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)

Glioblastoma is among the most aggressive and treatment resistant of all human cancers. Conventional therapeutic approaches are unsuccessful because of diffuse infiltrative invasion of glioma tumor cells into normal brain parenchyma. Stem cell-based therapies provide a promising approach for the treatment of malignant gliomas because of their migratory ability to invasive tumor cells. Our therapeutic strategy was to use human bone marrow-derived mesenchymal stromal cells (hMSCs) as a cellular vehicle for the targeted delivery and local production of the biologic agent tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) at the glioma tumor site. hMSCs were transduced with a lentivirus expressing secretable TRAIL (S-TRAIL) and mCherry (red fluorescent protein). Our results clearly demonstrate the retention of tumor tropic ability of hMSC S-TRAIL cells by in vitro and in vivo migration assays. In vitro assays confirmed the expression, release, and biological activity of S-TRAIL produced by hMSC S-TRAIL cells. For the in vivo assessment of therapeutic efficacy, hMSCs were injected ipsilateral to an established intracranial glioma tumor in a mouse xenograft model. Genetically engineered hMSC S-TRAIL cells were effective in inhibiting intracranial U87 glioma tumor growth (81.6%) in vivo and resulted in significantly longer animal survival. Immunohistochemical studies demonstrated significant, eight fold greater tumor cell apoptosis in the hMSC S-TRAIL-treated group than in controls. Our study demonstrates the therapeutic efficacy of hMSC S-TRAIL cells and confirms that hMSCs can serve as a powerful cell-based delivery vehicle for the site-specific release of therapeutic proteins.
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PMID:Human bone marrow-derived mesenchymal stromal cells expressing S-TRAIL as a cellular delivery vehicle for human glioma therapy. 1954 10

Glioblastoma is the most common and the most aggressive type of brain cancer. The median survival time from the time of diagnosis is approximately one year. Invasion of glioma cells from the core tumor into the surrounding brain tissue is a major reason for treatment failure: these migrating cells are not eliminated in surgical resection and cause tumor recurrence. Variations are seen in number of invading cells, and in the extent and patterns of migration. Cells can migrate diffusely and can also be seen as clusters of cells distinct from the main tumor mass. This kind of clustering is also evident in vitro using 3D spheroid models of glioma invasion. This has been reported for U87 cells stably expressing the constitutively active EGFRVIII mutant receptor, often seen expressed in glioblastoma. In this case the cells migrate as clusters rather than as single cells migrating in a radial pattern seen in control wild type U87 cells. Several models have been suggested to explain the different modes of migration, but none of them, so far, has explored the important role of cell-cell adhesion. The present paper develops a mathematical model which includes the role of adhesion and provides an explanation for the various patterns of cell migration. It is shown that, depending on adhesion, haptotactic, and chemotactic parameters, the migration patterns exhibit a gradual shift from branching to dispersion, as has been reported experimentally.
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PMID:A mathematical model for pattern formation of glioma cells outside the tumor spheroid core. 1959 56

Glioblastoma multiforme (GB) is the most aggressive, and the most frequent primary tumor of the brain in adults. Presence of less-differentiated areas which exhibit a small cell morphology and neural immunophenotype is quite uncommon in GBs. Tumor tissue which had been determined in the frontotemporal region of a 61-year-old female patient and evaluated to be consistent with GB radiologically was subjected to total excision. Histopathological examination revealed two different components making up the tumor tissue. Using a morphological and immunophenotypic approach, the predominant component of the tumor was found to bear the properties of classic GB. The other component was composed of undifferentiated areas exhibiting small cell morphology and diffuse neuronal immunophenotype. The case was diagnosed as 'Glioblastoma with primitive neuroectodermal tumor-like component'. The patient who had been subjected to postoperative radiotherapy, showed no sign of recurrence during the follow-up examination performed on the 9th month. The histogenesis and prognostic significance of neuronal differentiation observed in glial tumors are not known yet. Inclusion of this component in pathological reports is important regarding formation of a database for future studies.
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PMID:Glioblastoma with primitive neuroectodermal tumor-like features: case report. 1962 Dec 91

