losartan-potassium and von-Hippel-Lindau-Disease

Intracellular proteins continuously turn over by degradation and synthesis in all organ tissues. Owing to its irreversible nature, protein degradation is a highly selective process to avoid irreparable breakdown of cellular constituents, thereby disrupting cellular stability, integrity and signalling. The majority of intracellular proteins are degraded by the ubiquitin-proteasome system (UPS), a multi-enzyme process that involves the covalent conjugation of ubiquitin to a substrate protein and its recognition and degradation by the core multicomponent proteolytic complex of the UPS, the proteasome. In addition to labelling misfolded, damaged, aggregation-prone and intact but unneeded proteins for proteasomal degradation, ubiquitylation regulates a multitude of cellular processes, such as transcription, translation, endocytosis, and receptor activity and subcellular localization. In addition, the proteasome generates peptides for antigen presentation in the immune system and for further degradation by peptidases to provide amino acids for protein biosynthesis and gluconeogenesis. Alterations of the UPS or of protein substrates that render them more or less susceptible to degradation are responsible for disorders associated with renal cell dysfunction. In this Review, we provide insight into the elegant and complex nature of UPS-mediated proteostasis and focus on its established and potential roles in renal cell physiology and pathophysiology.

Topics: Autophagy; Biological Transport; Erythropoietin; Glucose; Homeostasis; Humans; Kidney; Kidney Diseases; Lysosomes; Muscular Atrophy; Podocytes; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Sodium; Ubiquitinated Proteins; Ubiquitination; von Hippel-Lindau Disease; Water-Electrolyte Balance

Regulation of the growth and metabolism of large organisms is tightly constrained by the need for precise oxygen homeostasis. Work on control of the haematopoietic growth factor erythropoietin has led to the recognition of a widespread transcriptional response to hypoxia which provides insights into how this is achieved. The central mediator of this response is a DNA binding complex termed hypoxia inducible factor 1 (HIF-1), which plays a key role in the regulation by oxygen of a large and rapidly growing panel of genes. In cancer, activity of the HIF system is up-regulated both by microenvironmental hypoxia and by genetic changes. The clearest example of genetic activation is seen in the hereditary cancer syndrome von Hippel-Lindau (VHL) disease. In normal cells the product of the VHL tumour suppressor gene targets the regulatory HIF subunits (HIF-1alpha and HIF-2alpha) for oxygen-dependent proteolysis, acting as the substrate recognition component of an E3 ubiquitin ligase. In pVHL defective cells this process is blocked leading to constitutive up-regulation of HIF-1alpha subunits, activation of the HIF complex and overexpression of HIF target genes. Using gene array screens we have defined a large number of VHL-regulated genes. The majority of these show hypoxia-inducible responses, supporting the central involvement of pVHL in gene regulation by oxygen. In addition to known HIF target genes involved in angiogenesis, glucose metabolism and vasomotor control, these new targets include examples with functions in matrix metabolism, apoptosis, carbon dioxide metabolism and secondary cascades of transcriptional control. Thus activation of HIF provides insights into the classical metabolic alterations in cancer cells, and into the mechanisms by which microenvironmental hypoxia might influence tumour behaviour. In the case of VHL disease, this activation can be linked to mutations in a defined tumour suppressor gene. Equally regulation of the HIF-1alpha/pVHL interaction in normal cells should provide insights into the physiological mechanisms operating in cellular oxygen sensing.

