losartan-potassium and Brain-Neoplasms

Recent meta-analysis of patients with small cell lung cancer has confirmed the effectiveness of prophylactic cranial irradiation in reducing the cumulative incidence of brain metastases and contributing to a significant increase in 3-year survival. Likewise, with increased median survivals being documented in patients with stage IIIA/B non-small cell lung cancer, there is evidence that the brain is emerging as a significant metastatic target site. Although prophylactic cranial irradiation is a reasonable option to explore, the potential for long-term neuropsychologic adverse effects is of concern in both diagnostic groups. Radiation-induced reactive oxygen intermediates and reactive nitrogen intermediates appear to play a major role in mediating this toxicity. Hypoxic stress results in a significant increase in erythropoietin (EPO) mRNA in mouse brain and, in two models, the administration of EPO improves performance function and prevents cognitive impairment. With the demonstration of EPO receptors in astrocytes, neurons, and brain capillary endothelial cells as well as the ability of EPO to cross the blood-brain barrier, a potential for EPO-mediated central nervous system radioprotection is postulated. The rationale and preliminary design for a phase III study of EPO as a neurocognitive protectant in patients with lung cancer receiving prophylactic cranial irradiation is presented.

Topics: Animals; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Hypoxia; Clinical Trials, Phase III as Topic; Cognition; Cranial Irradiation; Cytoprotection; Drug Evaluation, Preclinical; Erythropoietin; Humans; Lung Neoplasms; Neuroprotective Agents; Reactive Nitrogen Species; Reactive Oxygen Species; Signal Transduction

Topics: Brain Neoplasms; Diagnosis, Differential; Erythropoietin; Female; Glioma; Hemangiosarcoma; Humans; Immunohistochemistry; Lectins; Male; Meningioma; Plant Lectins; Receptors, Cell Surface; Receptors, Thrombin; von Willebrand Factor

Topics: Adenocarcinoma; Adrenal Gland Neoplasms; Animals; Brain Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Cysts; Erythropoietin; Esophageal Neoplasms; Female; Growth Substances; Haplorhini; Humans; In Vitro Techniques; Kidney Neoplasms; Leiomyoma; Leukemia; Leukemia, Experimental; Liver Neoplasms; Lymphoma; Male; Mice; Neoplasm Metastasis; Neoplasm Transplantation; Pheochromocytoma; Polycythemia; Rats; Sarcoma, Experimental; Skin Neoplasms; Time Factors; Wilms Tumor

Topics: Adolescent; Adrenocorticotropic Hormone; Adult; Brain Neoplasms; Carcinoma; Carcinoma, Bronchogenic; Carcinoma, Hepatocellular; Carcinoma, Squamous Cell; Cerebellar Neoplasms; Child; Child, Preschool; Choriocarcinoma; Cushing Syndrome; Diagnosis, Differential; Erythropoietin; Female; Gonadotropins; Hemangiosarcoma; Hormones, Ectopic; Humans; Hypercalcemia; Hypoglycemia; Infant; Infant, Newborn; Insulin; Insulin Secretion; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Parathyroid Hormone; Pheochromocytoma; Polycythemia; Pregnancy; Teratoma; Testicular Neoplasms; Thymus Neoplasms

We investigated dose-dense docetaxel and cisplatin in patients with measurable non-small cell lung cancer in a randomized phase II study without [A] or with [B] a putative chemoprotective agent, BNP7787.. Chemotherapy-naive patients with stage IIIB (effusion) or IV, performance status 0 to 1, and adequate organ function were eligible. Treatment with docetaxel 75 mg/m followed by cisplatin 75 mg/m over 1 hour day 1 with darbepoetin 200 mug day 1 and pegfilgrastim 6 mg day 2 without/with BNP7787 before cisplatin was repeated every other week for up to 6 cycles. The primary end point was to differentiate between grade >/=2 neurotoxicity rates of 30% on [A] and 10% on [B]. Feasibility was prospectively defined as febrile neutropenia in <10% of patients and /=2 occurred in 32% on [A] and 29% on [B]. The incidence of febrile neutropenia was 4% on [A] and 3% on [B]. Treatment delays occurred in 13% and 20% of patients on [A] and [B], respectively. Completion rates for 3/6 cycles were 84%/51% on [A] and 84%/53% on [B]. Objective response rates were 55% on [A] and 51% on [B]. Median progression-free/overall survival times were 5.5/10.7 on [A] and 6.5/14.1 month on [B].. This dose-dense treatment regimen is active, feasible, and tolerable. Its further investigation in the curative setting in non-small cell lung cancer should be considered. BNP7787 did not result in significant protection from neurotoxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Anemia; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Darbepoetin alfa; Docetaxel; Dose-Response Relationship, Drug; Drug Therapy, Combination; Erythropoietin; Feasibility Studies; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematinics; Humans; Lung Neoplasms; Male; Maximum Tolerated Dose; Mesna; Middle Aged; Neoplasm Staging; Neutropenia; Polyethylene Glycols; Prognosis; Recombinant Proteins; Survival Rate; Taxoids

