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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1899
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3747-3751
Copyright © 2005 by The Endocrine Society

Differential Expression of Erythropoietin and Its Receptor in von Hippel-Lindau-Associated and Multiple Endocrine Neoplasia Type 2-Associated Pheochromocytomas

Timothy W. A. Vogel, Frederieke M. Brouwers, Irina A. Lubensky, Alexander O. Vortmeyer, Robert J. Weil, McClellan M. Walther, Edward H. Oldfield, W. Marston Linehan, Karel Pacak and Zhengping Zhuang

Surgical Neurology Branch (T.W.A.V., I.A.L., A.O.V., R.J.W., E.H.O., Z.Z.), National Institute of Neurological Disorders and Stroke, Pediatric and Reproductive Endocrinology Branch (F.M.B., K.P.), National Institute of Child Health and Human Development, and Urologic Oncology Branch (M.M.W., W.M.L.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints 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 20892-1414. E-mail: zhuangp{at}ninds.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PHEOCHROMOCYTOMA IS A neuroendocrine tumor of the chromaffin cells in the adrenal medulla (1, 2). Advances in molecular genetics have illustrated an association between pheochromocytomas and various genetic diseases: multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL), neurofibromatosis type 1, hereditary paraganglioma, and succinate dehydrogenase (SDH) gene-related tumors (3, 4, 5, 6, 7). The genes implicated in the pathogenesis of inherited pheochromocytomas vary from the VHL tumor suppressor gene, to the RET protooncogene in MEN 2, to subunits (SDHB and SDHD) of the SDH mitochondrial gene mutated in SDH (5, 6, 8). In addition to genetic differences, biochemical and clinical phenotypic differences between the pheochromocytomas associated with the various genetic disorders were recently identified (1, 2, 8, 9). It is currently estimated that 24% of pheochromocytomas are associated with germline mutations (10).

Two genetic disorders in which distinct forms of pheochromocytomas have been identified, on both clinical and biochemical grounds, are those found in patients with VHL disease and MEN 2 syndrome. In work by Eisenhofer et al. (11), VHL patients with pheochromocytomas had elevated plasma normetanephrine, whereas MEN 2 patients had predominantly elevated levels of metanephrine (1). VHL-associated pheochromocytomas have decreased levels of phenylethanolamine N-methyltransferase, an enzyme required for the conversion of norepinephrine to epinephrine, and lower levels of tyrosine hydroxylase, the rate-limiting enzyme involved in catecholamine biosynthesis (11). Lower levels of these enzymes correlated with clinical presentation: patients with VHL-associated tumors had lower levels of secreted catecholamines and tended to be less symptomatic than patients with MEN 2-associated tumors, who had higher levels of secreted catecholamines (11). Although these genetic and biochemical differences between VHL- and MEN 2-associated pheochromocytomas have been established, the process of tumorigenesis remains to be elucidated.

Recent work with other VHL-associated tumors, including hemangioblastomas, (12, 13), renal cell carcinomas (14), and endolymphatic sac tumors (15), implicates coexpression of erythropoietin (Epo) and its receptor (Epo-R) in the genesis of a variety of the tumors found in patients with VHL disease. Because VHL-associated pheochromocytomas share the same genetic origin as these other VHL-associated tumors, we investigated coexpression of Epo and Epo-R and tumor morphology in VHL-associated pheochromocytomas and MEN 2-associated pheochromocytomas to determine whether expression of these proteins is shared. Comparison of the expression patterns of these protein markers may help to understand similarities or differences in pathways employed in the genesis of VHL- and MEN 2-associated pheochromocytomas.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tumor specimens

Ten pheochromocytoma samples were taken from patient specimens removed during surgery, promptly preserved in Tissue Tek OCT compound (Sakura, Tokyo, Japan), and frozen at –80 C until use. Five patients had VHL germ-line mutations and 5 had RET germ-line mutations. Specimens were procured with informed patient consent according to a National Institutes of Health Institutional Review Board protocol.

