losartan-potassium and Hemangioblastoma

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

Hemangioblastomas express erythropoietin and the patients often present with polycythemia.. Serum erythropoietin was measured using a commercial immunoassay, a functional erythropoietin assay and iso-electric focusing.. Despite the polycythemia, serum erythropoietin remained low, while a functional erythropoietin-assay showed a 4-5 higher activity in serum compared to the immunoassay. Iso-electric focusing of serum erythropoietin indicated overrepresentation of highly sialylated erythropoietin isoforms produced by the tumor. As a result, altered affinity of the monoclonal antibody used in the immunoassay for the hypersialylated isoforms was suggested.. Analysis of erythropoietin isoforms may be helpful in distinguishing the ectopic erythropoietin isoforms from normally glycosylated erythropoietin.

Topics: Antibodies, Monoclonal; Artifacts; Central Nervous System Neoplasms; Erythropoietin; Glycosylation; Hemangioblastoma; Humans; Immunoassay; Isoelectric Focusing; Male; Middle Aged; Polycythemia; Protein Isoforms

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

Topics: Adult; Cerebellar Neoplasms; Erythropoietin; Hemangioblastoma; Humans; Magnetic Resonance Imaging; Male; Polycythemia

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

Multiple hemangioblastomas (HBs) of the central nervous system (CNS) and retina are associated with von Hippel-Lindau disease (VHL) and also predispose individuals to renal cell carcinomas and visceral cysts. In VHL, microsurgery or radiosurgery cannot prevent new HBs from arising in the CNS or coagulation of retinal HBs. Multiple but thus far asymptomatic HBs pose a therapeutic problem. IFN-alpha-2a has antiangiogenic activity with an especially favorable effect on life-threatening hemangiomas of the liver in children. This is the first study to assess the efficacy of IFN-alpha-2a in treatment of asymptomatic HBs of the CNS and retina. Four patients (three with VHL) with a combined total of 15 HBs of the CNS, 3 HBs of the retina, and 14 renal and 2 pancreatic cysts were treated with s.c. IFN-alpha-2a for 12 months at 3 x 10(6) IU, 3 times/week. Baseline workup consisted of detailed neurological, ophthalmological, and radiological examinations. Follow-up studies at 3, 13, and 21 months were used to monitor the response. No de novo HBs were detected during the therapy, but one appeared 9 months after cessation of IFN-alpha-2a therapy. HBs of the CNS did not shrink markedly during the therapy. IFN-alpha-2a may decrease blood flow in HBs as suggested by shrinkage and diminished leakage of two retinal HBs. However, the therapy did not prevent visceral cysts from growing. The systemic response was also monitored by measurement of serum levels of vascular endothelial growth factor and erythropoietin, which remained essentially unchanged during the treatment. No serious side effects were recorded.

Topics: Adult; Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Dose-Response Relationship, Drug; Endothelial Growth Factors; Erythropoietin; Female; Hemangioblastoma; Humans; Interferon alpha-2; Interferon-alpha; Lymphokines; Male; Middle Aged; Recombinant Proteins; Retinal Neoplasms; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

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

This report deals with immunohistochemical studies performed on 21 cases of cerebellar hemangioblastomas. Antibodies against basic fibroblast growth factor, glial fibrillary acidic protein, vimentin, factor VIII, and erythropoietin were used. A considerable number of stromal cells and some endothelial cells were positive for basic fibroblast growth factor in all cases studied. The stromal cells of four cases were positive for erythropoietin; two of these cases were associated with secondary polycythemia. Our data suggest that basic fibroblast growth factor may contribute to angiogenesis in cerebellar hemangioblastomas.

Topics: Adolescent; Adult; Cerebellar Neoplasms; Erythropoietin; Female; Fibroblast Growth Factor 2; Hemangioblastoma; Humans; Immunohistochemistry; Male; Middle Aged

A 62-year-old man with a history of coronary insufficiency complained at his scheduled visit to the outpatient clinic of symptoms suggestive of gastritis. His blood hemoglobin concentration, however, was markedly increased. Results of a hematological work-up suggested an erythropoietin-producing tumor. Signs of increased intracranial pressure then led to the finding of a cerebellar tumor, which could explain his vertigo and abdominal symptoms. This cystic capillary hemangioblastoma probably was responsible for the erythropoietin production and also seemed to produce basic fibroblast growth factor. The clinical evaluation of polycythemia as well as erythropoietin biochemistry and clinical application are reviewed.

Topics: Capillaries; Cerebellar Neoplasms; Erythropoietin; Fibroblast Growth Factor 2; Hemangioblastoma; Humans; Male; Middle Aged; Polycythemia

Topics: Animals; Cerebellar Neoplasms; Epoetin Alfa; Erythropoietin; Hemangioblastoma; Hemangioma; Hematopoiesis; Pathology; Rabbits; Research