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Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers.

Zapperi S, La Porta CA - Sci Rep (2012)

Bottom Line: Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells.Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process.Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.

View Article: PubMed Central - PubMed

Affiliation: CNR-IENI, Via R. Cozzi 53, 20125 Milano, Italy. stefano.zapperi@cnr.it

ABSTRACT
The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells. Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.

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Related in: MedlinePlus

Phenotypic switching and Imperfect markers.(A) According to the phenotypic switching hypothesis, CCs (blue) have a small probability to revert to the CSC state (red). If a marker is used to sort the cells into different subpopulation, the negative subpopulation will eventually express again the marker due to phenotypic switching. (B) According to the imperfect marker idea, CCs can not transform back into CSCs, but both CCs and CSCs express the marker, although in different proportions: most of the CSCs are positive, while most of the CCs are negative.
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f1: Phenotypic switching and Imperfect markers.(A) According to the phenotypic switching hypothesis, CCs (blue) have a small probability to revert to the CSC state (red). If a marker is used to sort the cells into different subpopulation, the negative subpopulation will eventually express again the marker due to phenotypic switching. (B) According to the imperfect marker idea, CCs can not transform back into CSCs, but both CCs and CSCs express the marker, although in different proportions: most of the CSCs are positive, while most of the CCs are negative.

Mentions: From the biological point of view, it is not easy to determine if the tumor grows following the conventional or the hierarchical model and to understand the nature of phenotypic switching. In this respect, mathematical models can prove very useful to clarify the consequences of biologically motivated assumptions. The key issue is to explain how a purified subpopulation can express CSC markers after sorting. A possible explanation is provided by the phenotypic switching hypothesis: if phenotypes evolve dynamically it is possible that cells originally negative to the CSC phenotype may express it later due to stochastic fluctuations (See Fig. 1A). This explanation is somewhat problematic from the conceptual point of view: if cancer cells (CCs) can transform back into CSCs then the very notion of CSC becomes blurred. A key distinction between CSCs and other CCs is that the first generate the latter and not vice versa. Furthermore, CSC should be virtually immortal while CCs should stop replicating after a finite number of divisions. Once we accept that CCs can return to the CSC state, they become potentially immortal as well. Hence the distinction between phenotypic switching and the original conventional model risks of becoming purely semantic.


Do cancer cells undergo phenotypic switching? The case for imperfect cancer stem cell markers.

Zapperi S, La Porta CA - Sci Rep (2012)

Phenotypic switching and Imperfect markers.(A) According to the phenotypic switching hypothesis, CCs (blue) have a small probability to revert to the CSC state (red). If a marker is used to sort the cells into different subpopulation, the negative subpopulation will eventually express again the marker due to phenotypic switching. (B) According to the imperfect marker idea, CCs can not transform back into CSCs, but both CCs and CSCs express the marker, although in different proportions: most of the CSCs are positive, while most of the CCs are negative.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369193&req=5

f1: Phenotypic switching and Imperfect markers.(A) According to the phenotypic switching hypothesis, CCs (blue) have a small probability to revert to the CSC state (red). If a marker is used to sort the cells into different subpopulation, the negative subpopulation will eventually express again the marker due to phenotypic switching. (B) According to the imperfect marker idea, CCs can not transform back into CSCs, but both CCs and CSCs express the marker, although in different proportions: most of the CSCs are positive, while most of the CCs are negative.
Mentions: From the biological point of view, it is not easy to determine if the tumor grows following the conventional or the hierarchical model and to understand the nature of phenotypic switching. In this respect, mathematical models can prove very useful to clarify the consequences of biologically motivated assumptions. The key issue is to explain how a purified subpopulation can express CSC markers after sorting. A possible explanation is provided by the phenotypic switching hypothesis: if phenotypes evolve dynamically it is possible that cells originally negative to the CSC phenotype may express it later due to stochastic fluctuations (See Fig. 1A). This explanation is somewhat problematic from the conceptual point of view: if cancer cells (CCs) can transform back into CSCs then the very notion of CSC becomes blurred. A key distinction between CSCs and other CCs is that the first generate the latter and not vice versa. Furthermore, CSC should be virtually immortal while CCs should stop replicating after a finite number of divisions. Once we accept that CCs can return to the CSC state, they become potentially immortal as well. Hence the distinction between phenotypic switching and the original conventional model risks of becoming purely semantic.

Bottom Line: Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells.Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process.Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.

View Article: PubMed Central - PubMed

Affiliation: CNR-IENI, Via R. Cozzi 53, 20125 Milano, Italy. stefano.zapperi@cnr.it

ABSTRACT
The identification of cancer stem cells in vivo and in vitro relies on specific surface markers that should allow to sort cancer cells in phenotypically distinct subpopulations. Experiments report that sorted cancer cell populations after some time tend to express again all the original markers, leading to the hypothesis of phenotypic switching, according to which cancer cells can transform stochastically into cancer stem cells. Here we explore an alternative explanation based on the hypothesis that markers are not perfect and are thus unable to identify all cancer stem cells. Our analysis is based on a mathematical model for cancer cell proliferation that takes into account phenotypic switching, imperfect markers and error in the sorting process. Our conclusion is that the observation of reversible expression of surface markers after sorting does not provide sufficient evidence in support of phenotypic switching.

Show MeSH
Related in: MedlinePlus