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The Importance of Spatial Distribution of Stemness andProliferation State in Determining Tumor Radioresponse

Published online by Cambridge University Press:  05 June 2009

H. Enderling ,
D. Park ,
L. Hlatky  and
P. Hahnfeldt
H. Enderling*
Affiliation:
Center of Cancer Systems Biology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, 02135, USA
D. Park
Affiliation:
Center of Cancer Systems Biology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, 02135, USA
L. Hlatky
Affiliation:
Center of Cancer Systems Biology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, 02135, USA
P. Hahnfeldt
Affiliation:
Center of Cancer Systems Biology, Caritas St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, 02135, USA
*
[email protected]
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Abstract

Tumor growth and progression is a complex phenomenon dependent on theinteraction of multiple intrinsic and extrinsic factors. Necessary for tumordevelopment is a small subpopulation of potent cells, so-called cancer stemcells, that can undergo an unlimited number of cell divisions and which areproposed to divide symmetrically with a small probability to produce more cancerstem cells. We show that the majority of cells in a tumor must indeed benon-stem cancer cells with limited life span and limited replicative potential. Tumor development is dependent as well on the proliferative potential and deathof these cells, and on the migratory ability of all cancer cells. Withincreasing number of cells in the tumor, competition for space limits tumorprogression, and in agreement with in vitro observation, the majority of cancercells become quiescent, with proliferation primarily occurring on the outer rimwhere space is available. We present an agent-based model of early tumordevelopment that captures the spatial heterogeneity of stemness andproliferation status. We apply the model to simulations of radiotherapy topredict treatment outcomes for tumors with different stem cell pool sizes anddifferent quiescence radiosensitivities. We show by first presuming homogeneousradiosensitivity throughout the tumor, and then considering the greaterresistance of quiescent cells, that stem cell pool size and stem cellrepopulation during treatment determine treatment success. The results fortumor cure probabilities comprise upper bounds, as there is evidence that cancerstem cells are also more radioresistant than other tumor cells. Beyond justdemonstrating the influence of mass effects of stem to non-stem cell ratios andproliferating to quiescent cell ratios, we show that the spatiotemporalevolution of the developing heterogeneous population plays a pivotal role indetermining radioresponse and treatment optimization.

Keywords

cancerstem cellradiotherapyquiescenceproliferationrepopulation
Type
Research Article
Information
Mathematical Modelling of Natural Phenomena , Volume 4 , Issue 3: Cancer modelling (Part 2) , 2009 , pp. 117 - 133
Copyright
© EDP Sciences, 2009

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