Autocrine TGF-beta signaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors
- Cell Stem Cell. 2009 Nov 6;5(5):504-14. doi: 10.1016/j.stem.2009.08.018.
- 1. Department of Molecular Pathology, University of Tokyo, Japan.
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.