Topics: Basic Helix-Loop-Helix Transcription Factors; Cell Hypoxia; DNA-Binding Proteins; Erythropoietin; Extracellular Space; Gene Expression Regulation, Neoplastic; Helix-Loop-Helix Motifs; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Neoplasms; Nuclear Proteins; Trans-Activators; Transcription Factors; von Hippel-Lindau Disease

von Hippel-Lindau (VHL) patients develop multiple central nervous system hemangioblastomas (HB). Some HBs become symptomatic with exponential growth or cyst formation following long periods of quiescence. Understanding the factors underlying growth in hemangioblastoma may lead to better strategies to arrest or prevent tumor growth. In 5 VHL patients, we resected quiescent hemangioblastomas (Q-HB) that were en-route during surgical access to symptomatic hemangioblastomas (S-HB), for matched tumor analysis. Quantitative reverse transcriptase analysis demonstrated a 2-fold increase in EPO expression in all S-HB, while 4/5 showed either Hypoxia Inducible Factor-1α or 2α upregulation. Additionally, all S-HB had increased phosphorylated erythropoietin (EPO) receptor and phosphorylated STAT-5 relative to matched Q-HB, with increased phosphorylated JAK-2 largely confined to the stromal cells in clusters within the tumors. These findings suggest that Q-HB to S-HB conversion may be associated with an erythropoietin-signaling loop. Furthermore, we found that EPO is detectable in cyst fluid from S-HB (n = 14), while absent in CSF (n = 1). Additionally, S-HB presentation or S-HB resection does not result in discernible change in serum EPO or hemoglobin (n = 60). These observations suggest that the altered erythropoietin signaling is focal and suggests that studying modulation of erythropoietin receptor pathway may lead to strategies in preventing HB growth.

Topics: Adult; Biomarkers; Erythropoietin; Female; Hemangioblastoma; Humans; Male; Middle Aged; Radiography; Severity of Illness Index; Signal Transduction; von Hippel-Lindau Disease

On the basis of previous observations that deletion of the von Hippel-Lindau protein (pVHL) in juxtaglomerular (JG) cells of the kidney suppresses renin and induces erythropoietin expression, this study aimed to characterize the events underlying this striking change of hormone expression. We found that renin cell-specific deletion of pVHL in mice leads to a phenotype switch in JG cells, from a cuboid and multiple vesicle-containing form into a flat and elongated form without vesicles. This shift of cell phenotype was accompanied by the disappearance of marker proteins for renin cells (e.g., aldo-keto reductase family 1, member 7 and connexin 40) and by the appearance of markers of fibroblast-like cells (e.g., collagen I, ecto-5'-nucleotidase, and PDGF receptor-β). Furthermore, hypoxia-inducible transcription factor-2α (HIF-2α) protein constitutively accumulated in these transformed cells. Codeletion of pVHL and HIF-2α in JG cells completely prevented the phenotypic changes. Similar to renin expression in normal JG cells, angiotensin II negatively regulated erythropoietin expression in the transformed cells. In summary, chronic activation of HIF-2 in renal JG cells leads to a reprogramming of the cells into fibroblast-like cells resembling native erythropoietin-producing cells located in the tubulointerstitium.

Topics: 5'-Nucleotidase; Animals; Basic Helix-Loop-Helix Transcription Factors; Biomarkers; Collagen Type I; Erythropoietin; Fibroblasts; Juxtaglomerular Apparatus; Male; Mice; Mice, Knockout; Receptor, Platelet-Derived Growth Factor beta; Renin; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

Topics: Adrenal Gland Neoplasms; Adult; Anticoagulants; Aspirin; Biomarkers; Biopsy; DNA Mutational Analysis; Erythropoietin; Genetic Predisposition to Disease; Humans; In Situ Hybridization, Fluorescence; Male; Mutation; Pedigree; Phenotype; Pheochromocytoma; Phlebotomy; Polycythemia; Treatment Outcome; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

