A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.

Hierarchical organized tissue structures, with stem cell driven cell differentiation, are critical to the homeostatic maintenance of most tissues, and this underlying cellular architecture is potentially a critical player in the development of a many cancers. Here, we develop a mathematical model of...

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Autores principales:	Sara N Gentry, Trachette L Jackson
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2013
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c840580fb4cb41bda8a10f29de734ac5
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spelling	oai:doaj.org-article:c840580fb4cb41bda8a10f29de734ac52021-11-18T08:58:54ZA mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.1932-620310.1371/journal.pone.0071128https://doaj.org/article/c840580fb4cb41bda8a10f29de734ac52013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23990931/?tool=EBIhttps://doaj.org/toc/1932-6203Hierarchical organized tissue structures, with stem cell driven cell differentiation, are critical to the homeostatic maintenance of most tissues, and this underlying cellular architecture is potentially a critical player in the development of a many cancers. Here, we develop a mathematical model of mutation acquisition to investigate how deregulation of the mechanisms preserving stem cell homeostasis contributes to tumor initiation. A novel feature of the model is the inclusion of both extrinsic and intrinsic chemical signaling and interaction with the niche to control stem cell self-renewal. We use the model to simulate the effects of a variety of types and sequences of mutations and then compare and contrast all mutation pathways in order to determine which ones generate cancer cells fastest. The model predicts that the sequence in which mutations occur significantly affects the pace of tumorigenesis. In addition, tumor composition varies for different mutation pathways, so that some sequences generate tumors that are dominated by cancerous cells with all possible mutations, while others are primarily comprised of cells that more closely resemble normal cells with only one or two mutations. We are also able to show that, under certain circumstances, healthy stem cells diminish due to the displacement by mutated cells that have a competitive advantage in the niche. Finally, in the event that all homeostatic regulation is lost, exponential growth of the cancer population occurs in addition to the depletion of normal cells. This model helps to advance our understanding of how mutation acquisition affects mechanisms that influence cell-fate decisions and leads to the initiation of cancers.Sara N GentryTrachette L JacksonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 8, p e71128 (2013)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sara N Gentry Trachette L Jackson A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
description	Hierarchical organized tissue structures, with stem cell driven cell differentiation, are critical to the homeostatic maintenance of most tissues, and this underlying cellular architecture is potentially a critical player in the development of a many cancers. Here, we develop a mathematical model of mutation acquisition to investigate how deregulation of the mechanisms preserving stem cell homeostasis contributes to tumor initiation. A novel feature of the model is the inclusion of both extrinsic and intrinsic chemical signaling and interaction with the niche to control stem cell self-renewal. We use the model to simulate the effects of a variety of types and sequences of mutations and then compare and contrast all mutation pathways in order to determine which ones generate cancer cells fastest. The model predicts that the sequence in which mutations occur significantly affects the pace of tumorigenesis. In addition, tumor composition varies for different mutation pathways, so that some sequences generate tumors that are dominated by cancerous cells with all possible mutations, while others are primarily comprised of cells that more closely resemble normal cells with only one or two mutations. We are also able to show that, under certain circumstances, healthy stem cells diminish due to the displacement by mutated cells that have a competitive advantage in the niche. Finally, in the event that all homeostatic regulation is lost, exponential growth of the cancer population occurs in addition to the depletion of normal cells. This model helps to advance our understanding of how mutation acquisition affects mechanisms that influence cell-fate decisions and leads to the initiation of cancers.
format	article
author	Sara N Gentry Trachette L Jackson
author_facet	Sara N Gentry Trachette L Jackson
author_sort	Sara N Gentry
title	A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
title_short	A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
title_full	A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
title_fullStr	A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
title_full_unstemmed	A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
title_sort	mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.
publisher	Public Library of Science (PLoS)
publishDate	2013
url	https://doaj.org/article/c840580fb4cb41bda8a10f29de734ac5
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A mathematical model of cancer stem cell driven tumor initiation: implications of niche size and loss of homeostatic regulatory mechanisms.

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