Selective Calcium Sensitivity in Immature Glioma Cancer Stem Cells

Tumor-initiating cells are a subpopulation in aggressive cancers that exhibit traits shared with stem cells, including the ability to self-renew and differentiate, commonly referred to as stemness. In addition, such cells are resistant to chemo- and radiation therapy posing a therapeutic challenge. To uncover stemness-associated functions in glioma-initiating cells (GICs), transcriptome profiles were compared to neural stem cells (NSCs) and gene ontology analysis identified an enrichment of Ca(2+) signaling genes in NSCs and the more stem-like (NSC-proximal) GICs. Functional analysis in a set of different GIC lines regarding sensitivity to disturbed homeostasis using A23187 and Thapsigargin, revealed that NSC-proximal GICs were more sensitive, corroborating the transcriptome data. Furthermore, Ca(2+) drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca(2+) sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca(2+). Conversely, a higher number of and higher expression levels of Ca(2+) binding genes that may buffer Ca(2+), were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca(2+) sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca(2+) drug sensitivity. The correlation between high expression of Ca(2+) channels (such as GRIA1) and sensitivity to Ca(2+) drugs was confirmed in an additional nine novel GIC lines. Calcium drug sensitivity also correlated with expression of the NSC markers nestin (NES) and FABP7 (BLBP, brain lipid-binding protein) in this extended analysis. In summary, NSC-associated NES(+)/FABP7(+)/GRIA1(+) GICs were selectively sensitive to disturbances in Ca(2+) homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.