title: Candidate pathways for promoting differentiation or quiescence of oligodendrocyte progenitor-like cells in glioma.
abstract: Platelet-derived growth factor receptor alpha-positive oligodendrocyte progenitor cells (OPC) located within the mature central nervous system may remain quiescent, proliferate, or differentiate into oligodendrocytes. Human glioblastoma multiforme tumors often contain rapidly proliferating oligodendrocyte lineage transcription factor 2 (Olig2)-positive cells that resemble OPCs. In this study, we sought to identify candidate pathways that promote OPC differentiation or quiescence rather than proliferation. Gene expression profiling conducted in both normal murine OPCs and highly proliferative Olig2-positive glioma cells identified all the transcripts associated with the highly proliferative state of these cells and showed that among the various cell types found within the brain, Olig2-positive tumor cells are most similar to OPCs. We then subtracted OPC transcripts found in tumor samples from those found in normal brain samples and identified 28 OPC transcripts as candidates for promoting differentiation or quiescence. Systematic analysis of human glioma data revealed that these genes have similar expression profiles in human tumors and were significantly enriched in genomic deletions, suggesting an antiproliferative role. Treatment of primary murine glioblastoma cells with agonists of one candidate gene, Gpr17, resulted in a decreased number of neurospheres. Together, our findings show that comparison of the molecular phenotype of progenitor cells in tumors to the equivalent cells in the normal brain represents a novel approach for the identification of targeted therapies.
authors.affiliation: Department of Genetics and Psychiatry, Washington University, St. Louis, Missouri, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Dougherty
authors.forename: Elena I
authors.initials: EI
authors.lastname: Fomchenko
authors.forename: Afua A
authors.initials: AA
authors.lastname: Akuffo
authors.forename: Eric
authors.initials: E
authors.lastname: Schmidt
authors.forename: Karim Y
authors.initials: KY
authors.lastname: Helmy
authors.forename: Elena
authors.initials: E
authors.lastname: Bazzoli
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.forename: Ana
authors.initials: A
authors.lastname: Milosevic
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051379:Mice; D046228:Microarray Analysis; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D059467:Transcriptome