title: Differential expression of erythropoietin and its receptor in von hippel-lindau-associated and multiple endocrine neoplasia type 2-associated pheochromocytomas.
abstract: Pheochromocytoma is a neuroendocrine tumor associated with a variety of genetic disorders, which include von Hippel-Lindau disease (VHL), multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase gene-related tumors. Previous studies of VHL-associated and MEN 2-associated pheochromocytomas suggest morphological, biochemical, and clinical differences exist among the tumors, but the process by which they develop remains unclear. Studies in other VHL-associated tumors suggest that VHL gene deficiency causes coexpression of erythropoietin (Epo) and its receptor (Epo-R), which facilitates tumor growth. The objective of this study was to understand the different process of tumorigenesis for VHL and MEN 2-associated pheochromocytomas. Ten pheochromocytomas (VHL patients n = 5, MEN 2 patients n = 5) were examined for the presence or absence of Epo and Epo-R using Western blot, immunohistochemistry, and RT-PCR analyses. Coexpression of Epo and Epo-R was found in all five VHL-associated pheochromocytomas; in contrast, expression of Epo-R, but not Epo, was documented in all five MEN 2-associated pheochromocytomas. Expression of Epo appears to be a result of VHL gene deficiency, possibly through activation of the hypoxia inducible factor-1 pathway, whereas Epo-R is an embryonal marker whose sustained expression in both VHL- and MEN 2-associated pheochromocytomas reflects an arrest or defect in development. These findings suggest an alternative process of tumorigenesis in VHL- and MEN 2-associated pheochromocytomas and implicate Epo as a clinical biomarker to differentiate these tumors.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5D-37, Bethesda, Maryland 20892-1414, USA.
authors.forename: Timothy W A
authors.initials: TW
authors.lastname: Vogel
authors.forename: Frederieke M
authors.initials: FM
authors.lastname: Brouwers
authors.forename: Irina A
authors.initials: IA
authors.lastname: Lubensky
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Vortmeyer
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Weil
authors.forename: McClellan M
authors.initials: MM
authors.lastname: Walther
authors.forename: Edward H
authors.initials: EH
authors.lastname: Oldfield
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D015153:Blotting, Western; D017931:DNA Primers; D004921:Erythropoietin / Q000032:analysis / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010673:Pheochromocytoma / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D012333:RNA, Messenger / Q000235:genetics; D017467:Receptors, Erythropoietin / Q000032:analysis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006623:von Hippel-Lindau Disease / Q000235:genetics* / Q000473:pathology
chemical_list: D017931:DNA Primers; D012333:RNA, Messenger; D017467:Receptors, Erythropoietin; D004921:Erythropoietin