Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CD34 is a sialylated transmembrane glycoprotein of unknown function that is present in myeloid progenitor cells, endothelial cells, and some fibroblast-related mesenchymal cells. However, its tissue distribution is still incompletely characterized. In this study we evaluated the distribution of CD34 antigen in tumors of the central and peripheral nervous system. For comparison the tumors were also stained for CD31, also known as platelet-endothelium cell adhesion molecule (PECAM-1), a transmembrane glycoprotein so far considered to be endothelium specific beyond its reactivity with certain hematopoietic cells. Neurofibromas showed consistently high numbers of CD34-positive spindle cells, whereas peripheral and acoustic schwannomas were negative. A subset of meningiomas (15%) showed CD34-positive tumor cells, and some were also weakly positive for CD31. Gliomas were negative. Meningeal hemangiopericytomas were consistently CD34 positive, but CD31 negative. These results indicate a moderately widespread distribution of the CD34 antigen in nervous system tumors, and necessitate caution in making conclusions regarding endothelial cell differentiation of nervous system tumors on the basis of CD34 immunoreactivity.
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PMID:CD34 immunoreactivity in nervous system tumors. 753 84

The histopathological features, particularly hypervascularity, were examined in specimens resected from 21 patients, 15 with intractable epilepsy accompanying cortical dysplasia or dysembryoplastic neuroepithelial tumor (DNT), and 6 with benign brain tumors, such as ganglioglioma and low-grade glioma. Hypervascularity was found in resected specimens from 15 of the 21 patients (71.4%) and in 10 of the 12 patients (83.3%) who had double pathology. Counting of numbers of vessels by CD31 immunohistochemistry revealed that hypervascularity was prominent, especially in cases of vascular malformation or cortical dysplasia. However, almost all cases were negative for vascular endothelial growth factor (VEGF) staining, except for some cases of benign brain tumors. Moreover, all cases showed low or no proliferative potential in MIB-1 immunohistochemistry. These results suggest that the etiology of hypervascularity in the dysplastic lesions is one of a variety of cerebral malformations, as is the case with abnormal maturation and differentiation in neuroglial elements.
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PMID:Vascular abnormalities in surgical specimens obtained from the resected focus of intractable epilepsy. 1131 Sep 19

To facilitate the study of human endothelial cells we have used a replication defective retrovirus encoding the catalytic subunit of telomerase (hTERT) to derive populations of telomerase-immortalized human microvascular endothelial (TIME) cells. Whereas parental HMVECs became senescent on average within 35-45 population doublings (PDs), TIME cells have continued to proliferate for at least 200 PDs. TIME cells express readily detectable telomerase activity but display only a modest increase in telomere length. Karyotypic analysis reveals the cells to have a normal complement of human chromosomes with no evidence of gross genetic abnormalities. Furthermore, TIME cells retain many of the characteristics of the primary endothelial cells from which they were derived. For example, they express a panel of characteristic endothelial cell surface marker proteins such as CD31/PECAM-1 and alpha(v)beta3-integrin. In addition, TIME cells express receptors for low-density lipoprotein (LDL) receptor as they are competent for receptor-mediated endocytosis of fluorescent acetylated LDL. Importantly, when plated on matrigel, TIME cells undergo tubule formation. Moreover, when cocultured in the presence of human glioma cells, but not primary human astrocytes, TIME cells are induced to form stable tubules. Detachment of TIME cells from extracellular matrix leads to a form of programmed cell death known as anoikis. Conditional activation of the protein kinase Akt (Akt:ER*) significantly inhibited the onset of TIME cell anoikis under these conditions. We believe that the ability of hTERT to immortalize primary human endothelial cells, and the fact that such cells retain the endothelial characteristics of the cells from which they were derived, will greatly facilitate the analysis of human endothelial cell biology in vitro.
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PMID:Induction of tubulogenesis in telomerase-immortalized human microvascular endothelial cells by glioblastoma cells. 1179 43

