Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.

<h4>Background</h4>Modulation of cellular signaling pathways can change the replication/differentiation balance in cancer stem cells (CSCs), thus affecting tumor growth and recurrence. Analysis of a simple, experimentally verified, mathematical model suggests that this balance is maintai...

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Autores principales:	Zvia Agur, Oleg U Kirnasovsky, Genadiy Vasserman, Lilach Tencer-Hershkowicz, Yuri Kogan, Hannah Harrison, Rebecca Lamb, Robert B Clarke
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/357ff7d520244ea3a0cb1453ce4dd75a
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spelling	oai:doaj.org-article:357ff7d520244ea3a0cb1453ce4dd75a2021-11-18T06:46:39ZDickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.1932-620310.1371/journal.pone.0024225https://doaj.org/article/357ff7d520244ea3a0cb1453ce4dd75a2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21915302/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>Modulation of cellular signaling pathways can change the replication/differentiation balance in cancer stem cells (CSCs), thus affecting tumor growth and recurrence. Analysis of a simple, experimentally verified, mathematical model suggests that this balance is maintained by quorum sensing (QS).<h4>Methodology/principal findings</h4>To explore the mechanism by which putative QS cellular signals in mammary stem cells (SCs) may regulate SC fate decisions, we developed a multi-scale mathematical model, integrating extra-cellular and intra-cellular signal transduction within the mammary tissue dynamics. Preliminary model analysis of the single cell dynamics indicated that Dickkopf1 (Dkk1), a protein known to negatively regulate the Wnt pathway, can serve as anti-proliferation and pro-maturation signal to the cell. Simulations of the multi-scale tissue model suggested that Dkk1 may be a QS factor, regulating SC density on the level of the whole tissue: relatively low levels of exogenously applied Dkk1 have little effect on SC numbers, whereas high levels drive SCs into differentiation. To verify these model predictions, we treated the MCF-7 cell line and primary breast cancer (BC) cells from 3 patient samples with different concentrations and dosing regimens of Dkk1, and evaluated subsequent formation of mammospheres (MS) and the mammary SC marker CD44(+)CD24(lo). As predicted by the model, low concentrations of Dkk1 had no effect on primary BC cells, or even increased MS formation among MCF-7 cells, whereas high Dkk1 concentrations decreased MS formation among both primary BC cells and MCF-7 cells.<h4>Conclusions/significance</h4>Our study suggests that Dkk1 treatment may be more robust than other methods for eliminating CSCs, as it challenges a general cellular homeostasis mechanism, namely, fate decision by QS. The study also suggests that low dose Dkk1 administration may be counterproductive; we showed experimentally that in some cases it can stimulate CSC proliferation, although this needs validating in vivo.Zvia AgurOleg U KirnasovskyGenadiy VassermanLilach Tencer-HershkowiczYuri KoganHannah HarrisonRebecca LambRobert B ClarkePublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 9, p e24225 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Zvia Agur Oleg U Kirnasovsky Genadiy Vasserman Lilach Tencer-Hershkowicz Yuri Kogan Hannah Harrison Rebecca Lamb Robert B Clarke Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
description	<h4>Background</h4>Modulation of cellular signaling pathways can change the replication/differentiation balance in cancer stem cells (CSCs), thus affecting tumor growth and recurrence. Analysis of a simple, experimentally verified, mathematical model suggests that this balance is maintained by quorum sensing (QS).<h4>Methodology/principal findings</h4>To explore the mechanism by which putative QS cellular signals in mammary stem cells (SCs) may regulate SC fate decisions, we developed a multi-scale mathematical model, integrating extra-cellular and intra-cellular signal transduction within the mammary tissue dynamics. Preliminary model analysis of the single cell dynamics indicated that Dickkopf1 (Dkk1), a protein known to negatively regulate the Wnt pathway, can serve as anti-proliferation and pro-maturation signal to the cell. Simulations of the multi-scale tissue model suggested that Dkk1 may be a QS factor, regulating SC density on the level of the whole tissue: relatively low levels of exogenously applied Dkk1 have little effect on SC numbers, whereas high levels drive SCs into differentiation. To verify these model predictions, we treated the MCF-7 cell line and primary breast cancer (BC) cells from 3 patient samples with different concentrations and dosing regimens of Dkk1, and evaluated subsequent formation of mammospheres (MS) and the mammary SC marker CD44(+)CD24(lo). As predicted by the model, low concentrations of Dkk1 had no effect on primary BC cells, or even increased MS formation among MCF-7 cells, whereas high Dkk1 concentrations decreased MS formation among both primary BC cells and MCF-7 cells.<h4>Conclusions/significance</h4>Our study suggests that Dkk1 treatment may be more robust than other methods for eliminating CSCs, as it challenges a general cellular homeostasis mechanism, namely, fate decision by QS. The study also suggests that low dose Dkk1 administration may be counterproductive; we showed experimentally that in some cases it can stimulate CSC proliferation, although this needs validating in vivo.
format	article
author	Zvia Agur Oleg U Kirnasovsky Genadiy Vasserman Lilach Tencer-Hershkowicz Yuri Kogan Hannah Harrison Rebecca Lamb Robert B Clarke
author_facet	Zvia Agur Oleg U Kirnasovsky Genadiy Vasserman Lilach Tencer-Hershkowicz Yuri Kogan Hannah Harrison Rebecca Lamb Robert B Clarke
author_sort	Zvia Agur
title	Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
title_short	Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
title_full	Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
title_fullStr	Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
title_full_unstemmed	Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
title_sort	dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/357ff7d520244ea3a0cb1453ce4dd75a
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Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.

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