Differentiation therapy exerts antitumor effects on stem-like glioma cells.
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.
Campos
Benito
B
Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany.
Wan
Feng
F
Farhadi
Mohammad
M
Ernst
Aurélie
A
Zeppernick
Felix
F
Tagscherer
Katrin E
KE
Ahmadi
Rezvan
R
Lohr
Jennifer
J
Dictus
Christine
C
Gdynia
Georg
G
Combs
Stephanie E
SE
Goidts
Violaine
V
Helmke
Burkhard M
BM
Eckstein
Volker
V
Roth
Wilfried
W
Beckhove
Philipp
P
Lichter
Peter
P
Unterberg
Andreas
A
Radlwimmer
Bernhard
B
Herold-Mende
Christel
C
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
D000970:Antineoplastic Agents; D014212:Tretinoin