Glioblastoma is the most common and most malignant intrinsic human brain tumor, characterized by extensive invasion and proliferation of glial (astrocytic) tumor cells, frequent activation of tyrosine kinase receptor signaling pathways, relative resistance to chemotherapy and radiotherapy, and poor prognosis. Using the Gal4-UAS system, we have produced glioma models in Drosophila by overexpressing homologs of human tyrosine kinase receptors under control of the glia-specific promoter reversed polarity (repo). Glial overexpression of activated epidermal growth factor receptor (EGFR) resulted in enhanced proliferation and migration of larval glial cells with increased numbers in the eye imaginal disc, diffuse tumor-like enlargement of the optic stalk, and marked ectopic invasion of glial cells along the optic nerve. Glial overexpression of the downstream kinase PI3K showed similar pathology. Overexpression of activated pvr (platelet-derived growth factor receptor/vascular endothelial growth factor receptor homolog) led to migration of glial cells along the optic nerve, whereas expression of activated htl (fibroblast growth factor receptor 1 homolog) and INR (insulin receptor) showed markedly elevated numbers of glial cells in the optic stalk. The EGFR/phosphatidylinositol 3-phosphate kinase (PI3K) phenotype was partly reverted by the administration of the EGFR tyrosine kinase inhibitor gefitinib and completely rescued by the PI3K inhibitor wortmannin and the Akt inhibitor triciribine. We suggest that Drosophila models will be useful for deciphering signaling cascades underlying abnormal behavior of glioma cells for genetic screens to reveal interacting genes involved in gliomagenesis and for experimental therapy approaches.
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PMID:Modeling glioma growth and invasion in Drosophila melanogaster. 1972 82

Glioblastomas (GBMs) are the most frequent and malignant brain tumors in adults. Glucocorticoids (GCs) are routinely used in the treatment of GBMs for their capacity to reduce the tumor-associated edema. Few in vitro studies have suggested that GCs inhibit the migration and invasion of GBM cells through the induction of MAPK phosphatase 1 (MKP-1). Macrophage migration inhibitory factor (MIF), an endogenous GC antagonist is up-regulated in GBMs. Recently, MIF has been involved in tumor growth and migration/invasion and specific MIF inhibitors have been developed on their capacity to block its enzymatic tautomerase activity site. In this study, we characterized several glioma cell lines for their MIF production. U373 MG cells were selected for their very low endogenous levels of MIF. We showed that dexamethasone inhibits the migration and invasion of U373 MG cells, through a glucocorticoid receptor (GR)- dependent inhibition of the ERK1/2 MAPK pathway. Oppositely, we found that exogenous MIF increases U373 MG migration and invasion through the stimulation of the ERK1/2 MAP kinase pathway and that this activation is CD74 independent. Finally, we used the Hs 683 glioma cells that are resistant to GCs and produce high levels of endogenous MIF, and showed that the specific MIF inhibitor ISO-1 could restore dexamethasone sensitivity in these cells. Collectively, our results indicate an intricate pathway between MIF expression and GC resistance. They suggest that MIF inhibitors could increase the response of GBMs to corticotherapy.
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PMID:The dexamethasone-induced inhibition of proliferation, migration, and invasion in glioma cell lines is antagonized by macrophage migration inhibitory factor (MIF) and can be enhanced by specific MIF inhibitors. 1975 12

Target identification and validation remain difficult steps in the drug discovery process, and uncovering the core genes and pathways that are fundamental for cancer cell survival may facilitate this process. Glioblastoma represents a challenging form of cancer for chemotherapy. Therefore, we assayed 16,560 short interfering RNA (siRNA) aimed at identifying which of the 5520 unique therapeutically targetable gene products were important for the survival of human glioblastoma. We analyzed the viability of T98G glioma cells 96 h after siRNA transfection with two orthogonal statistical methods and identified 55 survival genes that encoded proteases, kinases, and transferases. It is noteworthy that 22% (12/55) of the survival genes were constituents of the 20S and 26S proteasome subunits. An expression survey of a panel of glioma cell lines demonstrated expression of the proteasome component PSMB4, and the validity of the proteasome complex as a target for survival inhibition was confirmed in a series of glioma and nonglioma cell lines by pharmacological inhibition and RNA interference. Biological networks were built with the other survival genes using a protein-protein interaction network, which identified clusters of cellular processes, including protein ubiquitination, purine and pyrimidine metabolism, nucleotide excision repair, and NF-kappaB signaling. The results of this study should broaden our understanding of the core genes and pathways that regulate cell survival; through either small molecule inhibition or RNA interference, we highlight the potential significance of proteasome inhibition.
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PMID:Identification of survival genes in human glioblastoma cells by small interfering RNA screening. 1978 22