To report the results of immunohistochemical analyses of a retinal angioma obtained from a patient with von Hippel-Lindau (VHL) disease.. A 13-year-old girl with VHL disease presented with bilateral retinal angiomas and decreased vision in the right eye. Although transpupillary thermotherapy was performed to treat the angiomas, the tractional and exudative retinal detachment progressed OD, requiring vitreous surgery. Intraoperatively, a large retinal angioma was excised together with the surrounding retina to aid in reattaching the retina. The excised tissue was prepared for standard histopathology and immunohistochemistry.. Histological examination showed that the excised tissue was made up of highly vascularized cells, and the retina was gliotic. The stromal cells had intracytoplasmic vacuoles and were located between the numerous vessels. These findings are identical to those of a hemangioblastoma. The stromal cells stained positively for vascular endothelial growth factor and neuron specific enolase, and weakly for glial fibrillary acidic protein. Some of the stromal cells stained positively for inhibin alpha. Isolated erythropoietin-positive cells, indicative of developmentally arrested angioblasts, were observed among the endothelial cells.. The results indicate that stromal cells in retinal angiomas are neuroectodermal in origin with immunohistochemical features, for example, inhibin alpha, similar to cerebellar hemangioblastomas and renal cell carcinomas associated with VHL disease.

Topics: Adolescent; Erythropoietin; Female; Glial Fibrillary Acidic Protein; Hemangioma; Humans; Immunoenzyme Techniques; Inhibins; Phosphopyruvate Hydratase; Retinal Neoplasms; Stromal Cells; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease

Erythropoiesis is critically dependent on erythropoietin (EPO), a glycoprotein hormone that is regulated by hypoxia-inducible factor (HIF). Hepatocytes are the primary source of extrarenal EPO in the adult and express HIF-1 and HIF-2, whose roles in the hypoxic induction of EPO remain controversial. In order to define the role of HIF-1 and HIF-2 in the regulation of hepatic EPO expression, we have generated mice with conditional inactivation of Hif-1alpha and/or Hif-2alpha (Epas1) in hepatocytes. We have previously shown that inactivation of the von Hippel-Lindau tumor suppressor pVHL, which targets both HIFs for proteasomal degradation, results in increased hepatic Epo production and polycythemia independent of Hif-1alpha. Here we show that conditional inactivation of Hif-2alpha in pVHL-deficient mice suppressed hepatic Epo and the development of polycythemia. Furthermore, we found that physiological Epo expression in infant livers required Hif-2alpha but not Hif-1alpha and that the hypoxic induction of liver Epo in anemic adults was Hif-2alpha dependent. Since other Hif target genes such phosphoglycerate kinase 1 (Pgk) were Hif-1alpha dependent, we provide genetic evidence that HIF-1 and HIF-2 have distinct roles in the regulation of hypoxia-inducible genes and that EPO is preferentially regulated by HIF-2 in the liver.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Hepatocytes; Liver; Mice; Mice, Knockout; Polycythemia Vera; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

Congenital erythrocytoses or polycythemias are rare and heterogeneous. A homozygous mutation (C598T->Arg200Trp) in the von Hippel-Lindau (VHL) gene was originally identified as the cause of the endemic Chuvash polycythemia. Subsequently this and other mutations in the VHL gene were also detected in several patients of different ethnic origin. Haplotype analyses of the VHL gene suggested a common origin for the Chuvash-type mutation.. Thirty-four patients with presumable congenital erythrocytosis due to an unknown underlying disorder were examined for VHL gene mutations and VHL region haplotypes.. Four patients were homozygous and one patient heterozygous for the Chuvash-type mutation. One additional patient presented a previously not described heterozygous mutation G311->T VHL in exon 1. The haplotype analyses were in agreement with recently published data for three of the four patients with homozygous mutations as well as for the patient with a heterozygous Chuvash-type mutation. One patient of Turkish origin with homozygous Chuvash-type mutation had a haplotype not previously found in individuals with Chuvash-type mutation.. These results confirm that mutations in the VHL gene are responsible for a substantial proportion of patients with congenital erythrocytoses. Erythrocytoses due to a C598->T mutation of the VHL gene are not geographically restricted. The majority of patients with Chuvash polycythemia share a common VHL gene haplotype. The different haplotype in one of the patients with Chuvash-type mutation indicates that this mutation was not spread only from a single founder but developed independently in other individuals.