EphA2 is a key factor underlying invasive propensity of gliomas, and is associated with poor prognosis of tumors. We aimed to develop a radiomics-based imaging index for predicting EphA2 expression in diffuse gliomas, and further estimating its value for grading of tumors.. A total of 182 patients with diffuse gliomas were included. All subjects underwent pre-operative MRI and post-operative pathological diagnosis. EphA2 expression of tumors was scored on pathological sections with immunohistochemical staining using monoclonal EphA2 antibody. MRI radiomics features were extracted from three-dimensional contrast-enhanced T1-weighted imaging and diffusion kurtosis imaging. Predictive models were constructed using machine learning-based radiomics features selection and three classifiers for predicting EphA2 expression and tumor grade. Features of best EphA2 expression model were subsequently used to construct another model of tumor grading. For each model, 146 cases (80%) were randomly picked as training and the rest 36 (20%) were testing cohorts. EphA2 expression was further correlated to the radiomics features in both grade models using Spearman's correlation.. Logistic regression model presented highest performance for predicting EphA2 expression (AUC: 0.836/0.724 in training/validation set). Tumor gradings model guided by features from EphA2 expression model demonstrated comparable performance (AUC: 0.930/0.983) to that constructed directly using imaging radiomics features (AUC: 0.960/0.977). Two radiomics features which included in both LR-grade models showed strong correlation (P < 0.05) with EphA2 expression.. The expression of EphA2 in gliomas could be predicted by radiomics features extracted from diffusion kurtosis MRI, which could also be used to assist tumor grading.

Topics: Brain; Brain Neoplasms; Carcinoma, Hepatocellular; Erythropoietin; Glioma; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Receptors, Erythropoietin; Retrospective Studies

Although erythropoietin (EPO) has been proven to significantly promote the proliferation of cancer cells, the mechanism for promoting glioma proliferation is poorly understood. Here, we examined the functional role of the AKT/GSK-3β/β-catenin signaling pathway in the EPO-mediated proliferation of glioma.. The distribution of EPO and Ki-67 among clinical samples with different WHO grades was plotted by Immunological Histological Chemistry analysis. U87 and U251 glioma cell lines were treated with short hairpin RNA targeting (shEPO), recombinant human erythropoietin (rhEPO) and/or AKT-specific inhibitor (MK-2206). The changes in phosphorylated AKT, nuclear β-catenin, cyclin D1 and p27kip1 expression were detected. Cell cycle distributions and glioma proliferation in vitro and in vivo were analyzed.. The expression level of EPO was significantly elevated with the increase of WHO grade and Ki67 in clinical glioma specimens. In vitro, knockdown of endogenous EPO in U87 and U251 cells effectively block the phosphorylation of AKT and GSK-3β and the expression of nuclear β-catenin. shEPO treatment also significantly decreased the expression of cyclin D1 and increased the expression of p27kip1. The cell cycle transition then slowed down and the proliferation of glioma cells or mouse xenograft tumors both decreased. Treatment of cells or tumors with extra rhEPO reversed the above biological effects mediated by shEPO. rhEPO-induced activation of the AKT/GSK-3β/β-catenin pathway and proliferation were abolished by MK-2206.. Our study identified the AKT/GSK-3β/β-catenin axis as a critical mediator of EPO-induced glioma proliferation and further provided a clinically significant dimension to the biology of EPO.

