title: Responsiveness of stem-like human glioma cells to all-trans retinoic acid and requirement of retinoic acid receptor isotypes α, β and γ.
abstract: Retinoic acid (RA) is required for development and homeostasis of the normal mammalian brain and may play a role in the initiation and progression of malignant brain tumors, such as the glioblastoma multiforme (GBM) and the gliosarcoma (Gsarc). The subpopulation of stem-like glioma cells (SLGCs) was shown to resist standard glioma radio-/chemotherapy and to propagate tumor regrowth. We used phenotypically distinct, self-renewing SLGC lines from six human GBMs, two Gsarcs, and two subcloned SLGC derivatives in order to investigate their responsiveness to all-trans retinoic acid (atRA) and to identify the RA-receptor (RAR) isotypes involved. In general, atRA exerted a pro-proliferative and pro-survival effect on SLGCs, though the efficacy was distinct. By means of RAR isotype-selective retinoids we disclosed that these effects were mediated by RARα and RARγ, except for one SLGC line, in which the pro-proliferative signal was induced by the RARβ-selective retinoid. Only one GBM-derived cell line (T1338) and a subpopulation of another (T1389) displayed neural differentiation in response to atRA. Differentiation of T1338 was induced by RARα and RARγ isotype-selective retinoids, associated with down-regulation of Sox2, and the failure to induce orthotopic tumors in the brains of SCID mice. The differential responsiveness of the SLGC lines appeared unrelated to the expression of RARβ, as (i) atRA augmented RAR isotype mRNA expression and particularly rarβ mRNA in all SLGC lines, (ii) rarβ promoter hypomethylation in the SLGC lines was not related to differentiation and (iii) the induction of T1338 differentiation was by RARα- and RARγ-selective ligands.
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Choschzick
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany; Department of Radiation Oncology, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Hirseland
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Cramer
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany; Department of Radiation Oncology, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schultz
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Leppert
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Tronnier
authors.affiliation: Department of Neurosurgery, University of Lübeck, D-23538 Lübeck, Germany. Electronic address: Christina.Zechel@uksh.de.
authors.forename: C
authors.initials: C
authors.lastname: Zechel
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D001932:Brain Neoplasms / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D019175:DNA Methylation / Q000502:physiology; D005260:Female; D005910:Glioma / Q000503:physiopathology*; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D055748:SOXB1 Transcription Factors; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C527782:SOX2 protein, human; C082925:retinoic acid receptor beta
keywords: malignant human glioma; retinoic acid; retinoic acid receptor isotypes; stem-like tumor cells