Topics: Adolescent; Adult; Alleles; Base Sequence; Child; Child, Preschool; Erythropoietin; Family Health; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Haplotypes; Humans; Middle Aged; Point Mutation; Polycythemia; Polymerase Chain Reaction; von Hippel-Lindau Disease

Topics: Chromosome Aberrations; Erythropoietin; Genes, Recessive; Genes, Tumor Suppressor; Humans; Point Mutation; Polycythemia; von Hippel-Lindau Disease

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.

Topics: Blotting, Western; Carcinoma, Renal Cell; Erythropoietin; Female; Gene Expression; Humans; Immunohistochemistry; Kidney Diseases, Cystic; Kidney Neoplasms; Male; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; von Hippel-Lindau Disease

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.

Topics: Adrenal Gland Neoplasms; Blotting, Western; DNA Primers; Erythropoietin; Humans; Immunohistochemistry; Multiple Endocrine Neoplasia Type 2a; Multiple Endocrine Neoplasia Type 2b; Pheochromocytoma; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; von Hippel-Lindau Disease

Patients with germ line mutations in the VHL tumor suppressor gene are predisposed to the development of highly vascularized tumors within multiple tissues. Loss of pVHL results in constitutive activation of the transcription factors HIF-1 and HIF-2, whose relative contributions to the pathogenesis of the VHL phenotype have yet to be defined. In order to examine the role of HIF in von Hippel-Lindau (VHL)-associated vascular tumorigenesis, we utilized Cre-loxP-mediated recombination to inactivate hypoxia-inducible factor-1alpha (Hif-1alpha) and arylhydrocarbon receptor nuclear translocator (Arnt) genes in a VHL mouse model of cavernous liver hemangiomas and polycythemia. Deletion of Hif-1alpha did not affect the development of vascular tumors and polycythemia, nor did it suppress the increased expression of vascular endothelial growth factor (Vegf) and erythropoietin (Epo). In contrast, phosphoglycerokinase (Pgk) expression was substantially decreased, providing evidence for target gene-dependent functional redundancy between different Hif transcription factors. Inactivation of Arnt completely suppressed the development of hemangiomas, polycythemia, and Hif-induced gene expression. Here, we demonstrate genetically that the development of VHL-associated vascular tumors in the liver depends on functional ARNT. Furthermore, we provide evidence that individual HIF transcription factors may play distinct roles in the development of specific VHL disease manifestations.

Topics: Animals; Aryl Hydrocarbon Receptor Nuclear Translocator; DNA-Binding Proteins; Erythropoietin; Gene Deletion; Gene Expression; Gene Silencing; Genes, Tumor Suppressor; Hemangioma, Cavernous; Hepatocytes; Hypoxia-Inducible Factor 1, alpha Subunit; Liver; Liver Neoplasms; Mice; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Polycythemia; Receptors, Aryl Hydrocarbon; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

To better understand the histogenesis of ocular hemangioblastomas associated with von Hippel-Lindau (VHL) disease.. We found that co-expression of Epo and EpoR may mediate developmental stagnation and induce proliferation of hemangioblastoma. All lesions were frozen and/or fixed in formalin and embedded in paraffin. The specimens were sectioned and subjected to routine histology, immunohistochemistry and molecular analyses. Avidin-biotin-complex immunoperoxidase was used to evaluate the expression of erythropoietin (Epo), Epo receptor (EpoR), CD31, CD34, CD117, and CD133. Ocular hemangioblastoma cells were microdissected in order to determine expression of Epo and EpoR transcripts using reverse transcription-polymerase chain reaction.. Tumorlet-like cells were identified in retinal and optic nerve hemangioblastomas. Co-expression of Epo and EpoR at both protein and messenger levels was detected in many hemangioblastoma cells. In addition, ocular VHL lesions expressed several stem cell markers including CD133 to various degrees.. The data suggest that VHL disease-associated ocular hemangioblastomas are comprised of developmentally arrested stem cells including hemangioblasts, endothelial, and neuronal progenitor cells. We found that co-expression of Epo and EpoR may not only mediate developmental stagnation, but may also induce proliferation. Suppression of the growth of AC133/CD133 positive stem cells might be considered as one of the therapeutic targets for VHL-associated hemangioblastoma.

