title: Activation of multiple angiogenic signaling pathways in hemangiopericytoma.
abstract: Hemangiopericytoma (HPC) is a highly vascularized mesenchymal tumor. Local recurrence and distant metastasis are common features of HPC. Considering the remarkable hyper-vasculature phenotype of HPC, we assumed that dysregulated angiogenic signaling pathways were involved in HPC. The key components of angiogenic signaling pathways including VEGF-VEGF-R2, EphrinB2-EphB4 and DLL4-Notch were examined by real-time RT-PCR, Western blotting and immunostaining in 17 surgical specimens of HPC patients and in 6 controls. A significant upregulation of VEGF and VEGF-R2 associated with elevated levels of p-Akt and proliferating cell nuclear antigen (PCNA) was detected in HPC. Moreover, a dramatic increase in the mRNA and protein expression of EphB4 and its downstream factor p-Erk1/2 was found in HPC. A massive activation of core-components of DLL4-Notch signaling was detected in HPC. Double-immunofluorescent staining confirmed the expression of these upregulated key factors in the endothelial cells of tumor vessels. The present study identified the activation of multiple and crucial angiogenic signaling pathways, which could function individually and/or synergistically to stimulate angiogenesis in HPC and eventually contribute to tumor growth and progression. Our findings emphasize the importance to target multiple angiogenic signaling pathways when an anti-angiogenic therapy is considered for this highly vascularized tumor.
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pierscianek
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Michel
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Nicolai El
authors.initials: NE
authors.lastname: Hindy
authors.affiliation: Institute of Neuropathology, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Dammann
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Neriman
authors.initials: N
authors.lastname: Oezkan
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mueller
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.affiliation: Department of Neurosurgery, University Hospital Essen, Hufelandstr. 55, 45147, Essen, Germany. yuan.zhu@uk-essen.de.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002135:Calcium-Binding Proteins; D016543:Central Nervous System Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D018450:Disease Progression; D036388:Ephrin-B2 / Q000235:genetics / Q000502:physiology; D005260:Female; D006393:Hemangiopericytoma / Q000098:blood supply* / Q000235:genetics* / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D036224:Receptor, EphB4 / Q000235:genetics / Q000502:physiology; D051880:Receptors, Notch / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics* / Q000502:physiology*; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; C000601239:EFNB2 protein, human; D036388:Ephrin-B2; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; D036224:Receptor, EphB4; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: DLL4-Notch signaling; EphrinB2-EphB4; Hemangiopericytoma; Tumor angiogenesis; VEGF–VEGF-R2