Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors.

Abstract

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.

• Authors: Hiroaki Ikushima, Tomoki Todo, Yasushi Ino, Masamichi Takahashi, Keiji Miyazawa, Kohei Miyazono
• Journal: Cell stem cell (Cell Stem Cell) Vol. 5 Issue 5 Pg. 504-14 (Nov 06 2009) ISSN: 1875-9777 [Electronic] United States
• PMID: 19896441 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
• Benzamides
• Dioxoles
• Receptors, Transforming Growth Factor beta
• SOX Transcription Factors
• SOX2 protein, human
• SOX4 protein, human
• SOXB1 Transcription Factors
• SOXC Transcription Factors
• Transforming Growth Factor beta

Topics

• Aged
• Animals
• Benzamides (pharmacology)
• Brain Neoplasms (genetics, metabolism, pathology)
• Cell Differentiation
• Cells, Cultured
• Dioxoles (pharmacology)
• Female
• Glioblastoma (genetics, metabolism, pathology)
• Humans
• Male
• Mice
• Mice, Nude
• Middle Aged
• Neoplasm Transplantation
• Neoplastic Stem Cells (metabolism, pathology)
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• SOX Transcription Factors (metabolism)
• SOXB1 Transcription Factors (genetics, metabolism)
• SOXC Transcription Factors
• Signal Transduction
• Transforming Growth Factor beta (pharmacology)