Only 1-2% of the entire population within a glioblastoma are glioma stem cells (also called tumor initiating cells). This cell population is characterized by specific gene expression profiles and an inherent resistance against cytotoxic stress. Under radiation and chemotherapy glioma stem cells survive and repopulate the tumor leading to recurrence of bulk tumor. The molecular characteristics and resistance mechanisms active in individual glioma stem cell lineages will determine the response to any treatment strategy for recurrent glioblastoma.
Stemness is characterized by clonogenic and tumorigenic growth in an undifferentiated state. Asymmetrical division results in tumor cell strains of varying differentiation and phenotypes resulting in a more or less heterogeneous recurrent tumor.
Glioma stem cells and tumor recurrence
Glioma stem cells proliferate in “self-renewal” state corresponding to an undifferentiated phenotype. The ability to differentiate under serum contain culture conditions is an important stemness feature.
The omics-based analysis and prediction of treatment response therefore requires significantly more than “just“ sequencing of the tumor genome or determination of individual dysfunctional genes within a tumor sample. We propose that a 4-dimensional analysis at key time points over the course of glioblastoma progression (newly diagnosed and untreated – at posttreatment progression and recurrence) is required and needs to incorporate several tumor regions. Rather than identification of single over- or underexpressed genes an integrated bioinformatic analysis needs to identify functional activation strength of entire signaling pathways and metabolic cascades and has to specifically identify mechanisms of resistance active in stem cell populations.
At this point glioma stem cells can only be safely identified and enriched for omics-based analyses by complex procedures in cell culture, which goes far beyond routine diagnostic procedures today.