title: Notch receptor and effector expression in von Hippel-Lindau disease-associated central nervous system hemangioblastomas.
abstract: OBJECTIVE
  Central nervous system hemangioblastomas are the most common manifestation of von Hippel-Lindau (VHL) disease, an autosomal dominant tumor suppressor syndrome that results in loss of VHL protein function and continuous upregulation of hypoxia-inducible factors. These tumors are composed of neoplastic stromal cells and abundant vasculature. Stromal cells express markers consistent with multipotent embryonically arrested hemangioblasts, which are precursors for hematopoietic and vascular lineages. Notch receptors are transmembrane signaling molecules that regulate multiple developmental processes including hematopoiesis and vasculogenesis. To investigate the importance of notch signaling in the development of VHL disease-associated CNS hemangioblastomas, the authors examined the presence of the four notch receptors and downstream notch effectors in this setting.
  
  
  METHODS
  The authors used surgical specimens obtained from confirmed VHL-associated hemangioblastomas. Immunohistochemical analysis for the four notch receptors and the downstream effectors was performed on formalin-fixed paraffin-embedded sections. Western blot analysis for HES1 was performed on frozen specimens.
  
  
  RESULTS
  All four notch receptors are present in hemangioblastomas. NOTCH1 and NOTCH4 receptors were widely and prominently expressed in both the stromal and vascular cells, NOTCH2 receptor expression was limited to primarily stromal cells, and NOTCH3 receptor expression was limited to vascular cells. All 4 receptors displayed a nuclear presence. Immunohistochemical analysis also demonstrated that downstream notch effectors, HES1 and HES5, were uniformly expressed in tumor stromal and vascular cells, but HES3, HEY1, and HEY2 were not. Strong HES1 expression was confirmed by Western blot analysis.
  
  
  CONCLUSIONS
  The presence of all four notch receptors and downstream effector molecules suggests that the notch signaling pathway plays a critical role in the maintenance of the undifferentiated pluripotent phenotype of these tumors and in the associated vascular response. Moreover, the prominent expression of notch receptors in VHL-associated CNS hemangioblastomas reveals a new and possibly potent therapeutic target.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-1414, USA. merrillm@ninds.nih.gov
authors.forename: Marsha J
authors.initials: MJ
authors.lastname: Merrill
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Edwards
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D016543:Central Nervous System Neoplasms / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018325:Hemangioblastoma / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D051880:Receptors, Notch / Q000378:metabolism*; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000378:metabolism; D006623:von Hippel-Lindau Disease / Q000378:metabolism* / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D051880:Receptors, Notch; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C495457:HES3 protein, human; C485631:HEY1 protein, human; C078493:HES1 protein, human