ABSTRACT
Glioblastoma is a deadly brain tumor characterized in part by the histological finding of pseudopallisading necrosis. The cause of this necrosis can be multifactorial, but the consequences are regions of necrosis and hypoxia interspersed throughout the tumors. This heterogeneity in oxygen availability has significant influence on not only cellular population dynamics but also on treatment response. Further, hypoxia has been strongly correlated with the emergence of metastatic and treatment resistant phenotypes. As well as microenvironmental heterogeneity, glioblastoma is one of a number of cancers which have been shown to be composed of a proliferative cellular hier-archy which includes cells with varying abilities to recapitulate the tumor phenotype – the most extreme of which have been recently labeled cancer stem cells, or tumor initiating cells. The interplay between microenvironmental and tumor heterogeneity can explain glioblastoma’s somatic evolution but neither clinical data nor biological models can recapitulate this clinical reality alone. Here we present a computational agent-based model of a tumor growing under the proliferative hierarchy in a heterogeneous domain. Our results show that the tempo of tumor stem cell evolution varies widely within the tumor, and is particularly increased at the peri-anoxic edge. We subsequently challenge this provocative in silico finding through analysis of primary histologic samples taken from patients with glioblastoma stained to elucidate areas of hypoxia and necrosis, and to identify heterogeneity in p53. Our results support the hypothesis that the peri-anoxic ridge increases the stem cell turnover, and that this leads to an increase in the mutational load compared to cells in well oxygenated environments. We develop maps of evolutionary tempo from the histology and find that hypoxia effectively ‘warps’ evolutionary velocity. Implications of this for both tumor evolution and control in glioblastoma are discussed. We develop maps of evolutionary tempo from the histology and find that hypoxia effectively ‘warps’ evolutionary velocity. Implications of this for both tumor evolution and control in glioblastoma are discussed.
