Methylation patterns and mathematical models reveal dynamics of stem cell turnover in the human colon

Ro, Simon Weonsang; Rannala, Bruce

doi:10.1073/pnas.201405498

Cited by 45 publications

(33 citation statements)

References 20 publications

(17 reference statements)

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“…This explanation is consonant with the idea that, as argued by others (33), being an SC is an all-ornone phenomenon. This is also consistent with the pattern of Mushashi-1 staining-there were fewer stained cells at higher crypt levels, but staining only identified isolated individual cells (presumed to be SC).…”

Section: Discussionsupporting

confidence: 88%

How Dysregulated Colonic Crypt Dynamics Cause Stem Cell Overpopulation and Initiate Colon Cancer

Boman

Fields²,

Cavanaugh³

et al. 2008

Cancer Research

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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. [Cancer Res 2008;68(9):3304-13]

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Section: Discussionsupporting

confidence: 88%

How Dysregulated Colonic Crypt Dynamics Cause Stem Cell Overpopulation and Initiate Colon Cancer

Boman

Fields²,

Cavanaugh³

et al. 2008

Cancer Research

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“…In biological systems, we expect there to be noise, and so such a model will be unrealistic. There is a similar but less stringent requirement on b 3 and ␤. For b 3 Ͻ 1͞2 (␤ Ͻ 0), there is a nontrivial steady state, whereas for b 3 Ͼ 1͞2 (␤ Ͼ 0), there is exponential growth.…”

Section: Steady States and Structural Instabilitymentioning

confidence: 99%

“…Stem cells are believed to reside near the bottom of the colorectal crypt (2), and these are capable of producing a variety of cell types that are required for tissue renewal and regeneration after injury (3). The stem cells divide to produce transit cells that migrate up the crypt wall toward the luminal surface.…”

mentioning

confidence: 99%

Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer

Johnston

Edwards

Bodmer

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

257

304

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Colorectal cancer is initiated in colonic crypts. A succession of genetic mutations or epigenetic changes can lead to homeostasis in the crypt being overcome, and subsequent unbounded growth. We consider the dynamics of a single colorectal crypt by using a compartmental approach [Tomlinson IPM, Bodmer WF (1995) Proc Natl Acad Sci USA 92:11130 -11134], which accounts for populations of stem cells, differentiated cells, and transit cells. That original model made the simplifying assumptions that each cell population divides synchronously, but we relax these assumptions by adopting an age-structured approach that models asynchronous cell division, and by using a continuum model. We discuss two mechanisms that could regulate the growth of cell numbers and maintain the equilibrium that is normally observed in the crypt. The first will always maintain an equilibrium for all parameter values, whereas the second can allow unbounded proliferation if the net per capita growth rates are large enough. Results show that an increase in cell renewal, which is equivalent to a failure of programmed cell death or of differentiation, can lead to the growth of cancers. The second model can be used to explain the long lag phases in tumor growth, during which new, higher equilibria are reached, before unlimited growth in cell numbers ensues.age-structure ͉ feedback ͉ mutations ͉ structural stability T he large intestine is one of the most frequent sites of carcinogenesis due, at least in part, to its continual selfrenewal and the large numbers of daily cell divisions (1). There are millions of invaginations in the lining of the colon, called crypts, and it is widely believed that colorectal cancer is initiated when mutations or relatively stable epigenetic changes occur in the single layer of epithelial cells that line the crypt. Consequently, much work has been directed toward understanding the mechanisms involved in the dynamics of the cells in healthy and neoplastic (abnormally growing) crypts.Stem cells are believed to reside near the bottom of the colorectal crypt (2), and these are capable of producing a variety of cell types that are required for tissue renewal and regeneration after injury (3). The stem cells divide to produce transit cells that migrate up the crypt wall toward the luminal surface. As the cells proceed up the crypt they differentiate into colonocytes, enteroendocrine cells, and Goblet cells (1). Once at the top, the cells either undergo apoptosis and͞or are shed into the lumen and transported away (4, 5).In the murine small intestine, the journey of the cells from the base of the crypt to its apex has been estimated to take between 2 and 3 days (6), and all the cells in the crypt, apart from the stem cells, will be renewed over this period. The stem cells are assumed to have a cycle time of between 12 and 32 h with an average of 24 h (7, 8). The transit cell population has an estimated cycle time of Ϸ11-12 h (4, 9).The crypt is homeostatic with an equilibrium maintained between cell proliferation and cell los...

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“…33,34 In these papers, two main mechanisms of SC reproduction have been proposed. In the deterministic model, each SC divides asymmetrically, and the number of SC is kept constant.…”

confidence: 99%

Initiation of Colorectal Cancer: Where do the Two Hits Hit?

Komarova¹,

Wang²

2004

Cell Cycle

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Methylation patterns and mathematical models reveal dynamics of stem cell turnover in the human colon

Cited by 45 publications

References 20 publications

How Dysregulated Colonic Crypt Dynamics Cause Stem Cell Overpopulation and Initiate Colon Cancer

How Dysregulated Colonic Crypt Dynamics Cause Stem Cell Overpopulation and Initiate Colon Cancer

Mathematical modeling of cell population dynamics in the colonic crypt and in colorectal cancer

Initiation of Colorectal Cancer: Where do the Two Hits Hit?

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