Topics: Animals; Apoptosis; beta Catenin; Biomarkers, Tumor; Brain Neoplasms; Cell Proliferation; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Glioma; Glycogen Synthase Kinase 3 beta; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Phosphorylation; Prognosis; Proto-Oncogene Proteins c-akt; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Erythropoietin (EPO) is a cytokine primarily involved in the regulation of erythropoiesis. In response to hypoxia-ischemia, hypoxia-inducible factor 1 induces EPO production, which, in turn, inhibits apoptosis of erythroid progenitor cells. By the same mechanism and acting through other signaling pathways, EPO exerts neuroprotective effects. Increased resistance to hypoxia and decreased apoptosis are thought to be important mechanisms for tumor progression, including malignant glioma. Because recent studies have demonstrated that EPO and its receptor (EPOR) are expressed in several tumors and can promote tumor growth, in the present study, we investigated EPO and EPOR expression in human glioma and the effect of EPO administration in a rat model of glioma implantation.. Using Western blotting and immunohistochemical analysis, we examined the expression of EPO, EPOR, platelet endothelial cell adhesion molecule, and Ki-67 in human glioma specimens and experimentally induced glioma in rats. In the experimental setting, a daily dose of recombinant human EPO (rHuEPO) or saline solution were administered for 21 days in Fischer rats subjected to 9L cell line implantation.. In both human and animal specimens, we found an increase in EPOR expression as long as the lesion presented with an increasing malignant pattern. A significant direct correlation was found between the expression of EPOR and Ki-67 and EPOR and platelet endothelial cell adhesion molecule in low- and high-grade gliomas. The rats treated with rHuEPO presented with significantly larger tumor spread compared with the saline-treated rats.. The results of our study have shown that the EPO/EPOR complex might play a significant role in the aggressive behavior of high-grade gliomas. The larger tumor spread in rHuEPO-treated rats suggests a feasible role for EPO in the aggressiveness and progression of malignant glioma.

Topics: Adult; Aged; Animals; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Disease Models, Animal; Erythropoietin; Female; Glioma; Humans; Immunohistochemistry; Ki-67 Antigen; Male; Middle Aged; Neoplasm Transplantation; Platelet Endothelial Cell Adhesion Molecule-1; Rats, Inbred F344; Receptors, Erythropoietin; Recombinant Proteins; Tumor Burden

Glioblastoma multiforme (GBM) is the most common primary brain tumor characterized with poor prognosis and short survival. In addition to the standard treatment protocols, targeted molecular treatment options are under trial. In the recent trials, erythropoietin and erythropoietin receptor were found to be linked with the progression of GBM cells.. In this study, we compared the expression of EPOR with survival in GBM patients with mortality.. Twenty-six patients operated for GBM in 2012-2014 were enrolled in this study. Tumor tissues were stained with EPOR, epidermal growth factor receptor, vascular endothelial growth factor, and assigned as (1+), (2+), and (3+) according to their immunohistochemical staining levels. The average postoperative follow-up time was 9.3 months. Kaplan-Meier's survival test and Spearman's correlation test were used in statistical analysis.. EPOR 1(+) stained group showed a median survival of 8 months (95% confidence interval [CI]: 0.954-15.046). EPOR 2(+) stained group showed a median survival of 6 months (95% CI: 2.901-9.090) EPOR 3(+) stained group showed a median survival of 2 months (95% CI: 0.400-3.600). (Kaplan-Meier P = 0.002).. These results portrayed that EPOR staining levels were inversely proportional with average survival time. In the future, specific inhibitors of this molecule could be used to form a novel treatment option for GBM.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Disease Progression; ErbB Receptors; Erythropoietin; Female; Follow-Up Studies; Glioblastoma; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Middle Aged; Prognosis; Receptors, Erythropoietin; Survival Rate; Vascular Endothelial Growth Factor A

