title: Differentiation therapy exerts antitumor effects on stem-like glioma cells.
abstract: OBJECTIVE
  Stem-like tumor cells comprise a highly tumorigenic and therapy-resistant tumor subpopulation, which is believed to substantially influence tumor initiation and therapy resistance in glioma. Currently, therapeutic, drug-induced differentiation is considered as a promising approach to eradicate this tumor-driving cell population; retinoic acid is well known as a potent modulator of differentiation and proliferation in normal stem cells. In glioma, knowledge about the efficacy of retinoic acid-induced differentiation to target the stem-like tumor cell pool could have therapeutic implications.
  
  
  METHODS
  Stem-like glioma cells (SLGC) were differentiated with all-trans retinoic acid-containing medium to study the effect of differentiation on angiogenesis, invasive growth, as well as radioresistance and chemoresistance of SLGCs. In vivo effects were studied using live microscopy in a cranial window model.
  
  
  RESULTS
  Our data suggest that in vitro differentiation of SLGCs induces therapy-sensitizing effects, impairs the secretion of angiogenic cytokines, and disrupts SLGCs motility. Further, ex vivo differentiation reduces tumorigenicity of SLGCs. Finally, we show that all-trans retinoic acid treatment alone can induce antitumor effects in vivo.
  
  
  CONCLUSIONS
  Altogether, these results highlight the potential of differentiation treatment to target the stem-like cell population in glioblastoma.
authors.affiliation: Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
authors.forename: Benito
authors.initials: B
authors.lastname: Campos
authors.forename: Feng
authors.initials: F
authors.lastname: Wan
authors.forename: Mohammad
authors.initials: M
authors.lastname: Farhadi
authors.forename: Aurélie
authors.initials: A
authors.lastname: Ernst
authors.forename: Felix
authors.initials: F
authors.lastname: Zeppernick
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Tagscherer
authors.forename: Rezvan
authors.initials: R
authors.lastname: Ahmadi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lohr
authors.forename: Christine
authors.initials: C
authors.lastname: Dictus
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.forename: Violaine
authors.initials: V
authors.lastname: Goidts
authors.forename: Burkhard M
authors.initials: BM
authors.lastname: Helmke
authors.forename: Volker
authors.initials: V
authors.lastname: Eckstein
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Andreas
authors.initials: A
authors.lastname: Unterberg
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects*; D002469:Cell Separation; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000473:pathology; D016133:Polymerase Chain Reaction; D014212:Tretinoin / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014212:Tretinoin