Microscopic evaluation and immunohistochemistry

Serial sections were taken from the 10 frozen tumors for morphologic analysis with hematoxylin and eosin (H&E) and for immunohistochemistry staining. Frozen tissue sections were fixed in 80% ethanol. Sections were placed at room temperature and washed three times in 1x PBS (pH 7.4). Frozen sections were quenched for 20 min in a solution of 2% H2O2 in methanol. After three washes in PBS, sections were incubated in 10% horse serum for 1 h. Primary antibody was diluted in 2% horse serum, and the sections were incubated in a humidified chamber at 4 C (277 K) overnight. Primary antibodies included antihuman CD34 (dilution, 1:200), rabbit polyclonal antihuman Epo (1:100, Oncogene, Cambridge, MA), and sheep polyclonal antihuman Epo-R (1:200, Calbiochem, San Diego, CA). The sections were then incubated with secondary antibody and avidin-biotin-complex for 1 h each. Diaminobenzidine was left on the sections for times from 20 sec to 1 min. The tissue reaction with diaminobenzidine was stopped by dipping sections in tap water. A 30-sec counterstaining with Gill’s hematoxylin followed. The sections were then dehydrated by graded ethanol washes of 95 and 100% and rinsed in xylene before mounting. The presence and intensity of antibody expression were examined in conjunction with the H&E sections. H&E staining added two immersions in eosin before hematoxylin staining.

Total RNA isolation and Epo/Epo-R RT-PCR

Tumors were sectioned at 12 µm and microdissected under a light microscope to obtain a relatively pure population of tumor cells. Total RNA was extracted using TRIZOL reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. First-strand cDNA from total RNA was synthesized as follows. To avoid amplification of possible contaminating genomic DNA, total RNA was treated with Rnase-free DNase I 0.2 U, total volume 10 µl (Invitrogen) at room temperature for 15 min, denatured at 65 C (338 K) for 10 min, and subsequently reverse transcribed by SuperScript II (Invitrogen) with 20 µg (0.5 µg) of oligo (dT) primer in a volume of 20 µl. The PCR amplification was performed using the following cycling parameters: initial denaturing at 95 C (368 K) for 1 min, 15 sec at 95 C (368 K), 30 sec at 68 C (341 K) for 35 cycles. The reaction mixture contained 2 µl of the cDNA template, 1.0 U of Advantage-2 DNA polymerase (Clontech, Palo Alto, CA), 1x PCR buffer, 200 µM of each deoxynucleotide triphosphate, and 200 nM of each primer. The sequences of oligonucleotides used for RT-PCR were: Epo, forward, 5'-TCTATGCCTGGAAGAGGATGGAGGTCG-3' and reverse, 5'-TGCGGAAAGTGTCAGCAGTGATTGTTC-3'; for Epo-R, forward, 5'- CACAAGGGTAACTTCCAGCTGTGGCTGTA-3' and reverse, 5'-CATT- TGTCCAGCACCAGATAGGTATCCTGG-3'.

PCR products were separated in 2.0% agarose gel and stained with ethidium bromide.

Western blotting

For Western blotting, 20 µl of cell lysate in NuPAGE sample buffer (Invitrogen) were separated by electrophoresis on 4–12% gradient Bis-Tris gels (Invitrogen). Proteins were electrotransferred onto 0.2-µm pore size polyvinyl difluoride membranes (Invitrogen). Blots were blocked in PBS/0.05% Tween 20 containing 5% powdered milk and incubated with anti-Epo (1:100) and anti-Epo-R (1:100) antibodies, respectively. Antibody binding was detected with horseradish peroxidase-conjugated secondary antibodies (Amersham, Arlington Heights, IL). Super signal chemiluminescence reagent (Pierce, Rockford, IL) was used for visualization with 2-min exposure of scientific film (Eastman Kodak, Rochester, NY).


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Tumor morphology in VHL-associated pheochromocytomas revealed a uniform collection of clear cells intermixed with numerous small vessels (Fig. 1AGo), similar to the histopathological findings in other VHL-associated tumors, such as renal cell carcinoma (16) and hemangioblastoma (12, 13) (Fig. 1CGo). In particular, the intense vascular pattern found in many VHL-associated pheochromocytomas (8) is consistent with other VHL-associated tumors (Fig. 1DGo). In contrast, MEN 2 pheochromocytomas (8) consist of large polygonal cells, intracytoplasmic granules, irregular nuclei, a thin tumor capsule, and isolated vessels localized to the stroma between the groups of tumor cells (Fig. 1BGo).



