Selective calcium sensitivity in immature glioma cancer stem cells

• Published in: PloS one 2014, Vol.9 (12), p.e115698-e115698
• Main Authors: Wee, Shimei, Niklasson, Maria, Marinescu, Voichita Dana, Segerman, Anna, Schmidt, Linnéa, Hermansson, Annika, Dirks, Peter, Forsberg-Nilsson, Karin, Westermark, Bengt, Uhrbom, Lene, Linnarsson, Sten, Nelander, Sven, Andäng, Michael
• Format: Article
• Language: English
• Subjects: Biochemistry; Biology and Life Sciences; Biomarkers, Tumor - genetics; Biophysics; Blotting, Western; Brain; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; Calcimycin; Calcium; Calcium - pharmacology; Calcium buffering; Calcium channels; Calcium homeostasis; Calcium signalling; Cancer therapies; Cell culture; Cell cycle; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Chemotherapy; Dopamine; Drugs; Fluorescent Antibody Technique; Functional analysis; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic - drug effects; Genes; Genomes; Glioma; Glioma - drug therapy; Glioma - genetics; Glioma - pathology; Glioma cells; Glutamate receptors; Glutamic acid receptors; Homeostasis; Humans; Immunology; Ion channels; Lipid-binding protein; Medical prognosis; Medicin och hälsovetenskap; Medicine and Health Sciences; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Nestin; Neural stem cells; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Oligonucleotide Array Sequence Analysis; Pathology; Physiology; Potassium; Potassium channels; Radiation; Radiation therapy; Radiation tolerance; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sensitivity; Sensitivity analysis; Signal Transduction - drug effects; Sodium; Sodium channels; Stem cells; Thapsigargin; Tumor Cells, Cultured; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0115698

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 Ca2+ 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, Ca2+ drug sensitivity was reduced in GICs after differentiation, with most potent effect in the NSC-proximal GIC, supporting a stemness-associated Ca2+ sensitivity. NSCs and the NSC-proximal GIC line expressed a larger number of ion channels permeable to potassium, sodium and Ca2+. Conversely, a higher number of and higher expression levels of Ca2+ binding genes that may buffer Ca2+, were expressed in NSC-distal GICs. In particular, expression of the AMPA glutamate receptor subunit GRIA1, was found to associate with Ca2+ sensitive NSC-proximal GICs, and decreased as GICs differentiated along with reduced Ca2+ drug sensitivity. The correlation between high expression of Ca2+ channels (such as GRIA1) and sensitivity to Ca2+ 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 Ca2+ homeostasis, providing a potential target mechanism for eradication of an immature population of malignant cells.