Little is known about the effects of antiangiogenic therapy on perfusion of human tumors and the mechanisms by which tumors can adapt to these treatments and recur. Here, we examined the effects of serial passaging of LN-229 human glioma xenografts overexpressing thrombospondin (TSP)-1 on tumor growth, vascularity, and perfusion. Persistence of TSP-1 overexpression was confirmed after three serial s.c. passages of small xenografted tumor blocks of cells stably transfected with TSP-1 cDNA (clones C9 and E7) or vector controls (pooled clones A7-A9) in immunodeficient nu/nu mice. The tumor vascularity was estimated by noninvasive near infrared spectroscopy measuring blood volume at 800 +/- 10 nm and by histological vessel scores in CD31-immunostained cryosections. The tumor perfusion was assessed by noninvasive laser Doppler flowmetry. Overexpression of TSP-1 significantly inhibited tumor growth. In size-matched tumors (approximately 300 mm(3)), the blood volume and the histological vessel scores were lower in the TSP-1-transfected tumors than in controls, and this effect was more pronounced in tumors derived from the clone with the highest TSP-1 expression (clone E9). Despite this clear reduction in tumor vascularity, the tumor perfusion was the same in TSP-1-transfected tumors and controls. This study shows that TSP-1 overexpression slows glioma growth in vivo but does not prevent it from reaching a large size (300 mm(3)). Whereas a clear reduction in blood volume during tumor growth and a reduced vascular index at sacrifice are observed in TSP-1-transfected tumors, this did not affect perfusion when size-matched comparisons were performed. Given the increased time needed to reach equal size, it indicates that a fixed rate of perfusion must be maintained in the tumor to allow for growth. Elucidation of the mechanisms that allow this to happen has important consequences for the understanding of tumor recurrence after antiangiogenic therapy.
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PMID:Overexpression of thrombospondin-1 reduces growth and vascular index but not perfusion in glioblastoma. 1186 3

Bone marrow-derived stromal cells (BMSC) possess a population of vascular progenitor cells that enable them to acquire a histology and immunophenotype coherent with endothelial cells (EC). Recent evidence indicates that a hypoxic environment such as that encountered in tumor masses regulates BMSC angiogenic properties by pathways that remain to be defined. It is also unclear as to what extent these marrow-derived precursor cells could contribute to the growth of endothelium-lined vessels at the vicinity of tumor masses. In this study, we found that BMSC exhibited the ability to generate three-dimensional capillary-like networks on Matrigel, and that this property was up-regulated by growth factors-enriched conditioned media isolated from several tumor-derived cell lines. In particular, basic fibroblast growth factor, a key mediator of angiogenesis, was found to be the most potent growth factor for inducing BMSC proliferation, migration, and tubulogenesis. The setup of a new two-dimensional in vitro co-culture assay further showed that BMSC were massively recruited when cultured in the presence of either cancerous or differentiated EC lines. In vivo, subcutaneous co-injection of BMSC with U-87 glioma cells in nude mice resulted in the formation of highly vascularized tumors, where BMSC differentiated into CD31-positive cells and localized at the lumen of vascular structures. Our data suggest that BMSC could be recruited at the sites of active tumor neovascularization through paracrine regulation of their angiogenic properties. These observations may have crucial implications in the development of novel therapies using BMSC engineered to secrete anti-cancerous agents and to antagonize tumor progression.
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PMID:Vascular progenitors derived from murine bone marrow stromal cells are regulated by fibroblast growth factor and are avidly recruited by vascularizing tumors. 1504 70

