title: Hypoxia-mediated cancer stem cells in pseudopalisades with activation of hypoxia-inducible factor-1α/Akt axis in glioblastoma.
abstract: Pseudopalisades (Ps) around necrotic foci are severely hypoxic and overexpress hypoxia-inducible factor (HIF) in glioblastoma (GBM). Hypoxic regions have been proposed as one of several distinct niches for cancer stem cells (CSCs) in GBM, but little is known about the association between Ps features and CSC properties. Herein, we focused on the biological role of Ps lesions. In clinical cases of GBM, expression of hypoxia-related molecules including HIF-1α, Glut-1, p27(Kip1), and pAkt was significantly increased in perinecrotic Ps lesions compared with nonnecrotic areas and perinecrotic lesions lacking Ps features. Significantly higher expression levels of several CSC-related markers, including CD133, Sox2, CD44s, and aldehyde dehydrogenase (ALDH) 1, were also observed in Ps lesions, which were positively correlated with expression of hypoxia-related molecules and pAkt. Ps lesions also showed increased number of apoptotic cells and decreased bcl-2 and survivin expression compared with the surrounding tissue. Short-term exposure of astrocytoma cell lines to cobalt chloride, which is known to mimic the effect of hypoxia, caused an increase in expression of both hypoxia- and CSC-related markers, in line with increases in the ALDH(high) cell population and number of spheroids. Inhibition of endogenous Akt by LY294002 resulted in decreased expression of Sox2, ALDH1, and CD133, leading to enhancement of cobalt chloride-mediated apoptotic events due to altered ratio of bcl-2 to bax expression. These findings suggest that Ps lesions within GBM may serve as a specialized hypoxic niche, in which the HIF-1α/pAkt axis is activated, in response to severe hypoxia.
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan; Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Inukai
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Atsuko
authors.initials: A
authors.lastname: Hara
authors.affiliation: Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Yasui
authors.affiliation: Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan. Electronic address: msaegusa@med.kitasato-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Saegusa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D055153:Stem Cell Niche / Q000502:physiology; D055815:Young Adult
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051057:Proto-Oncogene Proteins c-akt
keywords: Akt; Cancer stem cell; Glioblastoma; HIF-1α; Pseudopalisade