To determine whether erythropoietin (EPO) promotes rapid proliferation of glioma through Akt pathway.. We detected the expression of EPO in human glioma tissues using immunohistochemistry. A nude mouse model bearing human glioma U87 cell xenograft was established and given intraperitoneal injection of EPO or saline every other day, and the tumor growth was observed. In the in vitro experiment, U87 cells were treated with PBS (control), EPO, or EPO with Akt inhibitor, and the expression of p-Akt and cyclin D1 was detected using Western blotting; the cell proliferation rate was determined using cell counting kit-8 and clone formation assay, and the cell cycle changes were analyzed with flow cytometry.. Compared with low-grade glioma tissues, high-grade glioma tissues exhibited a significantly increased EPO expression (P=0.0002). In the tumor-bearing mice, EPO treatment significantly increased the expression of EPO (P=0.0006) and p-Akt (P=0.0003) in the tumor and obviously increased the tumor volume (P<0.0001) and weight (P=0.0003). In U87 cells cultured in vitro, EPO treatment obviously accelerated the cell proliferation (P=0.020 on day 3 and 0.028 on day 5), promoted clone formation (P=0.0010), and increased proliferation index (P=0.0028); EPO significantly enhanced the protein expression of p-Akt (P=0.0020) and cyclin D1 (P=0.0022). The application of Akt inhibitor significantly suppressed the effect of EPO in enhancing cyclin D1 and p-Akt expression (both P<0.0001) and promoting cell proliferation.. EPO can significantly accelerate the proliferation of glioma through Akt pathway.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cyclin D1; Erythropoietin; Glioma; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Proto-Oncogene Proteins c-akt; Signal Transduction

Hemoglobin is produced mainly in erythroid cells. However, it has been reported in non-erythroid cells of human and rodents. We have shown previously that neuroglobin, cytoglobin and hemoglobin are expressed in human glioblastoma multiforme (GBM) cells. We sought to determine whether hemoglobin expression is upregulated by hypoxia, and whether its expression is restricted to the cancer stem cell populations in different GBM cell lines or GBM brain tumor initiating cells (BTICs). Flow cytometry, magnetic cell sorting and qRT-PCR were used to examine the hypoxic upregulation of hemoglobins as well as erythropoietin (EPO) and erythropoietin receptor (EPOR) in GBM cell lines (M006x, M059J, M059K, U87R and U87T) and GBM-BTICs. The data showed significantly increased expression in globins (α, β, γ, δ, ζ and ε), EPO and EPOR mRNA levels under hypoxia. Globin expression is not limited to the stem cell populations or GBM-BTICs but is a property of the entire GBM population. We assumed that the total expression of mRNA of different normalized globins (α, β, γ, δ, ζ and ε) at different time‑points for the same cell line is 100%. Under aerobic conditions, ε globin was predominantly expressed, and then decreased gradually with increasing time in hypoxia. This was coupled to a concomitant increase in α and γ globins. Our findings suggest that hypoxic upregulation of hemoglobin expression in GBM cells may be a part of a repertoire of active defence and adaptation mechanisms enabling these cells to acquire resistance to aggressive multimodality treatments of chemotherapy and radiotherapy. New therapeutic strategies to interfere with hemoglobin expression or function in GBM cells are required.

Topics: Brain Neoplasms; Cell Hypoxia; Erythropoietin; Gene Expression Regulation, Neoplastic; Glioblastoma; Hemoglobins; Humans; Neoplastic Stem Cells; Receptors, Erythropoietin

In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.

Topics: Angiogenesis Inducing Agents; Animals; Biomarkers, Tumor; Brain Neoplasms; Chick Embryo; Chorioallantoic Membrane; Erythropoietin; Glioma; Humans; Immunoenzyme Techniques; Neovascularization, Pathologic; Prognosis; Receptors, Erythropoietin; Retrospective Studies

We describe a 19-year-old woman with onset of epileptic seizure, and a small mural nodule and multicystic lesions with severe brain edema located in the right frontal lobe. At surgery, the tumor and a clear margin was removed, and symptoms improved postoperatively. Extended local radiotherapy (60 Gy) was performed. Histopathological examination revealed oligodendroglioma-like tumor cells with a perinuclear halo. The tumor cells extended processes toward CD34-positive proliferating vessels, which resemble a basement membrane. These proliferating vessels formed a tumor membrane so that there was a clear margin between the tumor and brain tissue. Tumor cells were positive for epithelial membrane antigen in a dot-like pattern. MIB-1 staining index was 50.6%. Electron microscopy showed cilia and zipper-like junctions, and anaplastic clear-cell ependymoma grade III was diagnosed. A characteristic of the case was formation of a tumor membrane by proliferating tumor blood vessels. Fluorescence in situ hybridization showed 1p/19q deletions, and the concentration of erythropoietin in the cyst fluid was abnormally high, at 1,859.4 mIU/ml. Erythropoietin and erythropoietin receptors were verified with immunohistochemical staining.