Bone marrow-derived endothelial precursor cells incorporate into neovasculature and have been successfully used as vehicles for gene delivery to brain tumors. To determine whether systemically administered Sca1+ bone marrow cells labeled with superparamagnetic iron oxide nanoparticles can be detected by in vivo magnetic resonance imaging in a mouse brain tumor model, mouse Sca1+ cells were labeled in vitro with ferumoxides-poly-L-lysine complexes. Labeled or control cells were administered intravenously to glioma-bearing severe combined immunodeficient (SCID) mice. Magnetic resonance imaging (MRI) was performed during tumor growth. Mice that received labeled cells demonstrated hypointense regions within the tumor that evolved over time and developed a continuous dark hypointense ring at a consistent time point. This effect was not cleared by administration of a gadolinium contrast agent. Histology showed iron-labeled cells around the tumor rim in labeled mice, which expressed CD31 and von Willebrand factor, indicating the transplanted cells detected in the tumor have differentiated into endothelial-like cells. These results demonstrate that MRI can detect the incorporation of magnetically labeled bone marrow-derived precursor cells into tumor vasculature as part of ongoing angiogenesis and neovascularization. This technique can be used to directly identify neovasculature in vivo and to facilitate gene therapy by noninvasively monitoring these cells as gene delivery vectors.
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PMID:Noninvasive MR imaging of magnetically labeled stem cells to directly identify neovasculature in a glioma model. 1533 44

Gliomas are the most common intrinsic brain tumors. The degree of vascularization corresponds to malignancy and is related to prognosis. In order to retrieve information about tumor behavior in situ, the use of primary tissue material for experiments is advantageous. With increasing evidence for the importance of microenvironment and vascularization in tumor biology, we concentrated on the isolation of endothelial cells (EC) from primary tumor material to investigate the role of endothelium within tumor tissue. We developed a method for isolation and purification of tumor-derived endothelial cells. EC were isolated and cultivated from normal brain using tissue digestion and Percoll density gradient centrifugation resulting in a <95% of EC culture. For isolation of EC from gliomas of different malignancy grades a combination of tissue digestion, Percoll gradient centrifugation and magnetic bead sorting by anti-CD31, -VE-Cadherin and -CD 105 was employed. This approach provided a purity of <98%. Cells were classified and characterized by testing expression of CD105, CD31, VE-Cadherin, vWF, UEA-1 and measuring DiI-Ac-LDL-uptake. To exclude contamination, staining and negative selection with anti-SMA, -GFAP, and -CD68 was performed. Tumors were histopathologically diagnosed according to WHO classification. We isolated EC from normal brain (NBEC, n = 11), low-grade gliomas WHO II (LGEC, n = 22), and high-grade gliomas WHO III & IV (HGEC, n = 11). There were no clear differences in EC morphology between the different tumor grades. However, a significantly higher proliferation rate of HGEC compared to LGEC was observed as well as distinctive antigen expression. Already in early passages isolated EC showed a rapid change in antigen expression indicating a phenotypic shift under culture conditions. We could establish a protocol for reliable and reproducible isolation and culture of EC from gliomas with different WHO grading. In first phenotypical and functional analyses, NBEC, LGEC and HGEC show remarkable differences. EC from all tumors could be grown in culture. However, passage related changes of EC phenotype demand very early passages to work with.
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PMID:Isolation and culture of microvascular endothelial cells from gliomas of different WHO grades. 1615 23

The chemotherapeutic agent temozolomide (TMZ) and the anti-angiogenic agent thalidomide (THD) have both demonstrated anti-tumor activity in patients with recurrent malignant glioma. Combination treatment with TMZ and THD in patients with glioblastoma multiforme (GBM) appears to be more effective than treatment with either drug alone. To investigate the mechanism of this anti-tumor effect, we examined the combined effects of TMZ and THD in a rat glioma xenograft model. We found that combination treatment markedly inhibited the growth of tumors that were orthotopically implanted into rat brains. Using proliferating cell nuclear antigen (PCNA) staining, we observed a significant decrease in cell proliferation in these tumors. CD31 staining of the microvasculature revealed a significant decrease in angiogenesis. We also found increased apoptosis in treated tumors by terminal deoxynucleotidyl-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. We further demonstrated that the expression of angiogenic factors, such as vascular endothelial cell growth factor (VEGF) and basic fibroblastic growth factor (bFGF), were inhibited by THD. THD also decreased the number of ED1-positive, activated macrophages or microglial cells, which produce pro-angiogenic molecules around the glioma. Taken together, these results suggest that combination treatment with TMZ and THD inhibits tumor growth via the induction of apoptosis and the inhibition of angiogenesis in a rat model and may be a promising therapy for malignant gliomas.
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PMID:Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model. 1632 79

