title: PAR1 inhibition suppresses the self-renewal and growth of A2B5-defined glioma progenitor cells and their derived gliomas in vivo.
abstract: Glioblastoma (GBM) remains the most common and lethal intracranial tumor. In a comparison of gene expression by A2B5-defined tumor-initiating progenitor cells (TPCs) to glial progenitor cells derived from normal adult human brain, we found that the F2R gene encoding PAR1 was differentially overexpressed by A2B5-sorted TPCs isolated from gliomas at all stages of malignant development. In this study, we asked if PAR1 is causally associated with glioma progression. Lentiviral knockdown of PAR1 inhibited the expansion and self-renewal of human GBM-derived A2B5(+) TPCs in vitro, while pharmacological inhibition of PAR 1 similarly slowed both the growth and migration of A2B5(+) TPCs in culture. In addition, PAR1 silencing potently suppressed tumor expansion in vivo, and significantly prolonged the survival of mice following intracranial transplantation of human TPCs. These data strongly suggest the importance of PAR1 to the self-renewal and tumorigenicity of A2B5-defined glioma TPCs; as such, the abrogation of PAR1-dependent signaling pathways may prove a promising strategy for gliomas.
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Auvergne
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Connell
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Au
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Cornwell
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Osipovitch
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Benraiss
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Dangelmajer
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Guerrero-Cazares
authors.affiliation: Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Quinones-Hinojosa
authors.affiliation: Department of Neurology, Neurology University of Rochester Medical Center, Center for Translational Neuromedicine, Rochester, NY, USA.|Center for Translational Neuromedicine, Neurology University of Rochester Medical Center, Rochester, NY, USA.|Center for Basic and Translational Neuroscience, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S A
authors.initials: SA
authors.lastname: Goldman
mesh_terms: D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D000066673:Cell Self Renewal; D002470:Cell Survival / Q000235:genetics; D005732:Gangliosides / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D034622:RNA Interference; D044463:Receptor, PAR-1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D014183:Transplantation, Heterologous
chemical_list: D005732:Gangliosides; D044463:Receptor, PAR-1; C062875:ganglioside A2B5