RESUMO
Von Hippel-Lindau (VHL) disease is characterized by multiple tumors in specific target organs. The tumors at different sites share distinct morphologic and genetic characteristics but their cell of origin is unknown. We show that VHL disease-associated renal clear cell carcinomas (RCC) consistently coexpress erythropoietin (Epo) and Epo receptor (EpoR). In addition, coexpression of Epo and EpoR is detected in many renal cysts, providing further evidence that renal cysts are potential precursors for RCC. In conjunction with VHL gene deficiency, coexpression of Epo and EpoR in renal cysts and tumors may reflect a developmental arrest in immature mesenchymal cells. Such arrest may lead to autocrine stimulation, cell proliferation, and renal tumor development, similar to tumorigenesis of VHL disease-associated hemangioblastomas.
Assuntos
Carcinoma de Células Renais/patologia , Eritropoetina/genética , Doenças Renais Císticas/patologia , Neoplasias Renais/patologia , Receptores da Eritropoetina/genética , Doença de von Hippel-Lindau/complicações , Western Blotting , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/metabolismo , Eritropoetina/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Doenças Renais Císticas/genética , Doenças Renais Císticas/metabolismo , Neoplasias Renais/genética , Masculino , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Receptores da Eritropoetina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
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.
Assuntos
Neoplasias das Glândulas Suprarrenais/genética , Eritropoetina/genética , Neoplasia Endócrina Múltipla Tipo 2a/genética , Neoplasia Endócrina Múltipla Tipo 2b/genética , Feocromocitoma/genética , Receptores da Eritropoetina/genética , Doença de von Hippel-Lindau/genética , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Western Blotting , Primers do DNA , Eritropoetina/análise , Humanos , Imuno-Histoquímica , Neoplasia Endócrina Múltipla Tipo 2a/patologia , Neoplasia Endócrina Múltipla Tipo 2a/cirurgia , Neoplasia Endócrina Múltipla Tipo 2b/patologia , Neoplasia Endócrina Múltipla Tipo 2b/cirurgia , Feocromocitoma/patologia , Feocromocitoma/cirurgia , RNA Mensageiro/genética , Receptores da Eritropoetina/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Doença de von Hippel-Lindau/patologiaRESUMO
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.