Combination of a Ptgs2 Inhibitor and an Epidermal Growth Factor Receptor-Signaling Inhibitor Prevents Tumorigenesis of Oligodendrocyte Lineage-Derived Glioma-Initiating Cells

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  • Takuichiro Hide
    Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Japan
  • Tatsuya Takezaki
    Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Japan
  • Yuka Nakatani
    Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Japan
  • Hideo Nakamura
    Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan
  • Jun-ichi Kuratsu
    Department of Neurosurgery, Kumamoto University Graduate School of Medical Science, Kumamoto, Japan
  • Toru Kondo
    Laboratory for Cell Lineage Modulation, Center for Developmental Biology, RIKEN, Kobe, Japan

説明

<jats:title>Abstract</jats:title> <jats:p>Recent findings have demonstrated that malignant tumors, including glioblastoma multiforme (GBM), contain cancer-initiating cells (CICs; also known as cancer stem cells), which self-renew and are malignant. However, it remains controversial whether such CICs arise from tissue-specific stem cells, committed precursor cells, or differentiated cells. Here, we sought to examine the origin of the CICs in GBM. We first showed that the overexpression of oncogenic HRasL61 transformed p53-deficient oligodendrocyte precursor cells (OPCs) and neural stem cells (NSCs) into glioma-initiating cell (GIC)-like cells in mice. When as few as 10 of these GIC-like cells were transplanted in vivo, they formed a transplantable GBM with features of human GBM, suggesting that these GIC-like cells were enriched in CICs. DNA microarray analysis showed that widespread genetic reprogramming occurred during the OPCs' transformation: they largely lost their OPC characteristics and acquired NSC ones, including the expression of prominin1, hmga2, ptgs2, and epiregulin. In addition, the combination of a Ptgs2 inhibitor and an epidermal growth factor receptor (EGFR)-signaling inhibitor prevented the tumorigenesis of transformed OPCs and human GICs (hGICs) obtained from anaplastic oligodendroglioma, but not of transformed NSCs or hGICs obtained from GBM. Together, these findings suggest that GBM can arise from either OPCs or NSCs and that the therapeutic targets for GBM might be different, depending on each GIC's cell-of-origin.</jats:p>

収録刊行物

  • Stem Cells

    Stem Cells 29 (4), 590-599, 2011-04-01

    Oxford University Press (OUP)

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