Autocrine TGF-beta Signaling Maintains Tumorigenicity of Glioma-Initiating Cells through Sry-Related HMG-Box Factors

作者：Ikushima Hiroaki; Todo Tomoki; Ino Yasushi; Takahashi Masamichi; Miyazawa Keiji; Miyazono Kohei^*

来源：Cell Stem Cell, 2009, 5(5): 504-514.

DOI：10.1016/j.stem.2009.08.018

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 sternness of glioma-initiating cells (GICs) and describe the underlying mechanism for it. TGF-beta-induced 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.

• 出版日期2009-11-6