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  		FIG. 1. Morphologic comparison of VHL- and MEN2-associated pheochromocytomas and VHL-associated renal cell carcinoma. A, VHL-associated pheochromocytoma is composed of clear and amphophilic tumor cells intermixed with numerous small vessels (H&E, x400). B, MEN 2-associated pheochromocytoma is composed of polygonal cells with eosinophilic granular cytoplasm and hyaline globules; small vessels are located in the stromal septae between nests of tumor cells (H&E, x400). C, VHL-associated renal cell carcinoma is histologically similar to pheochromocytoma and is composed of clear cells intermixed with numerous small vessels (H&E, x400). D, The intense vascular pattern in VHL tumors is highlighted with CD34 immunohistochemistry stain (CD34, x400, renal cell carcinoma).

 
Immunohistochemical analysis of the five VHL-associated pheochromocytomas revealed consistent and strong coexpression of Epo and Epo-R (Fig. 2Go, A and C), whereas the five MEN 2-associated pheochromocytomas expressed Epo-R (Fig. 2DGo) but not Epo (Fig. 2BGo). To further examine Epo or Epo-R expression, RT-PCR and Western blot analysis was performed on the 10 tumor samples. The VHL-associated pheochromocytomas coexpressed Epo and Epo-R, whereas the MEN 2-associated pheochromocytomas expressed only Epo-R (Fig. 3Go). Trace amounts of Epo expression were present in the MEN 2 tumors.



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  		FIG. 2. Immunohistochemical staining of the VHL- and MEN 2-associated pheochromocytomas. Positive cytoplasmic immunohistochemical staining for Epo (A) and Epo-R (C) is detected in VHL-associated pheochromocytomas. Only Epo-R (D), and not Epo (B), is found in MEN 2-associated pheochromocytomas.

 


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  		FIG. 3. Epo and Epo-R mRNA are both expressed in VHL-associated pheochromocytomas and other VHL tumors, but only Epo-R, and not Epo, is expressed in MEN 2-associated pheochromocytomas. Epo-R mRNA is expressed in VHL disease-associated cerebellar hemangioblastoma (lane 1) and renal cell carcinoma (lane 2) as well as VHL-associated pheochromocytomas (lanes 3–7) and MEN 2-associated pheochromocytomas (lanes 8–12) but not in normal kidney tissue from a patient with VHL disease (lane 13). Epo mRNA is expressed in VHL-associated pheochromocytomas, hemangioblastomas, and renal cell carcinomas as well as normal kidney tissue (lane 13) but not in MEN 2-associated pheochromocytomas (lanes 8–12).

 
Western blot analysis revealed coexpression of Epo and Epo-R in all of the VHL-associated pheochromocytomas but only Epo-R, and not Epo, expression in the MEN 2-associated pheochromocytomas (Fig. 4Go). VHL-associated hemangioblastomas and renal cell cancers, in which high level coexpression of Epo and Epo-R has been previously demonstrated (14, 15), were used as a positive control (Fig. 4Go); normal kidney tissue from a patient with VHL disease served as a negative control.



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  		FIG. 4. Western blot analysis for Epo and Epo-R protein. Epo is expressed in VHL-associated hemangioblastoma (lane 1), renal cell cancer (lane 2), normal kidney (lane 13), and VHL-associated pheochromocytomas (lanes 3–7) as a 37 (kDa) protein. Epo expression is absent in MEN 2-associated pheochromocytomas (lanes 8–12). Epo-R (49 kDa) expression is detected in the VHL-associated hemangioblastoma and renal cell carcinoma and VHL- and MEN 2-associated pheochromocytomas but not in normal kidney tissue from a patient with VHL disease. ß-Actin expression was used a control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
VHL- and MEN 2-associated pheochromocytomas are genetically distinct tumors (4, 7, 8). In many cases, recent evidence has further differentiated these tumors based on morphological (8) and biochemical properties (1, 11). For example, tyrosine hydroxylase and phenylethanolamine N-methyltransferase are differentially expressed in VHL- and MEN 2-associated pheochromocytomas, with lower levels of both enzymes in the former. Work by Eisenhofer et al. (1) suggests that differing enzyme levels are responsible for the different secretion patterns of catecholamines found in these patients. Catecholamine levels can be used to diagnose and distinguish these tumors and correlate well with patient signs and symptoms. These biochemical differences between VHL- and MEN-2-associated pheochromocytomas may help illustrate the mechanisms that lead to tumor formation. In this study, VHL-associated pheochromocytomas have been shown to coexpress Epo and Epo-R, whereas MEN 2-associated pheochromocytomas express only Epo-R.