Topics: Adult; Brain Neoplasms; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Ependymoma; Erythropoietin; Female; Humans

Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

Topics: Animals; Astrocytes; Brain Neoplasms; Caudate Nucleus; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Culture Media, Conditioned; Erythropoietin; Extracellular Signal-Regulated MAP Kinases; Gene Expression; Glioma; Hep G2 Cells; Humans; Male; MAP Kinase Signaling System; Mice; Mice, Nude; Phosphorylation; Rats; Rats, Inbred F344; Receptors, Erythropoietin; RNA, Small Interfering; Sequence Deletion; Signal Transduction; Survival Analysis; Xenograft Model Antitumor Assays

Topics: Animals; Brain Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cell Proliferation; Cell Survival; Enhancer Elements, Genetic; Erythropoietin; Ganciclovir; Gene Expression Regulation; Genes, Reporter; Genes, Transgenic, Suicide; Genetic Therapy; Genetic Vectors; Glioblastoma; Intermediate Filament Proteins; Introns; Luciferases; Nerve Tissue Proteins; Nestin; Neuroglia; Promoter Regions, Genetic; Rats; Simian virus 40; Simplexvirus; Thymidine Kinase; Transfection; Viral Proteins

Despite beneficial effects of irradiation/chemotherapy on survival of glioblastoma (GBM) patients, collateral damage to intact neural tissue leads to "radiochemobrain" and reduced quality of life in survivors. For prophylactic neuroprotection, erythropoietin (EPO) is a promising candidate, provided that concerns regarding potential tumor promoting effects are alleviated.. Human GBM-derived cell lines U87, G44, G112, and the gliosarcoma-derived line G28 were treated with EPO, with and without combinations of irradiation or temozolomide (TMZ). Responsiveness of glioma cells to EPO was measured by cell migration from spheroids, cell proliferation, and clonogenic survival. Implantation of U87 cells into brains of nude mice, followed 5 days later by EPO treatment (5,000 U/kg intraperitoneal every other day for 2 weeks) should reveal effects of EPO on tumor growth in vivo. Reverse transcriptase-polymerase chain reaction was performed for EPOR, HIF-1alpha, and epidermal growth factor receptor (EGFR)vIII in cell lines and 22 human GBM specimens.. EPO did not modulate basal glioma cell migration and stimulated proliferation in only one of four cell lines. Importantly, EPO did not enhance tumor growth in mouse brains. Preincubation of glioma cells with EPO for 3 h, followed by irradiation and TMZ for another 24 h, resulted in protection against chemoradiation-induced cytotoxicity in three cell lines. Conversely, EPO induced a dose-dependent decrease in survival of G28 gliosarcoma cells. In GBM specimens, expression of HIF-1alpha correlated positively with expression of EPOR and EGFRvIII. EPOR and EGFRvIII expression did not correlate.. EPO is unlikely to appreciably influence basal glioma growth. However, concomitant use of EPO with irradiation/chemotherapy in GBM patients is not advisable.

Topics: Animals; Antineoplastic Agents, Alkylating; Brain Neoplasms; Cell Division; Cell Line, Tumor; Cell Movement; Cell Survival; Combined Modality Therapy; Dacarbazine; Erythropoietin; Glioma; Gliosarcoma; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Temozolomide; Transplantation, Heterologous

Topics: Antineoplastic Agents; Astrocytoma; Brain Neoplasms; Cell Hypoxia; Cisplatin; Erythropoietin; Humans; Signal Transduction