Topics: Antigens, CD; Biomarkers, Tumor; Erythropoietin; Hemangioblastoma; Humans; Immunoenzyme Techniques; Neoplastic Stem Cells; Optic Nerve Neoplasms; Receptors, Erythropoietin; Retinal Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; von Hippel-Lindau Disease

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.. 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.. 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.

Topics: Adult; Ear Neoplasms; Endolymphatic Sac; Erythropoietin; Gene Expression Profiling; Germ-Line Mutation; Humans; Immunohistochemistry; Male; Receptors, Erythropoietin; Reverse Transcriptase Polymerase Chain Reaction; von Hippel-Lindau Disease

The nature of the cell responsible for von Hippel-Lindau (VHL) disease-associated tumor formation has been controversial for decades. We demonstrate that VHL disease-associated central nervous system tumors are composed of developmentally arrested angioblasts that coexpress erythropoietin (Epo) and Epo receptor. The angioblasts are capable of differentiating into RBCs via formation of blood islands with extramedullary hematopoiesis. Because of VHL deficiency, Epo receptor-expressing, developmentally arrested angioblasts simultaneously coexpress Epo, which may represent a crucial pathogenetic step in tumor formation.

Topics: Cerebellar Neoplasms; Erythropoietin; Hemangioblastoma; Hematopoiesis, Extramedullary; Humans; Immunohistochemistry; Receptors, Erythropoietin; von Hippel-Lindau Disease

Chuvash polycythemia is an autosomal recessive disorder that is endemic to the mid-Volga River region. We previously mapped the locus associated with Chuvash polycythemia to chromosome 3p25. The gene associated with von Hippel-Lindau syndrome, VHL, maps to this region, and homozygosity with respect to a C-->T missense mutation in VHL, causing an arginine-to-tryptophan change at amino-acid residue 200 (Arg200Trp), was identified in all individuals affected with Chuvash polycythemia. The protein VHL modulates the ubiquitination and subsequent destruction of hypoxia-inducible factor 1, subunit alpha (HIF1alpha). Our data indicate that the Arg200Trp substitution impairs the interaction of VHL with HIF1alpha, reducing the rate of degradation of HIF1alpha and resulting in increased expression of downstream target genes including EPO (encoding erythropoietin), SLC2A1 (also known as GLUT1, encoding solute carrier family 2 (facilitated glucose transporter), member 1), TF (encoding transferrin), TFRC (encoding transferrin receptor (p90, CD71)) and VEGF (encoding vascular endothelial growth factor).

Topics: Adolescent; Adult; Alleles; Amino Acid Substitution; Cells, Cultured; Chromosomes, Human, Pair 3; DNA-Binding Proteins; Erythropoietin; Female; Gene Expression Regulation; Gene Frequency; Germ-Line Mutation; Haplotypes; Homeostasis; Homozygote; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Ligases; Male; Mutation, Missense; Nuclear Proteins; Oxygen; Pedigree; Polycythemia; Protein Binding; Receptors, Transferrin; Russia; Transcription Factors; Transferrin; Tumor Cells, Cultured; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Ubiquitins; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

Topics: Carcinoma, Renal Cell; Erythropoietin; Humans; Kidney Neoplasms; Ligases; Oxygen; Transcription Factors; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

