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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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