Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors.
Despite aggressive surgery, radiotherapy, and chemotherapy, treatment of malignant glioma remains formidable. Although the concept of cancer stem cells reveals a new framework of cancer therapeutic strategies against malignant glioma, it remains unclear how glioma stem cells could be eradicated. Here, we demonstrate that autocrine TGF-beta signaling plays an essential role in retention of stemness of glioma-initiating cells (GICs) and describe the underlying mechanism for it. TGF-beta induced [corrected] expression of Sox2, a stemness gene, and this induction was mediated by Sox4, a direct TGF-beta target gene. Inhibitors of TGF-beta signaling drastically deprived tumorigenicity of GICs by promoting their differentiation, and these effects were attenuated in GICs transduced with Sox2 or Sox4. Furthermore, GICs pretreated with TGF-beta signaling inhibitor exhibited less lethal potency in intracranial transplantation assay. These results identify an essential pathway for GICs, the TGF-beta-Sox4-Sox2 pathway, whose disruption would be a therapeutic strategy against gliomas.
Ikushima
Hiroaki
H
Department of Molecular Pathology, University of Tokyo, Japan.
Todo
Tomoki
T
Ino
Yasushi
Y
Takahashi
Masamichi
M
Miyazawa
Keiji
K
Miyazono
Kohei
K
D000368:Aged; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004149:Dioxoles / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D055747:SOX Transcription Factors / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D055751:SOXC Transcription Factors; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D055747:SOX Transcription Factors; C527782:SOX2 protein, human; C083431:SOX4 protein, human; D055748:SOXB1 Transcription Factors; D055751:SOXC Transcription Factors; D016212:Transforming Growth Factor beta