O34. TGF-β signaling maintains tumorigenicity of glioma-initiating cells through the Sox4–Sox2 axis

Abstract

Recent studies have identified essential signaling pathways for retention of cancer stem cells in various types of cancer. We show here that autocrine TGF-β signaling plays essential roles in retention of stemness of glioma-initiating cells. TGF-β induced expression of Sox2, and this induction was mediated by Sox4, a novel, direct target gene of TGF-β. Inhibitors of TGF-β signaling resulted in deprivation of tumorigenicity of glioma-initiating cells through induction of their differentiation, and these effects were attenuated in glioma-initiating cells transduced with exogenous Sox2 or Sox4. Furthermore, glioma-initiating cells pre-treated with a TGF-β signaling inhibitor exhibited less tumorigenic activity and lethal potency in an intracranial transplantation assay. To target cancer stem cells in clinical situations, elucidation of differences between cancer stem cells and normal stem cells, and identification of novel targets which can eradicate cancer stem cells without affecting normal stem cells will be important. We show that the regulatory mechanism of the Sox axis in glioma-initiating cells is distinct from that in neural progenitor cells. Our findings suggest important differences between glioma-initiating cells and neural progenitor cells, and may open the way to depriving glioma-initiating cells of the tumorigenic activity with minimally affecting normal brain tissues (Ikushima et al., 2009). Ikushima, H., et al., 2009. Autocrine TGF-βsignaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. Cell Stem Cell 5 (5), 504–514.