Coexpression of Epo and Epo-R in pheochromocytomas has been consistently present in all five VHL patients with both VHL type 2B and 2A mutations. Recently coexpression of Epo and Epo-R has been documented in other VHL- associated tumors (12, 13, 14, 15). The finding of Epo and Epo-R coexpression in VHL-associated pheochromocytomas, coupled with the distinctive and similar tumor morphology among different VHL-associated tumors, suggests that VHL-associated pheochromocytomas share properties with other VHL-associated tumors and that the process of tumorigenesis among these tumor types may be similar.

As previously presented, these observations suggest the possibility of a common cell of origin in VHL-associated tumors (12, 13, 14, 15). Furthermore, coexpression of Epo and Epo-R suggests a developmental origin of VHL-associated hemangioblastomas, renal cell carcinomas, and endolymphatic sac tumors. Expression of Epo is secondary to VHL gene deficiency (17, 18), whereas Epo-R expression normally occurs in development as part of a response to hypoxia (12, 13). During normal development, Epo-R expression in cells is transient; however, sustained expression of Epo-R may serve as a marker for delayed differentiation. With inactivation of VHL protein in cells of a patient with VHL disease, however, Epo and Epo-R coexpression persists in tumor precursor cells (12, 13). Retention of Epo and Epo-R coexpression may lead to cell proliferation via autocrine stimulation, which appears to be an essential step in tumorigenesis. Furthermore, it has been postulated that one way heightened expression of Epo and Epo-R may enhance cell proliferation and cell survival is through inhibition of apoptosis by up-regulation of the bcl-2 and bcl-xL pathways (19, 20, 21, 22, 23).

Coexpression of Epo and Epo-R as a process of tumorigenesis in VHL-associated pheochromocytomas is further supported by the development of the adrenal gland. The neural crest is a group of pluripotent cells that develop from embryonic progenitors during the process of neurulation (24). In response to the appropriate signaling mechanisms, these cells migrate to the developing adrenal gland to interact with mesenchymal cells (25). Other VHL-associated tumors, including hemangioblastomas, renal cell carcinomas, and endolymphatic sac tumors, appear to be derived from interactions with mesenchymal cells during development (12, 13, 14, 15, 26, 27). Interactions between the pluripotent adrenal mesenchyme and neural crest cells resemble the interactions seen in the formative stages of these other VHL-associated tumors. Thus, coexpression of Epo and Epo-R in VHL-associated pheochromocytomas suggests that interaction between adrenal mesenchyme and neural crest cells may delay neural crest differentiation. The arrested development may then lead to tumorigenesis. Whether VHL-associated pheochromocytomas originate from the pluripotent neural crest or derive from an angiomesenchymal precursor is unclear.

Exclusive expression of Epo-R, but not Epo, is found in MEN 2-associated pheochromocytomas. Epo-R expression in MEN 2-associated pheochromocytomas is consistent with previous reports of Epo-R expression in cells of neural crest origin (28). It has been also shown that adrenal chromaffin cells lose their neuronal traits as they differentiate during embryogenesis (29) and could, therefore, lose their expression of Epo-R. Expression of the RET protooncogene, however, has been shown to impair terminal differentiation in neuroepithelial cells (30). Our finding of persistent expression of Epo-R further suggests an arrest in differentiation in MEN 2-associated pheochromocytomas and is compatible with RET protooncogene inhibition of terminal differentiation as a pathogenic mechanism responsible for MEN 2 tumorigenesis (30). Lack of Epo expression in MEN 2-associated pheochromocytomas is also compatible with this process of tumorigenesis because overexpression or mutation of the RET protooncogene was not shown to be associated with Epo activation.

MEN 2-associated pheochromocytomas may, therefore, derive from a different cell than VHL-associated pheochromocytomas. In VHL-associated pheochromocytomas, Epo-R expression occurs as a response to hypoxia and may serve as a marker for delayed differentiation. Coexpression of Epo may complement or promote this developmental arrest. Similarly, expression of Epo-R may be a marker for delayed neural crest differentiation secondary to RET protooncogene activation. However, because Epo is not expressed in these tumors, the autocrine loop with Epo-R remains quiescent; thus, alternative mechanisms due to RET protooncogene pathway activation, or others, predominate in tumorigenesis. On the other hand, VHL-associated pheochromocytomas may originate from mesenchyme, as appears to be the case with other VHL-associated tumors, and may be the result of sustained coexpression of Epo and Epo-R, which may activate or potentiate signaling mechanisms, including the hypoxia inducible factor-1 hypoxia pathway, thereby initiating tumorigenesis (12, 13, 22). Furthermore, differential expression of Epo may represent a potential clinical biomarker by which VHL-associated pheochromocytomas can be differentiated from MEN 2-associated pheochromocytomas. Finally, these results suggest that manipulation of Epo expression and/or function may be an alternative molecular target for the treatment of VHL-associated pheochromocytomas. Additional studies to evaluate these findings are in progress.


