title: ZEB1 Promotes Invasion in Human Fetal Neural Stem Cells and Hypoxic Glioma Neurospheres.
abstract: Diffuse spread through brain parenchyma and the presence of hypoxic foci rimmed by neoplastic cells are two cardinal features of glioblastoma, and low oxygen is thought to drive movement of malignant gliomas in the core of the lesions. Transcription factors associated with epithelial-to-mesenchymal transition (EMT) have been linked to this invasion, and we found that hypoxia increased in vitro invasion up to fourfold in glioblastoma neurosphere lines and induced the expression of ZEB1. Immunohistochemical assessment of 295 surgical specimens consisting of various types of pediatric and adult brain cancers showed that ZEB1 expression was significantly higher in infiltrative lesions than less invasive tumors such as pilocytic astrocytoma and ependymoma. ZEB1 protein was also present in human fetal periventricular stem and progenitor cells and ZEB1 inhibition impaired migration of in vitro propagated human neural stem cells. The induction of ZEB1 protein in hypoxic glioblastoma neurospheres could be partially blocked by the HIF1alpha inhibitor digoxin. Targeting ZEB1 blocked hypoxia-augmented invasion of glioblastoma cells in addition to slowing them in normoxia. These data support the role for ZEB1 in invasive and high-grade brain tumors and suggest its key role in promoting invasion in the hypoxic tumor core as well as in the periphery.
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.|Department of Neurosurgery, University Medical Center Düsseldorf, Düsseldorf, Germany.
authors.forename: Ulf D
authors.initials: UD
authors.lastname: Kahlert
authors.affiliation: Department of Neurosurgery, University Medical Center Düsseldorf, Düsseldorf, Germany.
authors.forename: Abigail K
authors.initials: AK
authors.lastname: Suwala
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.
authors.forename: Eric H
authors.initials: EH
authors.lastname: Raabe
authors.affiliation: European Cancer Stem Cell Research Institute, Cardiff University, Cardiff, UK.
authors.forename: Florian A
authors.initials: FA
authors.lastname: Siebzehnrubl
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Suarez
authors.affiliation: Anatomical Pathology, St. Jude Children Research Hospital.
authors.forename: Brent A
authors.initials: BA
authors.lastname: Orr
authors.affiliation: Department of Neurosurgery, School of Medicine, Case Western Reserve University, Cleveland, OH.
authors.forename: Eli E
authors.initials: EE
authors.lastname: Bar
authors.affiliation: Department of Neurosurgery, University Medical Center Düsseldorf, Düsseldorf, Germany.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Maciaczyk
authors.affiliation: Department of Pathology, Division of Neuropathology, Johns Hopkins Hospital, Baltimore, MD.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
mesh_terms: D001932:Brain Neoplasms / Q000473:pathology / Q000503:physiopathology*; D018929:Cell Culture Techniques; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005910:Glioma / Q000473:pathology / Q000503:physiopathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism; D007150:Immunohistochemistry; D060787:Neoplasm Grading; D058953:Neural Stem Cells / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: C497442:HIF1A protein, human; D018398:Homeodomain Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1
keywords: EMT; ZEB1; glioma; hypoxia; neural stem cell