title: VHL-deficient vasculogenesis in hemangioblastoma.
abstract: Hemangioblasts are capable of differentiation into vascular structures and blood. Patients with von Hippel-Lindau (VHL) disease develop hemangioblastomas which are composed of VHL-deficient tumor cells with protracted hemangioblastic differentiation potential. In a subset of these tumors, hemangioblastic differentiation is characterized by different stages of red blood cell formation. It has remained controversial, however, whether VHL-deficient hemangioblastic cells are similarly capable of differentiating into vascular cells and functioning vascular structures in vivo. By histologic, immunohistologic and microdissection-based genetic analysis of 60 VHL disease-associated hemangioblastomas, we re-examined the controversial question whether VHL-deficient neoplastic hemangioblastic cells are capable of vascular differentiation (vasculogenesis). In most tumors (n=47), there was no evidence of either vasculogenesis or hematopoiesis; tumor cells were either scattered between reactive angiogenetic vascular structures or arranged in solid clusters. A subset of tumors (n=13), however, revealed vaculogenetic structures that were composed of cuboidal or flat cells and frequently contained red blood cell precursors or mature red blood cells. Microdissection-based deletion analysis of epithelial cells confirmed them to be VHL-deficient tumor cells. Immunohistochemistry for CD31 was consistently negative in these structures, and no evidence could be obtained for connectivity with reactive vasculature. We demonstrate that hemangioblastic differentiation capacity of VHL-deficient hemangioblastic cells includes not only erythropoiesis, but also differentiation into primitive vasculogenetic structures. Tumor cells, however, do not appear to have the potential of terminal differentiation into mature and functional vascular structures.
authors.affiliation: Department of Neurosurgery, Freiburg University Medical Center, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Gläsker
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Smith
authors.affiliation: Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Surgical Neurology Branch, NINDS, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: alexander.vortmeyer@yale.edu.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D004920:Erythropoiesis / Q000235:genetics; D018325:Hemangioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
chemical_list: D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
keywords: Angiogenesis; Hemangioblastoma; Vasculogenesis; von Hippel–Lindau disease