We reported recently that normal human, rat, and mouse tubular cells express authentic erythropoietin-receptors (EPO-R) through which EPO stimulates mitogenesis. The present study examines whether EPO could elicit such a proliferative and thereby potentially detrimental response in cells of human renal-cell carcinoma (RCC).. Nephrectomy samples were screened from patients with RCC (one chromophilic, two clear cell) as well as cell lines of human (Caki-2, 786-0) and mouse (RAG) renal adenocarcinomas for expression of EPO-R transcripts and protein. Cells were further tested for specific 125I-EPO binding and mitogenic response to EPO.. Authentic EPO-R transcripts and protein (approximately 72 kD) were detected in renal tumors and cell lines. Tumors showed low-level EPO expression, while cell lines did not. In cells, specific 125I-EPO binding to a single class of EPO-R (apparent Kd 1. 3 to 1.4 nmol/L, Bmax 2.2 to 2.6 fmol/mg protein) was observed. EPO stimulated cell proliferation dose dependently, and the individual mitogenic effects of either EPO or 10% newborn calf serum were markedly amplified when both were coadministered.. These data are the first to demonstrate, to our knowledge, that human RCCs express EPO-R message and protein and that receptor activation stimulates their proliferation in vitro. If these mitogenic effects of EPO are also operative in patients with RCC, endogenous EPO or its administration for the treatment of anemia could potentially hasten proliferation of renocellular malignancies.

Topics: Adenocarcinoma, Clear Cell; Anemia; Animals; Carcinoma, Renal Cell; Cell Division; Erythropoietin; Gene Expression; Humans; Iodine Radioisotopes; Kidney Neoplasms; Kidney Tubules, Proximal; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Middle Aged; Mitogens; Neovascularization, Pathologic; Receptors, Erythropoietin; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured; von Hippel-Lindau Disease

Hemangioblastomas are highly vascular tumors of the central nervous system that overexpress the hypoxia-inducible gene, vascular endothelial growth factor (VEGF), as a consequence of mutational inactivation of the von Hippel-Lindau tumor suppressor gene (VHL). Previous reports showed that hemangioblastomas can also express erythropoietin (Epo), which is also hypoxia-inducible. However, Epo expression in hemangioblastomas was observed only in individual cases, and the analyses were mainly based on indirect determination of erythropoiesis-stimulating activity. Therefore, we analyzed a series of 11 hemangioblastomas for Epo, VEGF, and VHL expression by Northern blot analysis and compared the results with normal brain and glioblastomas. Surprisingly, we observed Epo mRNA expression in all hemangioblastoma specimens analyzed, but in none of four glioblastomas. In contrast, VEGF mRNA was expressed in all hemangioblastomas and all glioblastomas. In situ hybridization revealed neoplastic stromal cells as Epo- and VEGF-producing cells in hemangioblastomas. These results suggest that in the nonhypoxic microenvironment of hemangioblastoma, Epo, similar to VEGF, might be negatively regulated by the VHL gene product.

Topics: Adult; Aged; Brain; Brain Neoplasms; Cell Hypoxia; Central Nervous System Neoplasms; Endothelial Growth Factors; Erythropoiesis; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Glioblastoma; Hemangioblastoma; Hormones, Ectopic; Humans; In Situ Hybridization; Ligases; Lymphokines; Male; Middle Aged; Neoplasm Proteins; Nerve Tissue Proteins; Protein Biosynthesis; Proteins; RNA, Messenger; Stromal Cells; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Erythropoietin; Female; Genetic Carrier Screening; Humans; Male; Middle Aged; von Hippel-Lindau Disease

A 59-year-old woman with von Hippel-Lindau disease developed erythrocytosis and a recurrent intracranial hemangioblastoma. Radioimmunoassay showed an elevated level of erythropoietin in her serum. Cyst fluid from the tumor also contained erythropoietin, concentrated a thousandfold relative to the serum level. Production of erythropoietin by hemangioblastomas may explain the erythrocytosis present in some patients with von Hippel-Lindau disease.

Topics: Brain Neoplasms; Brain Stem; Erythropoietin; Female; Hemangiosarcoma; Humans; Magnetic Resonance Imaging; Middle Aged; Polycythemia; Radioimmunoassay; von Hippel-Lindau Disease