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Cell Stem Cell. 2009 Nov 6;5(5):504-14. doi: 10.1016/j.stem.2009.08.018.

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

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Department of Molecular Pathology, University of Tokyo, Japan.

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  • Cell Stem Cell. 2009 Dec 4;5(6):666.


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.

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