Coexpression of erythropoietin and its receptor in endolymphatic sac tumors

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Object. Von Hippel—Lindau (VHL) disease is characterized by multiple tumors in specific organs. The cell of origin and the reason for the particular organ distribution of the tumors remains unknown. Endolymphatic sac tumor (ELST) is one of the lesions associated with VHL disease. Data from previous studies of VHL disease—associated hemangioblastomas (HBs) and renal cell carcinomas (RCCs) have indicated that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth.

Methods. The authors studied ELSTs from five patients with VHL germline mutations. Analysis of the five ELST samples revealed loss of the wild-type allele, consistent with Knudson's two-hit hypothesis for tumorigenesis. All five ELST specimens were characterized microscopically and by immunohistochemical analysis. Coexpression of Epo and Epo-R was found in all five tumors on immunohistochemical studies and confirmed through reverse transcription—polymerase chain reaction and Western blot analysis.

Conclusions. Expression of Epo appears to be a result of VHL gene deficiency, whereas the simultaneous coexpression of Epo-R may reflect a developmental mechanism of tumorigenesis. Coexpression of Epo and Epo-R in ELSTs together with the morphological and genetic similarities of these lesions with other VHL disease—associated tumors indicates that VHL disease—associated tumors in different organs share common pathogenetic pathways.

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Contributor Notes

Address reprint requests to: Zhengping Zhuang, M.D., Ph.D., Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D-37, Bethesda, Maryland 20892. email: zhuangp@ninds.nih.gov.

© AANS, except where prohibited by US copyright law.

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References
  • 1.

    Bagger-Sjöbäck D: Embryology of the human endolymphatic duct and sac. ORL J Otorhinolaryngol Relat Spec 53:61671991Bagger-Sjöbäck D: Embryology of the human endolymphatic duct and sac. ORL J Otorhinolaryngol Relat Spec 53:61–67 1991

    • Search Google Scholar
    • Export Citation
  • 2.

    Bagger-Sjöbäck D: Modern concepts of endolymphatic sac function. Acta Otorhinolaryngol Belg 45:1651691991Bagger-Sjöbäck D: Modern concepts of endolymphatic sac function. Acta Otorhinolaryngol Belg 45:165–169 1991

    • Search Google Scholar
    • Export Citation
  • 3.

    Bagger-Sjöbäck DLundberg AM: Developmental aspects of the human endolymphatic sac. Acta Otolaryngol Suppl 470:51551990Bagger-Sjöbäck D Lundberg AM: Developmental aspects of the human endolymphatic sac. Acta Otolaryngol Suppl 470:51–55 1990

    • Search Google Scholar
    • Export Citation
  • 4.

    George DJKaelin WG Jr: The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 349:4194212003George DJ Kaelin WG Jr: The von Hippel-Lindau protein vascular endothelial growth factor and kidney cancer. N Engl J Med 349:419–421 2003

    • Search Google Scholar
    • Export Citation
  • 5.

    Heffner DK: Low-grade adenocarcinoma of probable endolymphatic sac origin. A clinicopathologic study of 20 cases. Cancer 64:229223021989Heffner DK: Low-grade adenocarcinoma of probable endolymphatic sac origin. A clinicopathologic study of 20 cases. Cancer 64:2292–2302 1989

    • Search Google Scholar
    • Export Citation
  • 6.

    Horster MFBraun GSHuber SM: Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation. Physiol Rev 79:115711911999Horster MF Braun GS Huber SM: Embryonic renal epithelia: induction nephrogenesis and cell differentiation. Physiol Rev 79:1157–1191 1999

    • Search Google Scholar
    • Export Citation
  • 7.

    Hultcrantz MBagger-Sjöbäck D: Embryonic and postnatal development of endolymphatic sac blood vessels. Am J Otol 11:90941990Hultcrantz M Bagger-Sjöbäck D: Embryonic and postnatal development of endolymphatic sac blood vessels. Am J Otol 11:90–94 1990

    • Search Google Scholar
    • Export Citation
  • 8.

