Abstract
Epithelial cells in the colon are arranged in cylindrical structures called crypts in which cellular proliferation and migration are tightly regulated. We hypothesized that the proliferation patterns of cells may determine the stability of crypts as well as the rates of somatic evolution towards colorectal tumorigenesis. Here, we propose a linear process model of colonic epithelial cells that explicitly takes into account the proliferation kinetics of cells as a function of cell position within the crypt. Our results indicate that proliferation kinetics has significant influence on the speed of cell movement, kinetics of mutation propagation, and sensitivity of the system to selective effects of mutated cells. We found that, of all proliferation curves tested, those with mitotic activities concentrated near the stem cell, including the actual proliferation kinetics determined in in vivo labeling experiments, have a greater ability of delaying the rate of mutation accumulation in colonic stem cells compared to hypothetical proliferation curves with mitotic activities focused near the top of the crypt column. Our model can be used to investigate the dynamics of proliferation and mutation accumulation in spatially arranged tissues.
Highlights
Colorectal cancer is the third most prevalent cancer type for both men and women in the United States, accounting for 9% of all cancer deaths [1]
We present a novel approach to examine the effects of proliferation kinetics on the rate of somatic evolution in a spatially arranged model of the colon
Based on our simulation results, we demonstrate that spatially determined proliferation kinetics has the ability to delay the rate of somatic evolution, and changes in proliferation patterns can significantly affect the speed of mutation accumulation
Summary
Colorectal cancer is the third most prevalent cancer type for both men and women in the United States, accounting for 9% of all cancer deaths [1] This large incidence can be partially attributed to the rapid cell divisions that continuously replenish the colonic epithelium, as this large amount of cell turnover increases the risk of accumulating the genetic changes leading to colorectal tumorigenesis [2]. An important feature associated with tumors harboring CIN is the accelerated rate of loss of heterozygosity (LOH), which increases the rate of tumor suppressor gene inactivation. It is not unusual for more than half of the genes in colorectal tumor cells to display LOH [15]. More than one hundred genes associated with CIN have been identified in yeast, many of which have human homologs [16,17]
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