Angiogenic processes are regulated by vascular endothelial growth factors (VEGFs) and their receptors VEGFR1 (Flt-1), 2 (Flk-1) and 3 (Flt-4). While VEGFR2 is thought to play a central role in tumor angiogenesis, anti-angiogenic therapies targeting VEGFR2 in glioma models can show escape phenomena with secondary onset of angiogenesis. The purpose of this study was to find explanations for these processes by searching for alternative pathways regulating glioma angiogenesis and reveal a correlation with tumor grade. Thus, VEGFR3, which is not expressed in normal brain, and its ligands VEGF-C and -D, were assessed in high grade (WHO degrees IV, glioblastomas, GBM) and low grade gliomas [WHO degrees II astrocytomas (AII)]. In all GBM, a strong protein expression of VEGFR3 was found on tumor endothelium, VEGF-C and -D expression was found on numerous cells in areas of high vascularization. On RNA level, a significant up-regulation of VEGFR3 was detected in GBM compared to AII and non-neoplastic brain. In AII, only very moderate VEGFR3, VEGF-C and -D expression was found on protein and RNA level indicating a correlation of VEGFR3 expression with tumor grade. VEGFR3 signal in both grades was found predominantly on endothelial cells, confirmed by VEGFR3 expression on isolated CD31 positive cells and the expression of various endothelial markers on VEGFR3-positive cells isolated from GBM. The demonstration of a complete angiogenic signaling system that is dependent on tumor grade may influence the traditional paradigm of glioma angiogenesis and may provide a basis for more effective anti-angiogenic treatment strategies.
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PMID:Expression of VEGFR3 in glioma endothelium correlates with tumor grade. 1711 85

The abnormal function of tyrosine kinase receptors is a hallmark of malignant gliomas. Tie2 receptor tyrosine kinase is a specific endothelial cell receptor whose function is positively regulated by angiopoietin 1 (Ang1). Recently, Tie2 has also been found in the nonvascular compartment of several tumors, including leukemia as well as breast, gastric, and thyroid cancers. There is, however, little information on the function of the Ang1/Tie2 pathway in the non-stromal cells within human tumors. We found that surgical glioblastoma specimens contained a subpopulation of Tie2+/CD31- and Tie2+/GFAP+ cells, suggesting that Tie2 is indeed expressed outside the vascular compartment of gliomas. Furthermore, analysis of a tissue array consisting of 116 human glioma samples showed that Tie2 expression in the neoplastic glial cells was significantly associated with progression from a lower to higher grade. Importantly, Ang1 stimulation of Tie2+ glioma cells resulted in increased adherence of the cells to collagen I and IV, suggesting that Tie2 regulates glioma cell adhesion to the extracellular matrix. Conversely, the down-regulation of Tie2 levels by small interference RNA or the addition of soluble Tie2 abrogated the Ang1-mediated effect on cell adhesion. In studying the expression of cell adhesion molecules, we found that Tie2 activation was related to the up-regulation of integrin beta1 levels and the formation of focal adhesions. These results, together with the reported fact that malignant gliomas express high levels of Ang1, suggest the existence of an autocrine loop in malignant gliomas and that a Tie2-dependent pathway modulates cell-to-extracellular matrix adhesion, providing new insights into the highly infiltrative phenotype of human gliomas.
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PMID:Expression of the receptor tyrosine kinase Tie2 in neoplastic glial cells is associated with integrin beta1-dependent adhesion to the extracellular matrix. 1718 82


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