    Kim WKaelin WG Jr: The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Curr Opin Genet Dev 13:55602003Kim W Kaelin WG Jr: The von Hippel-Lindau tumor suppressor protein: new insights into oxygen sensing and cancer. Curr Opin Genet Dev 13:55–60 2003

    • Search Google Scholar
    • Export Citation
  • 9.

    Knudson AG Jr: Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45:143714431985Knudson AG Jr: Hereditary cancer oncogenes and antioncogenes. Cancer Res 45:1437–1443 1985

    • Search Google Scholar
    • Export Citation
  • 10.

    Kronenberg JHorowitz Z: Embryonic vascular drainage of the endolymphatic sac: the “embryonic endolymphatic glomerulus.” Isr J Med Sci 28:8968991992Kronenberg J Horowitz Z: Embryonic vascular drainage of the endolymphatic sac: the “embryonic endolymphatic glomerulus.” Isr J Med Sci 28:896–899 1992

    • Search Google Scholar
    • Export Citation
  • 11.

    Kronenberg JLeventon G: Histology of the endolymphatic sac of the rat ear and its relationship to surrounding blood vessels: the “endolymphatic glomerulus.” Am J Otol 7:1301331986Kronenberg J Leventon G: Histology of the endolymphatic sac of the rat ear and its relationship to surrounding blood vessels: the “endolymphatic glomerulus.” Am J Otol 7:130–133 1986

    • Search Google Scholar
    • Export Citation
  • 12.

    Latif FTory KGnarra JYao MDuh FMOrcutt MLet al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:131713201993Latif F Tory K Gnarra J Yao M Duh FM Orcutt ML et al: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320 1993

    • Search Google Scholar
    • Export Citation
  • 13.

    Lee YSVortmeyer AOLubensky IAVogel TWAIkejiri BFerlicot Set al: Co-expression of EPO and EPOR in Von Hippel-Lindau disease-associated renal cysts and renal cel carcinoma. Clin Cancer Res 11:105910642005Lee YS Vortmeyer AO Lubensky IA Vogel TWA Ikejiri B Ferlicot S et al: Co-expression of EPO and EPOR in Von Hippel-Lindau disease-associated renal cysts and renal cel carcinoma. Clin Cancer Res 11:1059–1064 2005

    • Search Google Scholar
    • Export Citation
  • 14.

    Li JCBrackmann DELo WWCarberry JNHouse JW: Reclassification of aggressive adenomatous mastoid neoplasms as endolymphatic sac tumors. Laryngoscope 103:134213481993Li JC Brackmann DE Lo WW Carberry JN House JW: Reclassification of aggressive adenomatous mastoid neoplasms as endolymphatic sac tumors. Laryngoscope 103:1342–1348 1993

    • Search Google Scholar
    • Export Citation
  • 15.

    Lindau A: Discussion on vascular tumours of the brain and spinal cord. Proc R Soc Med 24:3633701931Lindau A: Discussion on vascular tumours of the brain and spinal cord. Proc R Soc Med 24:363–370 1931

    • Search Google Scholar
    • Export Citation
  • 16.

    Lonser RRGlenn GMWalther MChew EYLibutti SKLinehan WMet al: von Hippel-Lindau disease. Lancet 361:205920672003Lonser RR Glenn GM Walther M Chew EY Libutti SK Linehan WM et al: von Hippel-Lindau disease. Lancet 361:2059–2067 2003

    • Search Google Scholar
    • Export Citation
  • 17.

    Manski TJHeffner DKGlenn GMPatronas NJPikus ATKatz Det al: Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA 277:146114661997Manski TJ Heffner DK Glenn GM Patronas NJ Pikus AT Katz D et al: Endolymphatic sac tumors. A source of morbid hearing loss in von Hippel-Lindau disease. JAMA 277:1461–1466 1997

    • Search Google Scholar
    • Export Citation
  • 18.

