3 results on '"H. zum Buttel"'
Search Results
2. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance
- Author
-
Franziska Foss, Sascha Seidel, Ángel M. Cuesta, María Rodríguez Aburto, Jan Hofmann, C. Depner, Boyan K. Garvalov, Till Acker, F. Finkelmeier, H. Zum Buttel, Guido Reifenberger, K. Kaulich, Marta Segarra, S. Barbus, Nuray Böğürcü, and Amparo Acker-Palmer
- Subjects
0301 basic medicine ,Cell signaling ,Science ,General Physics and Astronomy ,Repressor ,Down-Regulation ,Angiogenesis Inhibitors ,Ephrin-B2 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Neovascularization ,03 medical and health sciences ,Downregulation and upregulation ,ddc:570 ,Glioma ,medicine ,Gene silencing ,Animals ,Humans ,Neoplasm Invasiveness ,Psychological repression ,Zinc Finger E-box Binding Homeobox 2 ,Regulation of gene expression ,Mice, Knockout ,Multidisciplinary ,Neovascularization, Pathologic ,General Chemistry ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,Xenograft Model Antitumor Assays ,Cell Hypoxia ,Cell biology ,Up-Regulation ,Bevacizumab ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,030104 developmental biology ,Drug Resistance, Neoplasm ,medicine.symptom - 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)-1α 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., Ephrins are transmembrane proteins involved in cell-cell communication, and implicated in cancer cell growth and progression. Here, the authors show that EphrinB2 expression is reduced in glioma cells both by genetic and epigenetic alterations and under hypoxia, through a HIF1α-mediated direct regulation of ZEB2, which enhances invasion and anti-angiogenic resistance.
- Published
- 2015
3. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance.
- Author
-
Depner C, Zum Buttel H, Böğürcü N, Cuesta AM, Aburto MR, Seidel S, Finkelmeier F, Foss F, Hofmann J, Kaulich K, Barbus S, Segarra M, Reifenberger G, Garvalov BK, Acker T, and Acker-Palmer A
- Subjects
- Angiogenesis Inhibitors pharmacology, Angiogenesis Inhibitors therapeutic use, Animals, Bevacizumab pharmacology, Bevacizumab therapeutic use, Cell Hypoxia genetics, Down-Regulation genetics, Ephrin-B2 metabolism, Gene Expression Regulation, Neoplastic, Glioma blood supply, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mice, Inbred C57BL, Mice, Knockout, Neoplasm Invasiveness, Neovascularization, Pathologic drug therapy, Neovascularization, Pathologic metabolism, Up-Regulation genetics, Xenograft Model Antitumor Assays, Zinc Finger E-box Binding Homeobox 2 genetics, Drug Resistance, Neoplasm genetics, Ephrin-B2 genetics, Glioma genetics, Glioma pathology, Neovascularization, Pathologic genetics, Neovascularization, Pathologic pathology, Zinc Finger E-box Binding Homeobox 2 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)-1α 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.
- Published
- 2016
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