title: Histological Characterization of the Tumorigenic "Peri-Necrotic Niche" Harboring Quiescent Stem-Like Tumor Cells in Glioblastoma.
abstract: BACKGROUND
  Characterization of the niches for stem-like tumor cells is important to understand and control the behavior of glioblastomas. Cell-cycle quiescence might be a common mechanism underlying the long-term maintenance of stem-cell function in normal and neoplastic stem cells, and our previous study demonstrated that quiescence induced by hypoxia-inducible factor (HIF)-1α is associated with a high long-term repopulation capacity of hematopoietic stem cells. Based on this, we examined human astrocytoma tissues for HIF-1α-regulated quiescent stem-like tumor cells as a candidate for long-term tumorigenic cells and characterized their niche histologically.
  
  
  METHODS
  Multi-color immunohistochemistry was used to visualize HIF-1α-expressing (HIF-1α+) quiescent stem-like tumor cells and their niche in astrocytoma (WHO grade II-IV) tissues. This niche was modeled using spheroids of cultured glioblastoma cells and its contribution to tumorigenicity was evaluated by sphere formation assay.
  
  
  RESULTS
  A small subpopulation of HIF-1α+ quiescent stem-like tumor cells was found in glioblastomas but not in lower-grade astrocytomas. These cells were concentrated in the zone between large ischemic necroses and blood vessels and were closer to the necrotic tissues than to the blood vessels, which suggested that a moderately hypoxic microenvironment is their niche. We successfully modeled this niche containing cells of HIF-1α+ quiescent stem-like phenotype by incubating glioblastoma cell spheroids under an appropriately hypoxic condition, and the emergence of HIF-1α+ quiescent stem-like cells was shown to be associated with an enhanced sphere-forming activity.
  
  
  CONCLUSIONS
  These data suggest that the "peri-necrotic niche" harboring HIF-1α+ quiescent stem-like cells confers a higher tumorigenic potential on glioblastoma cells and therefore may be a therapeutic target to control the behavior of glioblastomas.
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Ishii
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Tokuhiro
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Neurosurgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sadahiro
authors.affiliation: Department of Basic Laboratory Sciences, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kawano
authors.affiliation: Research Institute National Center for Global Health and Medicine, Shinjuku, Tokyo, Japan.
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.affiliation: Department of Neurosurgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Ikeda
mesh_terms: D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000473:pathology; D014408:Biomarkers, Tumor / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005909:Glioblastoma / Q000473:pathology*; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071317:Nanog Homeobox Protein; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000473:pathology; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D055153:Stem Cell Niche; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C497442:HIF1A protein, human; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors