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Free keywords:
Angiogenesis Inhibitors/pharmacology/therapeutic use
Animals
Bevacizumab/pharmacology/therapeutic use
Cell Hypoxia/genetics
Down-Regulation/genetics
*Drug Resistance, Neoplasm/genetics
Ephrin-B2/*genetics/metabolism
Gene Expression Regulation, Neoplastic
Glioma/blood supply/*genetics/*pathology
Humans
Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Invasiveness
Neovascularization, Pathologic/drug therapy/*genetics/metabolism/*pathology
Up-Regulation/genetics
Xenograft Model Antitumor Assays
Zinc Finger E-box Binding Homeobox 2/genetics/*metabolism
Abstract:
Diffuse invasion of the surrounding brain parenchyma is a major obstacle in the treatment of gliomas with various therapeutics, including anti-angiogenic agents. Here we identify the epi-/genetic and microenvironmental downregulation of ephrinB2 as a crucial step that promotes tumour invasion by abrogation of repulsive signals. We demonstrate that ephrinB2 is downregulated in human gliomas as a consequence of promoter hypermethylation and gene deletion. Consistently, genetic deletion of ephrinB2 in a murine high-grade glioma model increases invasion. Importantly, ephrinB2 gene silencing is complemented by a hypoxia-induced transcriptional repression. Mechanistically, hypoxia-inducible factor (HIF)-1alpha induces the EMT repressor ZEB2, which directly downregulates ephrinB2 through promoter binding to enhance tumour invasiveness. This mechanism is activated following anti-angiogenic treatment of gliomas and is efficiently blocked by disrupting ZEB2 activity. Taken together, our results identify ZEB2 as an attractive therapeutic target to inhibit tumour invasion and counteract tumour resistance mechanisms induced by anti-angiogenic treatment strategies.
