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: | , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2011
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/357ff7d520244ea3a0cb1453ce4dd75a |
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| Sumario: | <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. |
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