Acute and Fractionated Irradiation Differentially Modulate Glioma Stem Cell Division Kinetics

Glioblastoma multiforme (GBM) is one of the most aggressive human malignancies with a poor patient prognosis. Ionizing radiation either alone or adjuvant after surgery is part of standard treatment for GBM but remains primarily noncurative. The mechanisms underlying tumor radioresistance are manifold and, in part, accredited to a special subpopulation of tumorigenic cells. The so-called glioma stemcells (GSC) are bestowed with the exclusive ability to self-renewand repopulate the tumor and have been reported to be less sensitive to radiationinduced damage through preferential activation of DNA damage checkpoint responses and increased capacity for DNA damage repair. During each fraction of radiation, non-stemcancer cells (CC) die and GSCs become enriched and potentially increase innumber, whichmay lead to accelerated repopulation. Wepropose a cellular Potts model that simulates the kinetics of GSCs and CCs in glioblastoma growth and radiation response. We parameterize and validate thismodel with experimental data of the U87-MGhuman glioblastomacell line. Simulations are conducted to estimate GSC symmetric and asymmetric division rates and explore potential mechanisms for increased GSC fractions after irradiation. Simulations reveal that in addition to their higher radioresistance, a shift from asymmetric to symmetric division or a fast cycle of GSCs following fractionated radiation treatment is required to yield results that match experimental observations. Wehypothesize a constitutive activation of stemcell division kinetics signaling pathways during fractionated treatment, which contributes to the frequently observed accelerated repopulation after therapeutic irradiation. Cancer Res; 73(5); 1481-90. (C) 2012 AACR.