title: ERBB receptor signaling promotes ependymoma cell proliferation and represents a potential novel therapeutic target for this disease.
abstract: OBJECTIVE
  This study was designed to investigate the biological and therapeutic significance of ERBB1, ERBB2, ERBB3, and ERBB4 in childhood ependymoma.
  
  
  METHODS
  The expression frequency and clinical significance of ERBB1-4 was analyzed in a large cohort of pediatric ependymoma (n = 121) using immunohistochemistry, Western blotting, and reverse transcription-PCR analysis. Histological markers of anaplasia (necrosis, microvascular proliferation, and Ki-67 proliferative index) were also determined. Functional assessment of ERBB-dependent cell signaling and proliferation, in addition to novel therapeutic inhibition of these processes, was conducted using short-term cultures of human ependymoma cells.
  
  
  RESULTS
  Coexpression of ERBB2 and ERBB4 was identified in over 75% of tumors. High-level coexpression of these receptors was significantly related to tumor proliferative activity [P < 0.05; Ki-67 labeling index (LI)] and, in combined survival analysis of clinical (degree of surgical resection) and molecular (ERBB2/ERBB4 expression status and Ki-67 LI) factors, enabled a greater resolution of patient prognosis than any individual variable alone. Ligand-dependent activation of ERBB receptor-signaling in cultured ependymoma cells resulted in AKT phosphorylation and cellular proliferation that was significantly blocked in a dose-dependent manner using WAY-177820, a novel inhibitor of ERBB2 tyrosine kinase activity.
  
  
  CONCLUSIONS
  This study suggests that ERBB receptor signaling results in aggressive disease behavior in ependymoma by promoting tumor cell proliferation. An analysis of ERBB2 and ERBB4 expression, in association with Ki-67 LI and the degree of surgical resection, may provide an accurate tool for assessing disease risk in children with this disease. In addition, these receptors may serve as a target for novel therapeutic approaches in ependymoma.
authors.affiliation: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. Richard. Gilbertson@stjude.org
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Lyndsay
authors.initials: L
authors.lastname: Bentley
authors.forename: Roberto
authors.initials: R
authors.lastname: Hernan
authors.forename: Teemu T
authors.initials: TT
authors.lastname: Junttila
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Frank
authors.forename: Hannu
authors.initials: H
authors.lastname: Haapasalo
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.forename: Cynthia
authors.initials: C
authors.lastname: Wetmore
authors.forename: Tom
authors.initials: T
authors.lastname: Curran
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
mesh_terms: D015139:Blotting, Southern; D015153:Blotting, Western; D002455:Cell Division; D016543:Central Nervous System Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004806:Ependymoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism; D066247:Receptor, ErbB-4; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
chemical_list: D066246:ErbB Receptors; D019394:Ki-67 Antigen; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; C587689:ERBB4 protein, human; C494918:AKT1 protein, human