The Role of Cell Density and Intratumoral Heterogeneity in Multidrug Resistance

Overview

Journal Cancer Res

Specialty Oncology

Date 2013 Oct 29

PMID 24163380

Citations 17

Authors

Orit Lavi

James M Greene

Doron Levy

Michael M Gottesman

Affiliations

Soon will be listed here.

Abstract

Recent data have demonstrated that cancer drug resistance reflects complex biologic factors, including tumor heterogeneity, varying growth, differentiation, apoptosis pathways, and cell density. As a result, there is a need to find new ways to incorporate these complexities in the mathematical modeling of multidrug resistance. Here, we derive a novel structured population model that describes the behavior of cancer cells under selection with cytotoxic drugs. Our model is designed to estimate intratumoral heterogeneity as a function of the resistance level and time. This updated model of the multidrug resistance problem integrates both genetic and epigenetic changes, density dependence, and intratumoral heterogeneity. Our results suggest that treatment acts as a selection process, whereas genetic/epigenetic alteration rates act as a diffusion process. Application of our model to cancer treatment suggests that reducing alteration rates as a first step in treatment causes a reduction in tumor heterogeneity and may improve targeted therapy. The new insight provided by this model could help to dramatically change the ability of clinical oncologists to design new treatment protocols and analyze the response of patients to therapy.

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References

Tutt A, van Oostrom C, Ross G, van Steeg H, Ashworth A . Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation. EMBO Rep. 2002; 3(3):255-60. PMC: 1084010. DOI: 10.1093/embo-reports/kvf037. View

Marusyk A, Polyak K . Cancer. Cancer cell phenotypes, in fifty shades of grey. Science. 2013; 339(6119):528-9. DOI: 10.1126/science.1234415. View

Wong K . Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009; 4(1):28-35. DOI: 10.2174/157489209787002461. View

Fodale V, Pierobon M, Liotta L, Petricoin E . Mechanism of cell adaptation: when and how do cancer cells develop chemoresistance?. Cancer J. 2011; 17(2):89-95. PMC: 5558433. DOI: 10.1097/PPO.0b013e318212dd3d. View

Buchholz T, Davis D, McConkey D, Fraser Symmans W, Valero V, Jhingran A . Chemotherapy-induced apoptosis and Bcl-2 levels correlate with breast cancer response to chemotherapy. Cancer J. 2003; 9(1):33-41. DOI: 10.1097/00130404-200301000-00007. View

Hodgkinson A, Eyre-Walker A . Variation in the mutation rate across mammalian genomes. Nat Rev Genet. 2011; 12(11):756-66. DOI: 10.1038/nrg3098. View

Spencer S, Gaudet S, Albeck J, Burke J, Sorger P . Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature. 2009; 459(7245):428-32. PMC: 2858974. DOI: 10.1038/nature08012. View

Shen H, Laird P . Interplay between the cancer genome and epigenome. Cell. 2013; 153(1):38-55. PMC: 3648790. DOI: 10.1016/j.cell.2013.03.008. View

McFarland C, Korolev K, Kryukov G, Sunyaev S, Mirny L . Impact of deleterious passenger mutations on cancer progression. Proc Natl Acad Sci U S A. 2013; 110(8):2910-5. PMC: 3581883. DOI: 10.1073/pnas.1213968110. View

10.

Sanz-Moreno V, Gadea G, Ahn J, Paterson H, Marra P, Pinner S . Rac activation and inactivation control plasticity of tumor cell movement. Cell. 2008; 135(3):510-23. DOI: 10.1016/j.cell.2008.09.043. View

11.

Lavi O, Gottesman M, Levy D . The dynamics of drug resistance: a mathematical perspective. Drug Resist Updat. 2012; 15(1-2):90-7. PMC: 3348255. DOI: 10.1016/j.drup.2012.01.003. View

12.

Robey R, Massey P, Amiri-Kordestani L, Bates S . ABC transporters: unvalidated therapeutic targets in cancer and the CNS. Anticancer Agents Med Chem. 2010; 10(8):625-33. PMC: 3119022. DOI: 10.2174/187152010794473957. View

13.

Kreso A, OBrien C, van Galen P, Gan O, Notta F, Brown A . Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2012; 339(6119):543-8. PMC: 9747244. DOI: 10.1126/science.1227670. View

14.

Sharma S, Lee D, Li B, Quinlan M, Takahashi F, Maheswaran S . A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010; 141(1):69-80. PMC: 2851638. DOI: 10.1016/j.cell.2010.02.027. View

15.

Lewis K . Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2006; 5(1):48-56. DOI: 10.1038/nrmicro1557. View

16.

Gerlinger M, Rowan A, Horswell S, Math M, Larkin J, Endesfelder D . Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012; 366(10):883-892. PMC: 4878653. DOI: 10.1056/NEJMoa1113205. View

17.

Klein T, Glazer P . The tumor microenvironment and DNA repair. Semin Radiat Oncol. 2010; 20(4):282-7. PMC: 2948843. DOI: 10.1016/j.semradonc.2010.05.006. View

18.

Reynolds T, Rockwell S, Glazer P . Genetic instability induced by the tumor microenvironment. Cancer Res. 1996; 56(24):5754-7. View

19.

Saunders N, Simpson F, Thompson E, Hill M, Endo-Munoz L, Leggatt G . Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives. EMBO Mol Med. 2012; 4(8):675-84. PMC: 3494067. DOI: 10.1002/emmm.201101131. View

20.

Koi M, Boland C . Tumor hypoxia and genetic alterations in sporadic cancers. J Obstet Gynaecol Res. 2011; 37(2):85-98. PMC: 3079283. DOI: 10.1111/j.1447-0756.2010.01377.x. View