.5, (c) Bias factor = 0.4.
<p>Time taken for the appearance of a second mutation assuming different effects for the APC+/− mutation.</p