   Footnotes
 
First Published Online March 15, 2005

Abbreviations: Epo, Erythropoietin; Epo-R, erythropoietin receptor; H&E, hematoxylin and eosin; MEN 2, multiple endocrine neoplasia type 2; SDH, succinate dehydrogenase; VHL, von Hippel-Lindau disease.

Received September 24, 2004.

Accepted March 3, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Eisenhofer G, Lenders JW, Linehan WM, Walther MM, Goldstein DS, Keiser HR 1999 Plasma normetanephrine and metanephrine for detecting pheochromocytoma in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. N Engl J Med 340:1872–1879[Abstract/Free Full Text]
  2. Pacak K, Linehan WM, Eisenhofer G, Walther MM, Goldstein DS 2001 Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134:315–329[Abstract/Free Full Text]
  3. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng Y, Duan DR, Glavic D, Richards FM, Crossey PA, Ferguson-Smith MA, Palier DL, Chumkov I, Cohen D, Chinault C, Maher ER, Linehan WM, Zbar B, Lerman MI 1993 Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260:1317–1320[Abstract/Free Full Text]
  4. Koch CA, Vortmeyer AO, Huang SC, Alesci S, Zhuang Z, Pacak K 2001 Genetic aspects of pheochromocytoma. Endocr Regul 35:43–52[Medline]
  5. Bryant J, Farmer J, Kessler LJ, Townsend RR, Nathanson KL 2003 Pheochromocytoma: the expanding genetic differential diagnosis. J Natl Cancer Inst 95:1196–1204[Abstract/Free Full Text]
  6. Ichihara M, Murakumo Y, Takahashi M 2004 RET and neuroendocrine tumors. Cancer Lett 204:197–211[CrossRef][Medline]
  7. Koch CA, Vortmeyer AO, Zhuang Z, Brouwers FM, Pacak K 2002 New insights into the genetics of familial chromaffin cell tumors. Ann NY Acad Sci 970:11–28[Abstract/Free Full Text]
  8. Koch CA, Mauro D, Walther MM, Linehan WM, Vortmeyer AO, Jaffe R, Pacak K, Chrousos GP, Zhuang Z, Lubensky IA 2002 Pheochromocytoma in von Hippel-Lindau disease: distinct histopathologic phenotype compared with pheochromocytoma in multiple endocrine neoplasia type 2. Endocr Pathol 13:17–27[CrossRef][Medline]
  9. Walther MM, Reiter R, Keiser HR, Choyke PL, Venzon D, Hurley K, Gnarra JR, Reynolds JC, Glenn GM, Zbar B, Linehan WM, Eisenhofer G, Lenders JW, Goldstein DS 1999 Clinical and genetic characterization of pheochromocytoma in von Hippel-Lindau families: comparison with sporadic pheochromocytoma gives insight into natural history of pheochromocytoma. J Urol 162:659–664[CrossRef][Medline]
  10. Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C 2002 Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346:1459–1466[Abstract/Free Full Text]
  11. Eisenhofer G, Walther MM, Huynh TT, Li ST, Bornstein SR, Vortmeyer A, Mannelli M, Goldstein DS, Linehan WM, Lenders JW, Pacak K 2001 Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. J Clin Endocrinol Metab 86:1999–2008[Abstract/Free Full Text]
  12. Vortemeyer AO, Yuan K., Lee Y.S., Zhuang Z., Oldfield E.H 2004 Developmental effects of von-Hippel-Lindau gene deficiency in the human central nervous system. Ann Neurol 55:721–728[CrossRef][Medline]
  13. Vortmeyer AO, Frank S, Jeong SY, Yuan K, Ikejiri B, Lee YS, Bhowmick D, Lonser RR, Smith R, Rodgers G, Oldfield EH, Zhuang Z 2003 Developmental arrest of angioblastic lineage initiates tumorigenesis in von Hippel-Lindau disease. Cancer Res 63:7051–7055[Abstract/Free Full Text]
  14. Lee Y-S, Vortmeyer AO, Lubensky IA, Vogel T, Ikejiri B, Ferlicot S, Benoît G, Giraud S, Oldfield EH, Linehan WM, The BT, Richard S, Zhuang Z. 2005 Coexpression of erythropoietin and erythropoietin receptor in von Hippel-Lindau disease-associated renal cell carcinoma. Clin Cancer Res 11:1059–1064[Abstract/Free Full Text]
