title: Identification of a SOX2-dependent subset of tumor- and sphere-forming glioblastoma cells with a distinct tyrosine kinase inhibitor sensitivity profile.
abstract: Putative cancer stem cells have been identified in glioblastomas and are associated with radio- and chemo-resistance. Further knowledge about these cells is thus highly warranted for the development of better glioblastoma therapies. Gene expression analyses of 11 high-grade glioma cultures identified 2 subsets, designated type A and type B cultures. The type A cultures displayed high expression of CXCR4, SOX2, EAAT1, and GFAP and low expression of CNP, PDGFRB, CXCL12, and extracellular matrix proteins. Clinical significance of the 2 types was indicated by the expression of type A- and type B-defining genes in different clinical glioblastoma samples. Classification of glioblastomas with type A- and type B-defining genes generated 2 groups of tumors composed predominantly of the classical, neural, and/or proneural subsets and the mesenchymal subset, respectively. Furthermore, tumors with EGFR mutations were enriched in the group of type A samples. Type A cultures possessed a higher capacity to form xenograft tumors and neurospheres and displayed low or no sensitivity to monotreatment with PDGF- and IGF-1-receptor inhibitors but were efficiently growth inhibited by combination treatment with low doses of these 2 inhibitors. Furthermore, siRNA-induced downregulation of SOX2 reduced sphere formation of type A cultures, decreased expression of type A-defining genes, and conferred sensitivity to monotreatment with PDGF- and IGF-1-receptor inhibitors. The present study thus describes a tumor- and neurosphere-forming SOX2-dependent subset of glioblastoma cultures characterized by a gene expression signature similar to that of the recently described classical, proneural, and/or neural subsets of glioblastoma. The findings that resistance to PDGF- and IGF-1-receptor inhibitors is related to SOX2 expression and can be overcome by combination treatment should be considered in ongoing efforts to develop novel stem cell-targeting therapies.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Karolinska University Hospital in Solna, SE-171 76, Stockholm, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hägerstrand
authors.forename: Xiaobing
authors.initials: X
authors.lastname: He
authors.forename: Maja
authors.initials: M
authors.lastname: Bradic Lindh
authors.forename: Saskia
authors.initials: S
authors.lastname: Hoefs
authors.forename: Göran
authors.initials: G
authors.lastname: Hesselager
authors.forename: Arne
authors.initials: A
authors.lastname: Ostman
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000145:classification / Q000188:drug therapy / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000145:classification / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D018874:Spheroids, Cellular / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors