Reversibility of glioma stem cells’ phenotypes explains their complex in vitro and in vivo behavior: Discovery of a novel neurosphere-specific enzyme, cGMP-dependent protein kinase 1, using the genomic landscape of human glioma stem cells as a discovery tool
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Thomas J. Wilson1, Daniel B. Zamler1, Robert Doherty1, Maria G. Castro1,2 and Pedro R. Lowenstein1,2
1 Department of Neurosurgery, The University of Michigan School of Medicine, Ann Arbor, MI, USA
2 Department of Cell and Developmental Biology, Training Programs in Cancer Biology, Immunology & Neurosciences, The University of Michigan School of Medicine, Ann Arbor, MI, USA
Pedro R. Lowenstein, email:
Keywords: glioblastoma, stem cells, plasticity, PRKG1, genomics
Received: June 09, 2016 Accepted: August 13, 2016 Published: August 24, 2016
Glioma cells grow in two phenotypic forms, as adherent monolayers and as free floating “neurospheres/tumorspheres”, using specific media supplements. Whether each phenotype is irreversible remains unknown. Herein we show that both states are reversible using patient derived glioblastoma cell cultures (i.e., HF2303, IN859, MGG8, IN2045). Both phenotypic states differ in proliferation rate, invasion, migration, chemotaxis and chemosensitivity. We used microarrays to characterize gene expression across the patient derived glioblastoma cell cultures, to find specific inhibitors of the sphere population. Traditional chemotherapeutics (i.e., doxorubicin or paclitaxel) inhibit rapidly dividing adherent cells; it has been more challenging to inhibit the growth of the sphere phenotype. PRKG1, known to induce apoptosis when activated, is increased in all patient derived glioblastoma spheres. Stimulation of PRKG1 activity preferentially reduced cell viability in the sphere phenotype. Computational network and gene ontology analysis identified novel potential target genes linked to the PRKG1 expression node.
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