title: Cytomegalovirus infection induces a stem cell phenotype in human primary glioblastoma cells: prognostic significance and biological impact.
abstract: Glioblastoma (GBM) is associated with poor prognosis despite aggressive surgical resection, chemotherapy, and radiation therapy. Unfortunately, this standard therapy does not target glioma cancer stem cells (GCSCs), a subpopulation of GBM cells that can give rise to recurrent tumors. GBMs express human cytomegalovirus (HCMV) proteins, and previously we found that the level of expression of HCMV immediate-early (IE) protein in GBMs is a prognostic factor for poor patient survival. In this study, we investigated the relation between HCMV infection of GBM cells and the presence of GCSCs. Primary GBMs were characterized by their expression of HCMV-IE and GCSCs marker CD133 and by patient survival. The extent to which HCMV infection of primary GBM cells induced a GCSC phenotype was evaluated in vitro. In primary GBMs, a large fraction of CD133-positive cells expressed HCMV-IE, and higher co-expression of these two proteins predicted poor patient survival. Infection of GBM cells with HCMV led to upregulation of CD133 and other GSCS markers (Notch1, Sox2, Oct4, Nestin). HCMV infection also promoted the growth of GBM cells as neurospheres, a behavior typically displayed by GCSCs, and this phenotype was prevented by either chemical inhibition of the Notch1 pathway or by treatment with the anti-viral drug ganciclovir. GBM cells that maintained expression of HCMV-IE failed to differentiate into neuronal or astrocytic phenotypes. Our findings imply that HCMV infection induces phenotypic plasticity of GBM cells to promote GCSC features and may thereby increase the aggressiveness of this tumor.
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.|Department of Neurology and Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: O
authors.initials: O
authors.lastname: Fornara
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.|Department of Neurology and Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.|Department of Neurosurgery, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Rahbar
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Odeberg
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.
authors.forename: Z
authors.initials: Z
authors.lastname: Khan
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Peredo
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: P
authors.initials: P
authors.lastname: Hamerlik
authors.affiliation: Danish Cancer Society Research Center, Copenhagen, Denmark.|Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.|Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Bartek
authors.affiliation: Department of Neurology and Neurosurgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Stragliotto
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Landázuri
authors.affiliation: Karolinska Institute, Department of Medicine, Center for Molecular Medicine, Cell and Molecular Immunology, Microbial Pathogenesis Unit, Stockholm, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Söderberg-Nauclér
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology* / Q000821:virology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D003587:Cytomegalovirus / Q000502:physiology*; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology* / Q000821:virology; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000821:virology*; D010641:Phenotype; D061251:Primary Cell Culture; D011379:Prognosis; D018874:Spheroids, Cellular / Q000473:pathology