title: Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.
abstract: There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma. However, in von Hippel-Lindau disease, hemangioblastomas are frequently observed in the cerebellum, suggesting an origin in the central nervous system. We performed a structural and topographic analysis of cerebellar tissues obtained from von Hippel-Lindau disease patients to identify and characterize developmentally arrested structural elements in the central nervous system. We examined the entire cerebella of five tumor-free von Hippel-Lindau disease patients and of three non-von Hippel-Lindau disease controls. In all, 9 cerebellar developmentally arrested structural elements were detected and topographically mapped in 385 blocks of von Hippel-Lindau disease cerebella. No developmentally arrested structural elements were seen in 214 blocks from control cerebella. Developmentally arrested structural elements are composed of poorly differentiated cells that express hypoxia-inducible factor (HIF)2α, but not HIF1α or brachyury, and preferentially involve the molecular layer of the dorsum cerebelli. For the first time, we identify and characterize developmentally arrested structural elements in the central nervous system of von Hippel-Lindau patients. We provide evidence that developmentally arrested structural elements in the cerebellum are composed of developmentally arrested hemangioblast progenitor cells in the molecular layer of the dorsum cerebelli.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Shively
authors.forename: Eric A
authors.initials: EA
authors.lastname: Falke
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Maxine G B
authors.initials: MG
authors.lastname: Tran
authors.forename: Eli R
authors.initials: ER
authors.lastname: Thompson
authors.forename: Patrick H
authors.initials: PH
authors.lastname: Maxwell
authors.forename: Erich
authors.initials: E
authors.lastname: Roessler
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
mesh_terms: D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology; D002528:Cerebellar Neoplasms / Q000209:etiology / Q000473:pathology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology*; D005260:Female; D018325:Hemangioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006623:von Hippel-Lindau Disease / Q000378:metabolism / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1