Modeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatment

Handle URI:
http://hdl.handle.net/10754/625819
Title:
Modeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatment
Authors:
Lorz, Alexander; Botesteanu, Dana-Adriana; Levy, Doron
Abstract:
Investigating the role of intrinsic cell heterogeneity emerging from variations in cell-cycle parameters and apoptosis is a crucial step toward better informing drug administration. Antimitotic agents, widely used in chemotherapy, target exclusively proliferative cells and commonly induce a prolonged mitotic arrest followed by cell death via apoptosis. In this paper, we developed a physiologically motivated mathematical framework for describing cancer cell growth dynamics that incorporates the intrinsic heterogeneity in the time individual cells spend in the cell-cycle and apoptosis process. More precisely, our model comprises two age-structured partial differential equations for the proliferative and apoptotic cell compartments and one ordinary differential equation for the quiescent compartment. To reflect the intrinsic cell heterogeneity that governs the growth dynamics, proliferative and apoptotic cells are structured in “age,” i.e., the amount of time remaining to be spent in each respective compartment. In our model, we considered an antimitotic drug whose effect on the cellular dynamics is to induce mitotic arrest, extending the average cell-cycle length. The prolonged mitotic arrest induced by the drug can trigger apoptosis if the time a cell will spend in the cell cycle is greater than the mitotic arrest threshold. We studied the drug's effect on the long-term cancer cell growth dynamics using different durations of prolonged mitotic arrest induced by the drug. Our numerical simulations suggest that at confluence and in the absence of the drug, quiescence is the long-term asymptotic behavior emerging from the cancer cell growth dynamics. This pattern is maintained in the presence of small increases in the average cell-cycle length. However, intermediate increases in cell-cycle length markedly decrease the total number of cells and can drive the cancer population to extinction. Intriguingly, a large “switch-on/ switch-off” increase in the average cell-cycle length maintains an active cell population in the long term, with oscillating numbers of proliferative cells and a relatively constant quiescent cell number.
KAUST Department:
Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
Citation:
Lorz A, Botesteanu D-A, Levy D (2017) Modeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatment. Frontiers in Oncology 7. Available: http://dx.doi.org/10.3389/fonc.2017.00189.
Publisher:
Frontiers Media SA
Journal:
Frontiers in Oncology
Issue Date:
30-Aug-2017
DOI:
10.3389/fonc.2017.00189
Type:
Article
ISSN:
2234-943X
Sponsors:
The work of AL was supported by the King Abdullah University of Science and Technology (KAUST) baseline and start-up funds (BAS/1/1648-01-01 and BAS/1/1648-01-02). The work of D-AB was partially supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute, as part of a seed grant from the UMD-NCI Partnership for Cancer Technology. The work of DL was supported in part by the John Simon Guggenheim Memorial Foundation, the Simons Foundation, and the Jayne Koskinas Ted Giovanis Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Additional Links:
https://www.frontiersin.org/articles/10.3389/fonc.2017.00189/full
Appears in Collections:
Articles; Computer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorLorz, Alexanderen
dc.contributor.authorBotesteanu, Dana-Adrianaen
dc.contributor.authorLevy, Doronen
dc.date.accessioned2017-10-05T12:47:10Z-
dc.date.available2017-10-05T12:47:10Z-
dc.date.issued2017-08-30en
dc.identifier.citationLorz A, Botesteanu D-A, Levy D (2017) Modeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatment. Frontiers in Oncology 7. Available: http://dx.doi.org/10.3389/fonc.2017.00189.en
dc.identifier.issn2234-943Xen
dc.identifier.doi10.3389/fonc.2017.00189en
dc.identifier.urihttp://hdl.handle.net/10754/625819-
dc.description.abstractInvestigating the role of intrinsic cell heterogeneity emerging from variations in cell-cycle parameters and apoptosis is a crucial step toward better informing drug administration. Antimitotic agents, widely used in chemotherapy, target exclusively proliferative cells and commonly induce a prolonged mitotic arrest followed by cell death via apoptosis. In this paper, we developed a physiologically motivated mathematical framework for describing cancer cell growth dynamics that incorporates the intrinsic heterogeneity in the time individual cells spend in the cell-cycle and apoptosis process. More precisely, our model comprises two age-structured partial differential equations for the proliferative and apoptotic cell compartments and one ordinary differential equation for the quiescent compartment. To reflect the intrinsic cell heterogeneity that governs the growth dynamics, proliferative and apoptotic cells are structured in “age,” i.e., the amount of time remaining to be spent in each respective compartment. In our model, we considered an antimitotic drug whose effect on the cellular dynamics is to induce mitotic arrest, extending the average cell-cycle length. The prolonged mitotic arrest induced by the drug can trigger apoptosis if the time a cell will spend in the cell cycle is greater than the mitotic arrest threshold. We studied the drug's effect on the long-term cancer cell growth dynamics using different durations of prolonged mitotic arrest induced by the drug. Our numerical simulations suggest that at confluence and in the absence of the drug, quiescence is the long-term asymptotic behavior emerging from the cancer cell growth dynamics. This pattern is maintained in the presence of small increases in the average cell-cycle length. However, intermediate increases in cell-cycle length markedly decrease the total number of cells and can drive the cancer population to extinction. Intriguingly, a large “switch-on/ switch-off” increase in the average cell-cycle length maintains an active cell population in the long term, with oscillating numbers of proliferative cells and a relatively constant quiescent cell number.en
dc.description.sponsorshipThe work of AL was supported by the King Abdullah University of Science and Technology (KAUST) baseline and start-up funds (BAS/1/1648-01-01 and BAS/1/1648-01-02). The work of D-AB was partially supported by the Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute, as part of a seed grant from the UMD-NCI Partnership for Cancer Technology. The work of DL was supported in part by the John Simon Guggenheim Memorial Foundation, the Simons Foundation, and the Jayne Koskinas Ted Giovanis Foundation. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.publisherFrontiers Media SAen
dc.relation.urlhttps://www.frontiersin.org/articles/10.3389/fonc.2017.00189/fullen
dc.rightsThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectApoptosisen
dc.subjectCell-cycle variationsen
dc.subjectIntrinsic heterogeneityen
dc.subjectMitotic arresten
dc.subjectOVCAR-8en
dc.subjectPartial differential equationsen
dc.subjectPopulation dynamicsen
dc.titleModeling Cancer Cell Growth Dynamics In vitro in Response to Antimitotic Drug Treatmenten
dc.typeArticleen
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Divisionen
dc.identifier.journalFrontiers in Oncologyen
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionSorbonne Universités, UPMC Univ Paris 06, UMR 7598, Laboratoire Jacques-Louis Lions, Paris, , , , Franceen
dc.contributor.institutionDepartment of Mathematics and Center for Scientific Computation and Mathematical Modeling (CSCAMM), University of Maryland, College Park, MD, , United Statesen
dc.contributor.institutionWomen's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, , United Statesen
kaust.authorLorz, Alexanderen
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