The hypoxia-inducible pleiotropic hormone, erythropoietin (EPO), has recently been found to promote the development and survival of neurons and astrocytes. Since hypoxia has been implicated in the malignant progression of some human cancers, the authors investigated whether EPO signaling influenced the malignant properties of human astrocytoma cells.. Reverse transcriptase-polymerase chain reaction, Western blot analysis, and immunohistochemical studies were used to measure EPO and its receptor (EPOR). Cell viability, Matrigel invasion assays, metalloprotease assays, EPO neutralizing antibodies, and EPOR overexpression were used to study the biological actions of EPO. Expression of both EPO and EPOR was observed in the hypoxic regions and invasive margins of glioma specimens obtained at biopsy, and expression of EPOR correlated with the stage of the tumor. The EPOR was also functionally upregulated by hypoxia in cultured glioblastoma multiforme (GBM) cells. Both hypoxia and EPO protected cultured GBM cells from cisplatin cytotoxicity and promoted the invasiveness of GBM cells through Matrigel by potentiating metalloprotease activity. Hypoxia-enhanced cell invasion was attenuated in cells that overexpressed a nonfunctional EPOR.. Hypoxia-inducible autocrine and paracrine EPO signaling participates in the malignant progression of GBMs.

Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Hypoxia; Cell Line, Tumor; Cisplatin; Epoetin Alfa; Erythropoietin; Glioma; Hematinics; Humans; Neoplasm Invasiveness; Rats; Rats, Wistar; Receptors, Erythropoietin; Recombinant Proteins; Signal Transduction

We report two cases of extramedullary erythropoiesis within chronic subdural hematoma that caused diagnostic confusion. In both cases, the initial favored diagnosis by the submitting pathologists was that of a metastatic malignant tumor, including lymphoma, carcinoma, and malignant melanoma. In both cases, the subdural chronic hematoma contained cohesive clusters of small round blue cells with scant cytoplasm and round hyperchromatic nuclei. In both cases, some mitotic figures were identified. There was no gross or microscopic evidence of a meningeal mass lesion. The erythroblastic nature of the cells was confirmed using immunohistochemistry for CD43, glycophorin A, and erythropoietin A. It is important for surgical pathologists to be aware of this benign process and not to overinterpret it as either a primary or metastatic malignant tumor.

Topics: Aged; Antigens, CD34; Brain Neoplasms; Carcinoma, Small Cell; Diagnosis, Differential; Erythropoiesis; Erythropoietin; Female; Gene Expression Regulation, Neoplastic; Glycophorins; Hematoma, Subdural, Chronic; Hematopoiesis, Extramedullary; Humans; Male; Middle Aged

Erythropoietin (EPO) is a glycoprotein hormone that is a primary regulator of erythropoiesis. In erythroid cells, EPO binds to its receptor (EPOR) to stimulate growth, prevent apoptosis, and promote differentiation. Both EPO and EPOR have been found in many normal and tumor nonerythroid cell types. EPO has been reported to stimulate proliferation and inhibit apoptosis of cancer cells. In this study, we found that EPOR is expressed in brain tumors, glioma cell lines and explants, as well as, normal brain. EPO slightly stimulated the growth of serum-starved glioma cells. Furthermore, EPO increased the phosphorylation of AKT through the PI3K pathway in the glioma cells. It also increased the phosphorylation of ERK, c-jun, JNK, as well as, the expression of BCL-2 and BCL-xl in these cells. These results suggest that the EPO-EPOR pathway may promote glioma cell survival and could become a therapeutic target in brain tumors.

Topics: Apoptosis; Brain Neoplasms; Cell Line, Tumor; Erythropoietin; Glioblastoma; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Signal Transduction

Although a significant negative prognostic factor, tumor hypoxia can be exploited for gene therapy. To maximize targeting within the tumor mass, we have developed synthetic gene promoters containing hypoxia-responsive elements (HREs) from the erythropoietin (Epo) gene as well as radiation-responsive CArG elements from the early growth response (Egr) 1 gene. Furthermore, to achieve high and sustained expression of the suicide gene herpes simplex virus thymidine kinase (HSVtk), our gene therapy vectors contain an expression amplification system, or 'molecular switch', based on Cre/loxP recombination. In human glioma and breast adenocarcinoma cells exposed to hypoxia and/or radiation, the HRE/CArG promoter rapidly activated Cre recombinase expression leading to selective and sustained HSVtk synthesis. Killing of transfected tumor cells was measured after incubation with the prodrug ganciclovir (GCV; converted by HSVtk into a cytotoxin). In vitro, higher and more selective GCV-mediated toxicity was achieved with the switch vectors, when compared with the same inducible promoters driving HSVtk expression directly. In tumor xenografts implanted in nude mice, the HRE/CArG-switch induced significant growth delay and tumor eradication. In conclusion, hypoxia- and radiation-activated 'molecular switch' vectors represent a promising strategy for both targeted and effective gene therapy of solid tumors.

