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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Public Library of Science (PLoS)
2011-01-01
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| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0024225&type=printable |
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| 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 |
| collection | DOAJ |
| 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 |
| id | doaj-art-357ff7d520244ea3a0cb1453ce4dd75a |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-357ff7d520244ea3a0cb1453ce4dd75a2025-08-20T02:05:29ZengPublic Library of Science (PLoS)PLoS ONE1932-62032011-01-0169e2422510.1371/journal.pone.0024225Dickkopf1 regulates fate decision and drives breast cancer stem cells to differentiation: an experimentally supported mathematical model.Zvia AgurOleg U KirnasovskyGenadiy VassermanLilach Tencer-HershkowiczYuri KoganHannah HarrisonRebecca LambRobert B Clarke<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.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0024225&type=printable |
| spellingShingle | 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. PLoS ONE |
| title | 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_short | 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 |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0024225&type=printable |
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