Open AccessZEB1 Promotes Invasion in Human Fetal Neural Stem Cells and Hypoxic Glioma Neurospheres
Author(s) -
Kahlert Ulf D.,
Suwala Abigail K.,
Raabe Eric H.,
Siebzehnrubl Florian A.,
Suarez Maria J.,
Orr Brent A.,
Bar Eli E.,
Maciaczyk Jaroslaw,
Eberhart Charles G.
Publication year - 2015
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12240
Subject(s) - neurosphere , glioma , biology , cancer research , pathology , neural stem cell , progenitor cell , stem cell , immunohistochemistry , astrocytoma , in vitro , medicine , microbiology and biotechnology , adult stem cell , endothelial stem cell , biochemistry
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 HIF1 alpha 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.