Topics: Adenocarcinoma; Adenoviridae; Animals; Antiviral Agents; Brain Neoplasms; Breast Neoplasms; Cell Death; Cell Hypoxia; Combined Modality Therapy; Early Growth Response Protein 1; Erythropoietin; Ganciclovir; Gene Expression Regulation, Neoplastic; Genes, Switch; Genes, Transgenic, Suicide; Genetic Engineering; Genetic Therapy; Genetic Vectors; Glioma; Humans; Mice; Mice, Nude; Neoplasms; Oncolytic Virotherapy; Promoter Regions, Genetic; Simplexvirus; Thymidine Kinase; Tumor Cells, Cultured

Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e.g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation.. Anemia was induced by total body irradiation (TBI, 2 x 4 Gy) of mice prior to tumor implantation into the subcuts of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm3), fractionated irradiation (4 x 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors.. Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 +/- 5 days vs. 79 +/- 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 +/- 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved.. These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation.

Topics: Anemia; Animals; Brain; Brain Neoplasms; Cell Hypoxia; Cell Line, Tumor; Dose Fractionation, Radiation; Erythropoietin; Glioblastoma; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Radiation Tolerance; Radiotherapy Dosage; Recombinant Proteins; Time Factors; Transplantation, Heterologous; Whole-Body Irradiation

Hypoxia induces transcription of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) genes. We set up the hypothesis that elevated intracranial pressure in patients with hydrocephalus triggers release of VEGF and EPO into cerebrospinal fluid (CSF).. VEGF and EPO concentrations, measured in 57 CSF aliquots obtained from infants and children with hydrocephalus undergoing surgery or therapeutic taps, were significantly elevated compared with those in 41 CSF aliquots of sex- and age-matched children undergoing routine diagnostic lumbar puncture for unrelated reasons ( P<0.001 and P=0.015, respectively). In hydrocephalus samples, median (interquartile range) VEGF concentrations were 135 (35-410) pg/ml, and 4 of 57 hydrocephalus samples had a VEGF concentration below the detection limit (1 pg/ml), compared with 38 of 41 control samples. Erythropoietin was undetectable (<0.1 pg/ml) in 34 of 57 hydrocephalus samples and in 34 of 41 controls.. We conclude that conditions necessitating surgical intervention in hydrocephalus patients result in increased CSF concentrations of VEGF and EPO.

Topics: Brain Neoplasms; Cerebral Hemorrhage; Child, Preschool; Endothelial Growth Factors; Erythropoietin; Female; Humans; Hydrocephalus; Infant; Lymphokines; Male; Reference Values; Spinal Dysraphism; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

1. Recent investigations have shown that the glycoprotein erythropoietin (Epo) and its specific receptor (EpoR) are present in the mammalian brain including human, monkey and mouse. These findings suggest a local action of Epo in the nervous system. The aim of this study was to elucidate a possible functional interaction of Epo with neuronal cells. 2. To examine the influence of externally applied Epo on Ca2+ homeostasis the human neuroblastoma cell line SK-N-MC was chosen as a suitable in vitro model for undifferentiated neuronal cells. 3. Expression of the EpoR in SK-N-MC cells was detected by reverse transcription-PCR, Western blot and immunofluorescence analysis. 4. Patch-clamp studies of SK-N-MC cells confirmed the expression of T-type Ca2+ channels, whose peak macroscopic current was increased by the addition of recombinant human Epo (rhEpo) to the bathing medium. 5. Confocal laser scanning microscopy analysis of SK-N-MC cells confirmed a transient increase in intracellular free [Ca2+] in response to externally applied rhEpo. 6. The transient response to Epo was dependent on external Ca2+ and remained even after depletion of internal Ca2+ stores by caffeine or thapsigargin. However, after depletion the response to Epo was absent when cells were superfused with the T-type Ca2+ channel blocker flunarizine. 7. This study demonstrates that Epo can interact with neuronal cells by affecting Ca2+ homeostasis through an increase in Ca2+ influx via plasma membrane T-type voltage-dependent Ca2+ channels.

