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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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Comparison with experiments.The evolution of the fraction of positive cells after sorting for positive (+) and negative (−) subpopulations as a function of time. Experimental data are extracted from Ref. [4] and compared with results of the phenotipic switching model (with M = 30, , p = 0.0085 and Rd = 1.8) and with the imperfect marker model (case (ii) with M = 30, , q = 0.02 and Rd = 1.8).
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f7: Comparison with experiments.The evolution of the fraction of positive cells after sorting for positive (+) and negative (−) subpopulations as a function of time. Experimental data are extracted from Ref. [4] and compared with results of the phenotipic switching model (with M = 30, , p = 0.0085 and Rd = 1.8) and with the imperfect marker model (case (ii) with M = 30, , q = 0.02 and Rd = 1.8).

Mentions: As discussed above, the simple Markov model, the CSC model with phenotypic switching, imperfect markers or imperfect sorting all yield the same outcome: after some time the fraction of cells that are positive to the marker returns to the original value. This proves that the expression of a putative CSC marker after positive cells have been eliminated by sorting is not a sufficient proof of phenotypic switching. To illustrate this point more clearly, we consider the experimental results reported by Gupta et al4 on breast cancer cell lines. In Fig. 7 we report the fraction of positive (stem-like) cells six days after the initial sorting. These data were interpreted in Ref. [4] by the simple Markov model. Here we show that the same data can be reproduced by the imperfect marker model or by the phenotypic switching model. To this end we have chosen parameters so that the asymptotic value of f+ is equal to the initial value, f+ = 1.9%, obtained in Ref. [4], thus assuming that the cell populations were originally in the steady-state. We notice that the experimental data could be interpreted as a result of an imperfect sorting if we assume that M ~ 5, which appears to be too small.


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

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

Comparison with experiments.The evolution of the fraction of positive cells after sorting for positive (+) and negative (−) subpopulations as a function of time. Experimental data are extracted from Ref. [4] and compared with results of the phenotipic switching model (with M = 30, , p = 0.0085 and Rd = 1.8) and with the imperfect marker model (case (ii) with M = 30, , q = 0.02 and Rd = 1.8).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f7: Comparison with experiments.The evolution of the fraction of positive cells after sorting for positive (+) and negative (−) subpopulations as a function of time. Experimental data are extracted from Ref. [4] and compared with results of the phenotipic switching model (with M = 30, , p = 0.0085 and Rd = 1.8) and with the imperfect marker model (case (ii) with M = 30, , q = 0.02 and Rd = 1.8).
Mentions: As discussed above, the simple Markov model, the CSC model with phenotypic switching, imperfect markers or imperfect sorting all yield the same outcome: after some time the fraction of cells that are positive to the marker returns to the original value. This proves that the expression of a putative CSC marker after positive cells have been eliminated by sorting is not a sufficient proof of phenotypic switching. To illustrate this point more clearly, we consider the experimental results reported by Gupta et al4 on breast cancer cell lines. In Fig. 7 we report the fraction of positive (stem-like) cells six days after the initial sorting. These data were interpreted in Ref. [4] by the simple Markov model. Here we show that the same data can be reproduced by the imperfect marker model or by the phenotypic switching model. To this end we have chosen parameters so that the asymptotic value of f+ is equal to the initial value, f+ = 1.9%, obtained in Ref. [4], thus assuming that the cell populations were originally in the steady-state. We notice that the experimental data could be interpreted as a result of an imperfect sorting if we assume that M ~ 5, which appears to be too small.

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