title: Study of angiogenic signaling pathways in hemangioblastoma.
abstract: Hemangioblastoma (HB) is mainly located in the brain and the spinal cord. The tumor is composed of two major components, namely neoplastic stromal cells and abundant microvessels. Thus, hyper-vascularization is the hallmark of this tumor. Despite the identification of germline and/or epigenetic mutations of Von Hippel Lindau (VHL) gene as an important pathogenic mechanism of HB, little is known about the molecular signaling involved in this highly vascularized tumor. The present study investigated the key players of multiple angiogenic signaling pathways including VEGF/VEGFR2, EphB4/EphrinB2, SDF1α/CXCR4 and Notch/Dll4 pathways in surgical specimens of 22 HB. The expression of key angiogenic factors was detected by RT2-PCR and Western blot. Immunofluorescent staining revealed the cellular localization of these proteins. We demonstrated a massive upregulation of mRNA levels of VEGF and VEGFR2, CXCR4 and SDF1α, EphB4 and EphrinB2, as well as the main components of Dll4-Notch signaling in HB. An increase in the protein expression of VEGF, CXCR4 and the core-components of Dll4-Notch signaling was associated with an activation of Akt and Erk1/2 and accompanied by an elevated expression of PCNA. Immuofluorescent staining revealed the expression of VEGF and CXCR4 in endothelial cells as well as in tumor cells. Dll4 protein was predominantly found in tumor cells, whereas EphB4 immunoreactivity was exclusively detected in endothelial cells. We conclude that multiple key angiogenic pathways were activated in HB, which may synergistically contribute to the abundant vascularization in this tumor. Identification of these aberrant pathways provides potential targets for a possible future application of anti-angiogenic therapy for this tumor, particularly when a total surgical resection becomes difficult due to the localization or multiplicity of the tumor.
authors.affiliation: Department of Neurosurgery, Universitatsklinikum Essen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pierscianek
authors.affiliation: Department of Neurosurgery, Universitatsklinikum Essen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Institute of Neuropathology, University Hospital Essen, Essen, Germany.
authors.forename: Kathy
authors.initials: K
authors.lastname: Keyvani
authors.affiliation: Department of Neurosurgery, Universitatsklinikum Essen, Germany.
authors.forename: Nicolai
authors.initials: N
authors.lastname: El Hindy
authors.affiliation: Department of Neurosurgery, KRH Hospital Nordstadt, Hannover, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Stein
authors.affiliation: Department of Neurosurgery, KRH Hospital Nordstadt, Hannover, Germany.
authors.forename: I Erol
authors.initials: IE
authors.lastname: Sandalcioglu
authors.affiliation: Department of Neurosurgery, Universitatsklinikum Essen, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sure
authors.affiliation: Department of Neurosurgery, Universitatsklinikum Essen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mueller
authors.affiliation: Department of Neurosurgery, Universitatsklinikum Essen, Germany.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D003388:Cranial Fossa, Posterior / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018325:Hemangioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019292:Skull Base Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013125:Spinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D036388:Ephrin-B2; D019718:Receptors, CXCR4; D051880:Receptors, Notch; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D036224:Receptor, EphB4; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Dll4/Notch; EphrinB2/EphB4; SDF1α/CXCR4; VEGF/VEGFR2; angiogenesis; hemangioblastoma