Selective calcium sensitivity in immature glioma cancer stem cells

PLoS One. 2014 Dec 22;9(12):e115698. doi: 10.1371/journal.pone.0115698. eCollection 2014.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Blotting, Western
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology
  • Calcium / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Proliferation / drug effects
  • Fluorescent Antibody Technique
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Glioma / drug therapy*
  • Glioma / genetics
  • Glioma / pathology
  • Humans
  • Neoplastic Stem Cells / drug effects*
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / pathology
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Tumor Cells, Cultured

Substances

  • Biomarkers, Tumor
  • RNA, Messenger
  • Calcium

Grant support

Swedish Childhood Cancer foundation PR2013-0084 (www.barncancerfonden.se), Swedish Cancer Foundation CAN 2011/783 (www.cancerfonden.se), Swedish Research Council 2011-4567 (vr.se), Karolinska Institutet (www.ki.se), Linnaeus center in Developmental Biology for Regenerative Medicine (www.dbrm.se). SW was partially funded by the Karolinska Institutet PhD scholarship program. MN was funded by a post-doc scholarship from the Swedish Cancer Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.