Examples of Mathematical Modeling: Tales from the Crypt

Johnston, Matthew D.; Edwards, Carina M.; Bodmer, Walter F.; Maini, Philip K.; Chapman, S. Jonathan

doi:10.4161/cc.6.17.4649

Cited by 51 publications

(70 citation statements)

References 19 publications

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“…The probability is that this happens during the amplification of the CSC-derived progenitor cells. This would be consistent with models of the colorectal cancer process (30,31), which suggest that the cell of origin for CSCs may mostly be a progenitor cell, before the commitment has been made to a particular differentiation pathway, rather than, as is often assumed, the normal crypt stem cell (32), and that the proportion of CSCs in a CRC can be highly variable (33).…”

Section: Discussionsupporting

confidence: 85%

Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

Yeung

Gandhi

Bodmer

2011

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

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Hypoxia is an important regulator of normal and cancer stem cell (CSC) differentiation. Colorectal CSCs from SW1222, LS180, and CCK81 colorectal cancer-derived cell lines are able to differentiate into complex 3D lumen-containing structures in normoxia, whereas in hypoxia, they form undifferentiated dense colonies that have reduced expression of the enterocyte differentiation marker CDX1, lack goblet cell formation, and have increased expression of BMI1 and activated Notch1. Hypoxia increases the clonogenicity of CSCs, which is cumulative as each round of hypoxia enriches for more CSCs. The hypoxic phenotype is reversible, because cells from hypoxic-dense colonies are able to reform differentiated structures when regrown in normoxia. We show that CDX1 is able to stimulate the generation of lumens even in hypoxia and has a negative feedback on BMI1 expression. Knockdown of CDX1 reduces lumen formation but does not affect goblet cell formation, suggesting that enterocytes and goblet cells form from different progenitor cells. Notch inhibition by dibenzazepine (DBZ) allowed CSCs to form goblet cells in both normoxia and hypoxia. Finally, we show that Hif1α, but not CA9, is an important mediator of the effects of hypoxia on the clonogenicity and differentiation of CSCs. In summary, hypoxia maintains the stem-like phenotype of colorectal cell linederived CSCs and prevents differentiation of enterocytes and goblet cells by regulating CDX1 and Notch1, suggesting that this regulation is an important component of how hypoxia controls the switch between stemness and differentiation in CSCs.

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Section: Discussionsupporting

confidence: 85%

Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

Yeung

Gandhi

Bodmer

2011

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

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“…22 We capture the dynamics of hematopoiesis combining three different approaches including population dynamics in discrete time, age-structured populations and a continuous model when the cell population is large enough. This is similar to cell dynamics in the colonic crypt as described by Johnston et al 24,25 where these approaches are discussed in detail.…”

Section: Normal Hematopoiesissupporting

confidence: 76%

“…19,26 The active hematopoietic stem cell pool is not expanded in CML, 3 hence the evolutionary dynamics of hematopoietic stem cells and LSC can be described by a neutral Moran process in a population of approximately 400 cells. 22,23 Disease dynamics typically starts with the appearance of the first LSC and at a given interval of time, one cell is chosen at random for reproduction and subsequently another cell is chosen for export (differentiation) so that the cell population remains constant under an appropriate feedback mechanisms 24,25 ( Figure 2). When 400 'selection-reproductionexport' events have occurred, 1 year has passed.…”

Section: Stem Cell Dynamicsmentioning

confidence: 99%

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

Lenaerts¹,

Pacheco²,

Traulsen³

et al. 2009

Haematologica

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BackgroundTyrosine kinase inhibitors, such as imatinib, are not considered curative for chronic myeloid leukemia -regardless of the significant reduction of disease burden during treatment -since they do not affect the leukemic stem cells. However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited. Design and MethodsWe studied the natural history of a large cohort of virtual patients with chronic myeloid leukemia under tyrosine kinase inhibitor therapy using a computational model of hematopoiesis and chronic myeloid leukemia that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool. ResultsWe found that in the overwhelming majority of patients the leukemic stem cell population undergoes extinction before disease diagnosis. Hence leukemic progenitors, susceptible to tyrosine kinase inhibitor attack, are the natural target for chronic myeloid leukemia treatment. Response dynamics predicted by the model closely match data from clinical trials. We further predicted that early diagnosis together with administration of tyrosine kinase inhibitor opens the path to eradication of chronic myeloid leukemia, leading to the wash out of the aberrant progenitor cells, ameliorating the patient's condition while lowering the risk of blast transformation and drug resistance. ConclusionsTyrosine kinase inhibitor therapy can cure chronic myeloid leukemia, although it may have to be prolonged. The depth of response increases with time in the vast majority of patients. These results illustrate the importance of stochastic effects on the dynamics of acquired hematopoietic stem cell disorders and have direct relevance for other hematopoietic stem cell-derived diseases.Key words: chronic myeloid leukemia, tyrosine kinase inhibitors, cure, stochastic dynamics. Citation: Lenaerts T, Pacheco JM, Traulsen

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“…Theoretical models (33) can readily explain substantial variation in the proportion of CSCs versus differentiated cells in a cancer. The ratio between CSCs and differentiated cells can be shown, on reasonable assumptions, to depend on the rate of differentiation relative to the turnover rate of the CSCs.…”

Section: Cd24mentioning

confidence: 99%

Cancer stem cells from colorectal cancer-derived cell lines

Yeung

Gandhi²,

Wilding³

et al. 2010

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

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332

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Cancer stem cells (CSCs) are the subpopulation of cells within a tumor that can self-renew, differentiate into multiple lineages, and drive tumor growth. Here we describe a two-pronged approach for the identification and characterization of CSCs from colorectal cancer cell lines, using a Matrigel-based differentiation assay, and cell surface markers CD44 and CD24. About 20 to 30% of cells from the SW1222 cell line form megacolonies in Matrigel that have complex 3D structures resembling colonic crypts. The megacolonies' capacity to self-renew in vitro is direct evidence that they contain the CSCs. Furthermore, just 200 cells from SW1222 megacolonies initiate tumors in NOD/SCID mice. We also showed that CD44 + CD24 + cells enriched for colorectal CSCs in the HT29 and SW1222 cell lines, which can self-renew and reform all four CD44/CD24 subpopulations, are the most clonogenic in vitro and can initiate tumors in vivo. A single SW1222 CD44 + CD24 + CSC, when grown in Matrigel, can form large megacolonies that differentiate into enterocyte, enteroendocrine, and goblet cell lineages. The HCT116 line does not differentiate or express CDX1, nor does it contain subpopulations of cells with greater tumor-forming capacity, suggesting that HCT116 contains mainly CSCs. However, forced expression of CDX1 in HCT116 leads to reduced clonogenicity and production of differentiating crypt-containing colonies, which can explain the selection for reduced CDX1 expression in many colorectal cancers. In summary, colorectal cancer cell lines contain subpopulations of CSCs, characterized by their cell surface markers and colony morphology, which can self-renew and differentiate into multiple lineages.clonogenicity | matrigel | CD44 | goblet cells

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Examples of Mathematical Modeling: Tales from the Crypt

Cited by 51 publications

References 19 publications

Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

Hypoxia and lineage specification of cell line-derived colorectal cancer stem cells

Tyrosine kinase inhibitor therapy can cure chronic myeloid leukemia without hitting leukemic stem cells

Cancer stem cells from colorectal cancer-derived cell lines

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