Glioblastoma multiform (GBM) is the most common malignant brain tumour in adults. Despite decades of experimentation to improve the outcome of patients with GBM this highly aggressive tumour remains fatal. Primary GBM are often characterized by the over-expression of epidermal growth factor (EGF) receptor/HER1 and/or its mutational variants, with ligand-independent, constitutively active EGF receptor vIII variant most frequently observed in GBM. EGF receptor signalling can promote tumorigenesis by increasing cell proliferation, tissue invasion, neoangiogenesis, tumour cell chemoresistance, and by inhibiting apoptosis of cancer cells. EGF receptor was the first receptor to serve as target for cancer therapy of many solid tumours. After 2 decades of intensive targeting of EGF receptor for molecular therapy, several anti-EGF receptor inhibitors are now available in the clinic. Therapeutic strategies to target EGF receptor and EGF receptor mutant forms in GBM include humanized monoclonal antibodies, tyrosine kinase inhibitors, and RNAi compounds. However, despite the fact that most EGF receptor-directed glioma therapies to date have focused on single therapeutic agents, a multi-directional approach involving targeted inhibition of multiple signalling pathways has emerged as a more robust therapeutical approach. Furthermore, the emergence of the hypothesis of "brain cancer stem cells" in the bulb of GBM identifies this population of cells with self-renewal capacity as novel obligatory targets for efficient cure of GBM. Here we summarize current findings on the clinical role of these EGF receptor inhibitory therapeutic agents in the treatment of GBM.
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PMID:EGF receptor inhibitors in the treatment of glioblastoma multiform: old clinical allies and newly emerging therapeutic concepts. 1983 72

Glioblastoma (GBM) is the most aggressive and malignant brain tumor. Recent studies indicated that glioma samples are characterized by increased expression of CXCR4, the CXCL12/SDF-1 chemokine receptor. To better understand the role of CXCR4 in GBM biology we performed an integrated study where we simultaneously evaluate the contribution of the CXCR4/CXCL12 signaling pathway to the proliferation, survival and motility of a human GBM cell line. Our results indicated that CXCR4/CXCL12 axis induced an increase in cell proliferation and in cell motility. The blockage of CXCR4 induced a significant increase of apoptosis. Together, our results indicated that CXCR4/CXCL12 signalling pathway may contribute to GBM development and emphasize the therapeutic potential of this pathway in patients with GBM.
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PMID:CXCL12/CXCR4 promotes motility and proliferation of glioma cells. 1992 6

The proliferative and antiapoptotic actions of endothelin (ET)-1 in cancer cells have been documented and ET receptor antagonists have been exploited as potential anticancer drugs. Glioblastoma cell lines express both ETA and ETB receptors and previous works have shown that ETB receptors are involved in the proliferation of different cancer cell types. In this study we have investigated the effects of two structurally unrelated ETB receptor antagonists, BQ788 and A192621, on cell survival, proliferation and apoptosis in 1321-N1, U87 and IPDDCA2 glioma cell lines. BQ788 and A192621 reduced glioma cells viability and proliferation assessed by BrdU incorporation and cell cycle analysis by flow cytometry, while in contrast the ETA receptor antagonist BQ123 had no effect on cell survival. TUNEL assay and immunocytochemical experiments showed that BQ788 and A192621 trigger apoptotic processes mainly via activation of the intrinsic mitochondrial pathway involving caspase-9 activation, AIF release and cytochrome c translocation. Furthermore, treatment with ETB antagonists downregulates ERK- and p38MAPK-dependent pathways but does not affect VEGF mRNA levels. Our findings support the hypothesis that ETB antagonists represent a new promising therapeutic strategy for the treatment of high grade gliomas.
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PMID:Endothelin B receptor antagonists block proliferation and induce apoptosis in glioma cells. 1993 93

Glioblastoma is the most frequent and devastating primary malignant brain tumor in adults. Surgery followed by standard radiotherapy with concomitant and adjuvant chemotherapy with temozolomide is the standard of care in patients with glioblastoma, however the prognosis remains poor with a median survival in the range of 12-15 months. Common genetic abnormalities in glioblastoma are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Special attention has been focused on targets such as epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and on pathways such as the phosphatidylinositol-3kinase/Akt/mammalian target of rapamycin and Ras/Raf/mitogen-activated protein-kinase pathways. Several signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials, including antiangiogenic agents (bevacizumab, enzastaurin), and inhibitors of epidermal growth factor receptor tyrosine kinase (gefitinib and erlotinib), mammalian target of rapamycin (temsirolimus, everolimus) and integrin (cilengitide). Although preliminary clinical results of the use of targeted agents have not translated into significantly better survival, more recent phase II trials are exploring the combination of multitargeted drugs with cytotoxic chemotherapy and radiotherapy in order to overcome the resistance of tumors to single-agent targeted therapies. This review summarizes the current results with cytotoxic and targeted molecular agents in glioblastoma and the development of new chemoradiation strategies under evaluation to increase their effectiveness.
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PMID:Chemotherapy for glioblastoma: current treatment and future perspectives for cytotoxic and targeted agents. 2004 33


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