STAT3 is essential for the maintenance of neurosphere-initiating tumor cells in patients with glioblastomas: a potential for targeted therapy?
Glioblastoma (GBM), the highest-grade form of gliomas, is the most frequent and the most aggressive. Recently, a subpopulation of cells with stem cells characteristics, commonly named "tumor-initiating stem cells" (TISCs) or "cancer stem cells" (CSCs) were identified in GBM. These cells were shown to be highly resistant to chemotherapeutic drugs and to ionizing radiations. Consequently, the knowledge of the signals that regulate the functions and survival of TISCs is crucial. In our work, we describe a neurosphere-initiating cell (NS-IC) assay to quantify TISC/CSCs from patients with GBM and show that these cells are tumorigenic in vivo. We demonstrate that the intracellular signal transducer and activator of transcription STAT3 is constitutively activated by phosphorylation preferentially on serine 727 in these cells. Moreover, we demonstrate that the selective inhibition of STAT3 by the chemical compound Stattic or by siRNA STAT3 abrogates TISC/CSC proliferation and NS-IC suggesting that self-renewal of GBM "stem-like" cells depends on the presence of STAT3 for their maintenance. Finally, we show that inhibition of STAT3 by Stattic sensitizes TISC/CSCs to the inhibitory action of Temozolomide with a strong synergistic effect of both drugs. Overall, these results suggest that strategies focused on STAT3 inhibition are efficient at the level of "stem-like" cells and could be of interest for therapeutic purposes in patients with malignant GBM.
Villalva
Claire
C
INSERM U935, Université de Poitiers, Poitiers F-86021, France.
Martin-Lannerée
Severine
S
Cortes
Ulrich
U
Dkhissi
Fatima
F
Wager
Michel
M
Le Corf
Amélie
A
Tourani
Jean-Marc
JM
Dusanter-Fourt
Isabelle
I
Turhan
Ali G
AG
Karayan-Tapon
Lucie
L
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D003499:Cyclic S-Oxides; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C517409:stattic; D003606:Dacarbazine; D000077204:Temozolomide