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Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model
BACKGROUND: Cancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from th...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553611/ https://www.ncbi.nlm.nih.gov/pubmed/28800767 http://dx.doi.org/10.1186/s13062-017-0188-z |
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author | Reher, David Klink, Barbara Deutsch, Andreas Voss-Böhme, Anja |
author_facet | Reher, David Klink, Barbara Deutsch, Andreas Voss-Böhme, Anja |
author_sort | Reher, David |
collection | PubMed |
description | BACKGROUND: Cancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from the primary tumour mass. This complex process depends on intracellular cues that are subject to genetic and epigenetic variability, as well as extrinsic cues from the local environment resulting in a spatial heterogeneity in the adhesive phenotype of individual tumour cells. Here, we use a novel mathematical model to study how adhesion heterogeneity, influenced by intrinsic and extrinsic factors, affects the dissemination of tumour cells from an epithelial cell population. The model is a multiscale cellular automaton that couples intracellular adhesion receptor regulation with cell-cell adhesion. RESULTS: Simulations of our mathematical model indicate profound effects of adhesion heterogeneity on tumour cell dissemination. In particular, we show that a large variation of intracellular adhesion receptor concentrations in a cell population reinforces cell dissemination, regardless of extrinsic cues mediated through the local cell density. However, additional control of adhesion receptor concentration through the local cell density, which can be assumed in healthy cells, weakens the effect. Furthermore, we provide evidence that adhesion heterogeneity can explain the remarkable differences in adhesion receptor concentrations of epithelial and mesenchymal phenotypes observed during EMT and might drive early dissemination of tumour cells. CONCLUSIONS: Our results suggest that adhesion heterogeneity may be a universal trigger to reinforce cell dissemination in epithelial cell populations. This effect can be at least partially compensated by a control of adhesion receptor regulation through neighbouring cells. Accordingly, our findings explain how both an increase in intra-tumour adhesion heterogeneity and the loss of control through the local environment can promote tumour cell dissemination. REVIEWERS: This article was reviewed by Hanspeter Herzel, Thomas Dandekar and Marek Kimmel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13062-017-0188-z) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5553611 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-55536112017-08-15 Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model Reher, David Klink, Barbara Deutsch, Andreas Voss-Böhme, Anja Biol Direct Research BACKGROUND: Cancer cell invasion, dissemination, and metastasis have been linked to an epithelial-mesenchymal transition (EMT) of individual tumour cells. During EMT, adhesion molecules like E-cadherin are downregulated and the decrease of cell-cell adhesion allows tumour cells to dissociate from the primary tumour mass. This complex process depends on intracellular cues that are subject to genetic and epigenetic variability, as well as extrinsic cues from the local environment resulting in a spatial heterogeneity in the adhesive phenotype of individual tumour cells. Here, we use a novel mathematical model to study how adhesion heterogeneity, influenced by intrinsic and extrinsic factors, affects the dissemination of tumour cells from an epithelial cell population. The model is a multiscale cellular automaton that couples intracellular adhesion receptor regulation with cell-cell adhesion. RESULTS: Simulations of our mathematical model indicate profound effects of adhesion heterogeneity on tumour cell dissemination. In particular, we show that a large variation of intracellular adhesion receptor concentrations in a cell population reinforces cell dissemination, regardless of extrinsic cues mediated through the local cell density. However, additional control of adhesion receptor concentration through the local cell density, which can be assumed in healthy cells, weakens the effect. Furthermore, we provide evidence that adhesion heterogeneity can explain the remarkable differences in adhesion receptor concentrations of epithelial and mesenchymal phenotypes observed during EMT and might drive early dissemination of tumour cells. CONCLUSIONS: Our results suggest that adhesion heterogeneity may be a universal trigger to reinforce cell dissemination in epithelial cell populations. This effect can be at least partially compensated by a control of adhesion receptor regulation through neighbouring cells. Accordingly, our findings explain how both an increase in intra-tumour adhesion heterogeneity and the loss of control through the local environment can promote tumour cell dissemination. REVIEWERS: This article was reviewed by Hanspeter Herzel, Thomas Dandekar and Marek Kimmel. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13062-017-0188-z) contains supplementary material, which is available to authorized users. BioMed Central 2017-08-11 /pmc/articles/PMC5553611/ /pubmed/28800767 http://dx.doi.org/10.1186/s13062-017-0188-z Text en © The Author(s) 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Reher, David Klink, Barbara Deutsch, Andreas Voss-Böhme, Anja Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
title | Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
title_full | Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
title_fullStr | Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
title_full_unstemmed | Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
title_short | Cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
title_sort | cell adhesion heterogeneity reinforces tumour cell dissemination: novel insights from a mathematical model |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553611/ https://www.ncbi.nlm.nih.gov/pubmed/28800767 http://dx.doi.org/10.1186/s13062-017-0188-z |
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