    Maxwell PHPugh CWRatcliffe PJ: The pVHL-hIF-1 system. A key mediator of oxygen homeostasis. Adv Exp Med Biol 502:3653762001Maxwell PH Pugh CW Ratcliffe PJ: The pVHL-hIF-1 system. A key mediator of oxygen homeostasis. Adv Exp Med Biol 502:365–376 2001

    • Search Google Scholar
    • Export Citation
  • 19.

    Megerian CAMcKenna MJNuss RCManiglia AJOjemann RGPilch BZet al: Endolymphatic sac tumors: histopathologic confirmation, clinical characterization, and implication in von Hippel-Lindau disease. Laryngoscope 105:8018081995Megerian CA McKenna MJ Nuss RC Maniglia AJ Ojemann RG Pilch BZ et al: Endolymphatic sac tumors: histopathologic confirmation clinical characterization and implication in von Hippel-Lindau disease. Laryngoscope 105:801–808 1995

    • Search Google Scholar
    • Export Citation
  • 20.

    Ng MLinthicum FH: Morphology of the developing human endolymphatic sac. Laryngoscope 108:1901941998Ng M Linthicum FH: Morphology of the developing human endolymphatic sac. Laryngoscope 108:190–194 1998

    • Search Google Scholar
    • Export Citation
  • 21.

    Pallanch JFWeiland LHMcDonald TJFacer GWHarner SG: Adenocarcinoma and adenoma of the middle ear. Laryngoscope 92:47541982Pallanch JF Weiland LH McDonald TJ Facer GW Harner SG: Adenocarcinoma and adenoma of the middle ear. Laryngoscope 92:47–54 1982

    • Search Google Scholar
    • Export Citation
  • 22.

    Stein AASchilp AOWhitfield RD: The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:7517601960Stein AA Schilp AO Whitfield RD: The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:751–760 1960

    • Search Google Scholar
    • Export Citation
  • 23.

    Traweek STKandalaft PLMehta PBattifora H: The human hematopoietic progenitor cell antigen (CD34) in vascular neoplasia. Am J Clin Pathol 96:25311991Traweek ST Kandalaft PL Mehta P Battifora H: The human hematopoietic progenitor cell antigen (CD34) in vascular neoplasia. Am J Clin Pathol 96:25–31 1991

    • Search Google Scholar
    • Export Citation
  • 24.

    Treitel L: Ueber das carcinom des ohres. Z Ohrenheilkd 33:1521641898Treitel L: Ueber das carcinom des ohres. Z Ohrenheilkd 33:152–164 1898

    • Search Google Scholar
    • Export Citation
  • 25.

    Vortmeyer AOChoo DPack SDOldfield EZhuang Z: von Hippel-Lindau disease gene alterations associated with endolymphatic sac tumor. J Natl Cancer Inst 89:9709721997Vortmeyer AO Choo D Pack SD Oldfield E Zhuang Z: von Hippel-Lindau disease gene alterations associated with endolymphatic sac tumor. J Natl Cancer Inst 89:970–972 1997

    • Search Google Scholar
    • Export Citation
  • 26.

    Vortmeyer AOFrank SJeong SYYuan KIkejiri BLee YSet al: Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 63:705170552003Vortmeyer AO Frank S Jeong SY Yuan K Ikejiri B Lee YS et al: Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 63:7051–7055 2003

    • Search Google Scholar
    • Export Citation
  • 27.

    Vortmeyer AOYuan QLee YSZhuang ZOldfield EH: Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol 55:7217282004Vortmeyer AO Yuan Q Lee YS Zhuang Z Oldfield EH: Developmental effects of von Hippel-Lindau gene deficiency. Ann Neurol 55:721–728 2004

    • Search Google Scholar
    • Export Citation
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