Daniel Tran

Introduction. Glioblastoma Multiforme (GBM) is the most aggressive and most common form of primary brain tumors.^3,4. Despite extensive research and evolving therapeutics, GBM remains difficult to treat, with overall mean survival remaining unchanged at <2 years for the last decade.3 The challenge in the treatment of GBM is attributed the extensive intratumoral heterogeneity generated by cancer stem cells (CSC) and much of the focus in recent therapeutic strategies have been to target these cells utilizing their associated stem cell markers.^2,5,6 Unlike other CSCs, GBM CSCs lack a universal marker and display a continuum of stem-cell properties challenging the traditional hierarchical model held. Recent studies have shown that CSC marker expression reflects a transient cellular state undergoing reversible adaptive changes influenced by tumor microenvironment rather than selection and survival of a specific clonal entity with specific functional capacities. These findings provide a new consideration in the treatment of GBM. Methods.  Pearson analysis of 10 CSC Markers utilizing The Cancer Genome Atlas (TCGA) to identify statistically significant gene expression correlations. Multicolor flow cytometry on fresh GBM tissue to establish relationships between marker expression and tumor phenotype. 7 genetically stable GBM CSC cultures were isolated and characterized using Fluorescence Activated Cell Sorting (FACS) to establish cellular properties such as regenerative, proliferative, and multipotency capacities. Lastly, GBM CSCs were exposed to severe hypoxic conditions modeling GBM tumor microenvironment to determine the impact of environment on marker expression.  Results. From this study, it was found that there was no statistically significant correlation in gene expression or histopathological phenotype with CSC marker expression. Additionally, it was found that all GBM CSC populations retain full potential in their ability to regenerate, proliferate, and retain their multipotency. No hierarchical organization was found as one might expect from traditional views of CSC development. Hypoxic conditions dramatically changed GBM marker expression but that transformation was reversible. Conclusions.  It was concluded then that CSC marker expression was a reversible dynamic process that reflected these cells adapting to their environment. Hypoxia, a key pathological hallmark of GBM tumor microenvironment may be the key driver in these changes. This new understanding could provide a novel route in which developing therapeutics could be further investigated.

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