Topics: Blotting, Western; Brain Neoplasms; Calcium; Calcium Channels; Cell Line; Electrophysiology; Erythropoietin; Fluorescent Antibody Technique, Direct; Humans; Microscopy, Confocal; Neuroblastoma; Patch-Clamp Techniques; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

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

The concept of ex vivo expansion of the human progenitor cell population was tested in this study. In the presence of interleukin-3 and -6 we compared the abilities of various liquid culture conditions of human blood-derived hematopoietic progenitor cells to yield a suitable condition for the expansion of blood progenitor cells. Although the best result was obtained in the gastpermeable bag culture system, the enhancement effect (maximum of 3.8-fold for granulocyte/macrophage colony-forming units and 3.0-fold for erythroid burst-forming units) lasted for only a short period (less than 6 d). The results of this study are disappointing for clinical use, and attempts with currently available technology appear to be limited in their potential.

Topics: Adolescent; Brain Neoplasms; Cell Division; Cells, Cultured; Child; Child, Preschool; Colony-Forming Units Assay; Cytokines; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Interferon-gamma; Interleukin-3; Interleukin-6; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins

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

Immunohistochemical studies for erythropoietin were carried out in six capillary haemangioblastomas, three of which were also studied by electron microscopy. The immunohistochemical studies showed that positively stained cells were scattered in the vicinity of capillaries, and that neither endothelial cells nor stromal cells were stained. In their morphology and distribution, the positively stained cells were identical to mast cells as observed by electron microscopy. In one case, erythropoietin was demonstrated in the cyst fluid of the tumour. These findings suggest that mast cells with abundant secreting granules in haemangioblastomas are capable of producing erythropoietin.

Topics: Adult; Brain Neoplasms; Erythropoietin; Female; Hemangiosarcoma; Histocytochemistry; Humans; Immunoenzyme Techniques; Male; Mast Cells; Middle Aged

Capillary hemangioblastoma is a tumor known to be associated with secondary polycythemia. Therefore, specimens from ten hemangioblastomas were studied by immunohistochemistry for the presence of erythropoietin, renin substrate, and for various endothelial, histiocytic and glial markers. In all tumors scattered cells among the stromal cells showed a positive-staining reaction with both anti-erythropoietin and anti-renin substrate. The same cells also stained positively for alpha-1-anti-trypsin. It is concluded that, in addition to the capillary endothelial cells, pericytes and stromal cells, capillary hemangioblastomas harbor cells containing and perhaps producing renin substrate and/or erythropoietin or a substance with similar antigenic determinants.

Topics: Angiotensinogen; Brain Neoplasms; Cerebellar Neoplasms; Erythropoietin; Hemangiosarcoma; Humans; Immunologic Techniques; Medulla Oblongata

Topics: Angiotensinogen; Antibodies; Brain Neoplasms; Cross Reactions; Electrophoresis, Polyacrylamide Gel; Erythropoietin; Female; Fluorescent Antibody Technique; Hemangiosarcoma; Humans; Molecular Weight; Radioimmunoassay

Topics: Adult; Aged; Animals; Brain Neoplasms; Child, Preschool; Colony-Forming Units Assay; Erythropoietin; Female; Hematopoietic Stem Cells; Humans; Kidney Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Neoplasm Transplantation; Neoplasms; Polycythemia; Transplantation, Heterologous; Uterine Neoplasms

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Animals; Brain Neoplasms; Child; Child, Preschool; Dogs; Electric Stimulation; Erythropoiesis; Erythropoietin; Ethacrynic Acid; Haplorhini; Humans; Hydronephrosis; Hypertension; Hypothalamus; Infant; Iron Isotopes; Kidney Diseases; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Middle Aged; Polycythemia Vera; Rats; Testicular Neoplasms; Testosterone; Urinary Calculi; Urologic Diseases; Wilms Tumor; Wounds and Injuries