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Epithelial-Mesenchymal Transition in Metastatic Cancer Cell Populations Affects Tumor Dormancy in a Simple Mathematical Model

1
Theoretical Systems Biology, Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, London SW7 2AZ, UK
2
Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA
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Author to whom correspondence should be addressed.
Biomedicines 2014, 2(4), 384-402; https://doi.org/10.3390/biomedicines2040384
Received: 29 August 2014 / Revised: 7 November 2014 / Accepted: 28 November 2014 / Published: 9 December 2014
(This article belongs to the Special Issue New aspects of the Hepatocyte Growth Factor/c-Met System)
Signaling from the c-Met receptor tyrosine kinase is associated with progression and metastasis of epithelial tumors. c-Met, the receptor for hepatocyte growth factor, triggers epithelial-mesenchymal transition (EMT) of cultured cells, which is thought to drive migration of tumor cells and confer on them critical stem cell properties. Here, we employ mathematical modeling to better understand how EMT affects population dynamics in metastatic tumors. We find that without intervention, micrometastatic tumors reach a steady-state population. While the rates of proliferation, senescence and death only have subtle effects on the steady state, changes in the frequency of EMT dramatically alter population dynamics towards exponential growth. We also find that therapies targeting cell proliferation or cell death are markedly more successful when combined with one that prevents EMT, though such therapies do little when used alone. Stochastic modeling reveals the probability of tumor recurrence from small numbers of residual differentiated tumor cells. EMT events in metastatic tumors provide a plausible mechanism by which clinically detectable tumors can arise from dormant micrometastatic tumors. Modeling the dynamics of this process demonstrates the benefit of a treatment that eradicates tumor cells and reduces the rate of EMT simultaneously. View Full-Text
Keywords: cancer growth; metastasis; chemotherapy; mathematical modeling cancer growth; metastasis; chemotherapy; mathematical modeling
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MacLean, A.L.; Harrington, H.A.; Stumpf, M.P.H.; Hansen, M.D.H. Epithelial-Mesenchymal Transition in Metastatic Cancer Cell Populations Affects Tumor Dormancy in a Simple Mathematical Model. Biomedicines 2014, 2, 384-402.

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