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

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.

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.

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