  15. Vogel T, Vortmeyer AO, Lubensky IA, Lee Y-S, Furuta M, Ikejiri B, Kim HJ, Lonser RR, Oldfield EH, Zhuang Z, 2005 Co-expression of erythropoietin and its receptor in endolymphatic sac tumors. J Neurosurg, in press
  16. Lubensky IA, Gnarra JR, Bertheau P, Walther MM, Linehan WM, Zhuang Z 1996 Allelic deletions of the VHL gene detected in multiple microscopic clear cell renal lesions in von Hippel-Lindau disease patients. Am J Pathol 149:2089–2094[Abstract]
  17. Kaelin Jr WG 2002 Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2:673–682[CrossRef][Medline]
  18. Maxwell PH, Pugh CW, Ratcliffe PJ 2001 The pVHL-hIF-1 system. A key mediator of oxygen homeostasis. Adv Exp Med Biol 502:365–376[Medline]
  19. Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A, Onozaki M, Hashimoto M, Musha T, Ogawa K, Fujita H, Nakamura Y, Shiozaki H, Utsumi H 2003 Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis 24:1021–1029[Abstract/Free Full Text]
  20. Dolznig H, Habermann B, Stangl K, Deiner EM, Moriggl R, Beug H, Mullner EW 2002 Apoptosis protection by the Epo target Bcl-X(L) allows factor-independent differentiation of primary erythroblasts. Curr Biol 12:1076–1085[CrossRef][Medline]
  21. Silva M, Grillot D, Benito A, Richard C, Nunez G, Fernandez-Luna JL 1996 Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2. Blood 88:1576–1582[Abstract/Free Full Text]
  22. Acs G, Acs P, Beckwith SM, Pitts RL, Clements E, Wong K, Verma A 2001 Erythropoietin and erythropoietin receptor expression in human cancer. Cancer Res 61:3561–3565[Abstract/Free Full Text]
  23. Silva M, Benito A, Sanz C, Prosper F, Ekhterae D, Nunez G, Fernandez-Luna JL 1999 Erythropoietin can induce the expression of bcl-x(L) through Stat5 in erythropoietin-dependent progenitor cell lines. J Biol Chem 274:22165–22169[Abstract/Free Full Text]
  24. Tischler AS 2002 Chromaffin cells as models of endocrine cells and neurons. Ann NY Acad Sci 971:366–370[Abstract/Free Full Text]
  25. Kalcheim C, Langley K, Unsicker K 2002 From the neural crest to chromaffin cells: introduction to a session on chromaffin cell development. Ann NY Acad Sci 971:544–546[Abstract/Free Full Text]
  26. Stein AA, Schilp AO, Whitfield RD 1960 The histogenesis of hemangioblastoma of the brain. A review of twenty-one cases. J Neurosurg 17:751–761[Medline]
  27. Lindau A 1931 Discussion on vascular tumors of the brain and spinal cord. Proc R Soc Med 24:363–370
  28. Masuda S, Nagao M, Takahata K, Konishi Y, Gallyas Jr F, Tabira T, Sasaki R 1993 Functional erythropoietin receptor of the cells with neural characteristics. Comparison with receptor properties of erythroid cells. J Biol Chem 268:11208–11216[Abstract/Free Full Text]
  29. Vogel KS, Weston JA 1990 The sympathoadrenal lineage in avian embryos. I. Adrenal chromaffin cells lose neuronal traits during embryogenesis. Dev Biol 139:1–12[CrossRef][Medline]
  30. Califano D, D’Alessio A, Colucci-D’Amato GL, De Vita G, Monaco C, Santelli G, Di Fiore PP, Vecchio G, Fusco A, Santoro M, de Franciscis V 1996 A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells. Proc Natl Acad Sci USA 93:7933–7937[Abstract/Free Full Text]



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Risk-Oriented Approach to Hereditary Adrenal Pheochromocytoma.
Ann. N.Y. Acad. Sci., August 1, 2006; 1073: 417 - 428.
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