title: Essential role of the Hedgehog signaling pathway in human glioma-initiating cells.
abstract: Recent findings have demonstrated that malignant tumors, including glioblastoma multiforme, contain cancer-initiating cells (also known as cancer stem cells), which self-renew and are malignant, with features of tissue-specific stem cells. As these cells are resistant to irradiation and anti-cancer drugs, it is important to characterize them and find targeting therapies. In this study, we established two primary human glioma cell lines from anaplastic oligodendroglioma and glioblastoma multiforme. These lines were enriched in glioma-initiating cells, as just 10 cells formed malignant glioma when injected into mouse brain. We used these cell lines to examine the roles of the Notch, Hedgehog and Wnt signaling pathways, which are involved in stem-cell maintenance and tumorigenesis, to determine which of these pathways are crucial to glioma-initiating cells and their regulation. Here we show that the Hedgehog pathway is indispensable for glioma-initiating cell proliferation and tumorigenesis; the Hedgehog signaling inhibitors prevented glioma-initiating cell proliferation, while signaling inhibitors for Notch or Wnt did not. Overexpression of Gli2ΔC, a C-terminal-truncated form of Gli2 that antagonizes Gli transcription factor functions, blocked glioma-initiating cell proliferation in culture and tumorigenesis in vivo. Knockdown of the Gli downstream factor Cdc2 also prevented glioma-initiating cell proliferation. Taken together, these results show that the Hedgehog→ Gli→Cdc2 signaling cascade plays a role in the proliferation and malignancy of glioma-initiating cells.
authors: Laboratory for Cell Lineage Modulation, RIKEN Center for Developmental Biology, Kobe, Japan.
authors: Tatsuya
authors: T
authors: Takezaki
authors: Takuichiro
authors: T
authors: Hide
authors: Hiromi
authors: H
authors: Takanaga
authors: Hideo
authors: H
authors: Nakamura
authors: Jun-Ichi
authors: J
authors: Kuratsu
authors: Toru
authors: T
authors: Kondo
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000209:etiology / Q000473:pathology*; D049109:Cell Proliferation; D002470:Cell Survival; D005260:Female; D005910:Glioma / Q000209:etiology / Q000473:pathology*; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D051880:Receptors, Notch / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins / Q000502:physiology
chemical_list: D053823:Hedgehog Proteins; D051880:Receptors, Notch; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051153:Wnt Proteins