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Consequences of cell-to-cell P-glycoprotein transfer on acquired multidrug resistance in breast cancer: a cell population dynamics model.

Pasquier J, Magal P, Boulangé-Lecomte C, Webb G, Le Foll F - Biol. Direct (2011)

Bottom Line: We confirmed cell-to-cell transfer of functional P-gp.The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time.Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimens.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Ecotoxicology UPRES EA 3222, University of Le Havre, Le Havre cedex, France.

ABSTRACT

Background: Cancer is a proliferation disease affecting a genetically unstable cell population, in which molecular alterations can be somatically inherited by genetic, epigenetic or extragenetic transmission processes, leading to a cooperation of neoplastic cells within tumoural tissue. The efflux protein P-glycoprotein (P-gp) is overexpressed in many cancer cells and has known capacity to confer multidrug resistance to cytotoxic therapies. Recently, cell-to-cell P-gp transfers have been shown. Herein, we combine experimental evidence and a mathematical model to examine the consequences of an intercellular P-gp trafficking in the extragenetic transfer of multidrug resistance from resistant to sensitive cell subpopulations.

Methodology and principal findings: We report cell-to-cell transfers of functional P-gp in co-cultures of a P-gp overexpressing human breast cancer MCF-7 cell variant, selected for its resistance towards doxorubicin, with the parental sensitive cell line. We found that P-gp as well as efflux activity distribution are progressively reorganized over time in co-cultures analyzed by flow cytometry. A mathematical model based on a Boltzmann type integro-partial differential equation structured by a continuum variable corresponding to P-gp activity describes the cell populations in co-culture. The mathematical model elucidates the population elements in the experimental data, specifically, the initial proportions, the proliferative growth rates, and the transfer rates of P-gp in the sensitive and resistant subpopulations.

Conclusions: We confirmed cell-to-cell transfer of functional P-gp. The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time. Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimens.

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Related in: MedlinePlus

Estimation of parameters for the transfer model. This graph corresponds to the distribution of P-gp activity at day 6 of co-culture. The initial distribution of P-gp activity at day 0 (not shown here) was obtained from a mixture of 50:50 MCF-7:MCF-7/Doxo cells analyzed by cytometry as in Figure 4. The transfer model was run over 6 days. The dotted curve corresponds to the efflux activity of the co-culture measured at day 6, and the solid curve corresponds to the distribution of activity derived from model. The fitting parameters are given above the curves and were obtained by least squares minimization.
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Figure 6: Estimation of parameters for the transfer model. This graph corresponds to the distribution of P-gp activity at day 6 of co-culture. The initial distribution of P-gp activity at day 0 (not shown here) was obtained from a mixture of 50:50 MCF-7:MCF-7/Doxo cells analyzed by cytometry as in Figure 4. The transfer model was run over 6 days. The dotted curve corresponds to the efflux activity of the co-culture measured at day 6, and the solid curve corresponds to the distribution of activity derived from model. The fitting parameters are given above the curves and were obtained by least squares minimization.

Mentions: The best fit to data distribution at day 6 was estimated by using the least square minimization method over 100,000 different values of the parameters (Figure 6). An algorithm was implemented to search for the minimal Euclidian distance between the experimental data and the numerical simulations at day 6. More precisely, we used the experimental data to define the initial distribution and to compute the solution of theoretical model. Then, we looked for the parameters providing the minimal Euclidian distance between the theoretical distribution and the experimental one at day 6.


Consequences of cell-to-cell P-glycoprotein transfer on acquired multidrug resistance in breast cancer: a cell population dynamics model.

Pasquier J, Magal P, Boulangé-Lecomte C, Webb G, Le Foll F - Biol. Direct (2011)

Estimation of parameters for the transfer model. This graph corresponds to the distribution of P-gp activity at day 6 of co-culture. The initial distribution of P-gp activity at day 0 (not shown here) was obtained from a mixture of 50:50 MCF-7:MCF-7/Doxo cells analyzed by cytometry as in Figure 4. The transfer model was run over 6 days. The dotted curve corresponds to the efflux activity of the co-culture measured at day 6, and the solid curve corresponds to the distribution of activity derived from model. The fitting parameters are given above the curves and were obtained by least squares minimization.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3038988&req=5

Figure 6: Estimation of parameters for the transfer model. This graph corresponds to the distribution of P-gp activity at day 6 of co-culture. The initial distribution of P-gp activity at day 0 (not shown here) was obtained from a mixture of 50:50 MCF-7:MCF-7/Doxo cells analyzed by cytometry as in Figure 4. The transfer model was run over 6 days. The dotted curve corresponds to the efflux activity of the co-culture measured at day 6, and the solid curve corresponds to the distribution of activity derived from model. The fitting parameters are given above the curves and were obtained by least squares minimization.
Mentions: The best fit to data distribution at day 6 was estimated by using the least square minimization method over 100,000 different values of the parameters (Figure 6). An algorithm was implemented to search for the minimal Euclidian distance between the experimental data and the numerical simulations at day 6. More precisely, we used the experimental data to define the initial distribution and to compute the solution of theoretical model. Then, we looked for the parameters providing the minimal Euclidian distance between the theoretical distribution and the experimental one at day 6.

Bottom Line: We confirmed cell-to-cell transfer of functional P-gp.The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time.Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimens.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratory of Ecotoxicology UPRES EA 3222, University of Le Havre, Le Havre cedex, France.

ABSTRACT

Background: Cancer is a proliferation disease affecting a genetically unstable cell population, in which molecular alterations can be somatically inherited by genetic, epigenetic or extragenetic transmission processes, leading to a cooperation of neoplastic cells within tumoural tissue. The efflux protein P-glycoprotein (P-gp) is overexpressed in many cancer cells and has known capacity to confer multidrug resistance to cytotoxic therapies. Recently, cell-to-cell P-gp transfers have been shown. Herein, we combine experimental evidence and a mathematical model to examine the consequences of an intercellular P-gp trafficking in the extragenetic transfer of multidrug resistance from resistant to sensitive cell subpopulations.

Methodology and principal findings: We report cell-to-cell transfers of functional P-gp in co-cultures of a P-gp overexpressing human breast cancer MCF-7 cell variant, selected for its resistance towards doxorubicin, with the parental sensitive cell line. We found that P-gp as well as efflux activity distribution are progressively reorganized over time in co-cultures analyzed by flow cytometry. A mathematical model based on a Boltzmann type integro-partial differential equation structured by a continuum variable corresponding to P-gp activity describes the cell populations in co-culture. The mathematical model elucidates the population elements in the experimental data, specifically, the initial proportions, the proliferative growth rates, and the transfer rates of P-gp in the sensitive and resistant subpopulations.

Conclusions: We confirmed cell-to-cell transfer of functional P-gp. The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time. Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimens.

Show MeSH
Related in: MedlinePlus