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)

Cluster of differentiation 15 (CD15) monoclonal antibodies recognise cell adhesion molecules on the surface of many cells including normal astrocytes and metastatic carcinoma cells. The CD15 epitope (fucosyl-N-acetyl-lactosamine), an adhesive oligosaccharide, functions as a ligand for the selectin family of membrane receptors. These include CD62, a cytokineinducible glycoprotein found in platelets and endothelial cells. CD15 is one of a series of putative adhesion molecules expressed in nervous tissue. Selectin-carbohydrate interactions have been implicated in the metastatic spread of cancer cells. We have immunostained a variety of cultured human brain tumours, three cell lines derived from experimental rat gliomas, two specimens of cultured human foetal astrocytes, two metastatic carcinoma cell lines and human umbilical vein endothelial cells (HUVEC) using two monoclonal antibodies which recognise CD15. While all of the animal glioma cells were positive for CD15, only two human glioma cell lines, derived from an anaplastic astrocytoma and a glioblastoma multiforme, respectively, displayed limited reactivity. Chromium radiolabel binding assays of CD15-positive and -negative cell lines including glioma and carcinoma-derived cells, using HUVEC as an attachment substrate, were carried out in the presence and absence of CD15 monoclonal antibody. The level of adhesion of neoplastic cells to HUVEC not only corresponded to CD 15 expression but application of anti-CD 15 monoclonal antibodies considerably reduced adhesion. We postulate that the absence of CD15 on human glioma cells may explain, to some extent, the general failure of intrinsic brain tumours to metastasis by precluding the adhesion of circulating neoplastic glia to 'target' organ endothelium.
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PMID:Nonexpression of CD15 by neoplastic glia: a barrier to metastasis? 765 94

Hyaluronan (HA) and the hyaluronan-binding glycoprotein hyaluronectin (HN) were measured in 23 gliomas and 8 meningiomas and their location was revisited in 35 tumours. A clear-cut difference was found in the HN/HA ratio values of glioblastomas (below 0.5) and that of astrocytomas (above 0.5 P < 0.001). Besides their location in the intercellular part of gliomas, HA and HN displayed a perivascular location in 1/3 astrocytomas, 17/24 glioblastomas, and 3/7 meningiomas, suggesting they could be produced also by the vascular stroma of tumours and that they would characterise the neoangiogenesis. All cultivated glioma cells tested produced HA in vitro, whereas only 1/11 cell lines produced HN, at a low level. The results obtained suggest that glioma HA and HN are produced by both cancer cells and vascular stroma cells, which contribute to the edification of the extracellular matrix. In meningiomas only the stroma would be responsible for HA and HN production.
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PMID:Hyaluronan and hyaluronectin in the extracellular matrix of human brain tumour stroma. 768 96

We have identified the major cellular endoprotease that activates the fusion (F) glycoprotein of measles virus (MV) and have engineered a serine protease inhibitor (serpin) to target the endoprotease and inhibit the production of infectious MV. The F-protein precursor of MV was not cleaved efficiently into the mature F protein in human colon carcinoma cells lacking functional furin, indicating that furin is the major enzyme responsible for activation of the MV F protein. A human serpin alpha 1-antitrypsin variant was engineered to specifically inhibit furin. When expressed from a recombinant vaccinia virus in primate cells infected by MV, the engineered serpin (alpha 1-PDX) specifically inhibited furin-catalyzed cleavage of the F-protein precursor without affecting synthesis of other MV proteins. We generated human glioma cells stably expressing alpha 1-PDX. MV infection in these cells did not result in syncytia. The infected cells produced all the MV proteins, but the F-protein precursor remained largely uncleaved. This did not prevent virus assembly. However, the released virions contained inactive F-protein precursor rather than mature F protein, and infectious-virus titers were reduced by 3 to 4 orders of magnitude. These results show that a mature F protein is not required for the assembly of MV but is crucial for virus infectivity. The engineered serpin may offer a novel molecular antiviral approach against MV.
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PMID:Engineered serine protease inhibitor prevents furin-catalyzed activation of the fusion glycoprotein and production of infectious measles virus. 770 52

Resistance to chemotherapy in brain tumors is complex and may involve multiple mechanisms. For commonly used drugs, such as nitrosoureas and platinum compounds, major mechanisms may involve increaded DNA repair or removal of the drug-DNA adducts. For water soluble nitrosoureas and also for platinum compounds, other mechanisms, such as alteration in drug transport, may be important. Another major mechanism may involve glutathione and glutathione-S-transferase pathways. For vinca alkaloids and epipodophyllotoxins p-glycoprotein mediated MDR appears to be the major feature in drug resistance. In addition, alteration of tubulin and topoisomerase II have been described in resistance to vinca alkaloids and epipodophyllotoxins respectively. Recently, increased multidrug resistance associated protein gene expression has been found in glioma cells and brain tumor samples; its clinical significance requires further investigation.
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PMID:Drug resistance in brain tumors. 780 93

Resistance to multiple drugs is often observed in malignant gliomas. The authors used a microtiter tetrazolium test to analyze primary in vitro chemoresistance and chemosensitivity of 15 early cultures of human malignant glioma exposed to 50 micrograms/ml (1,4-amino-2-methyl-5-pyrimidinyl)-methyl-3-(2-chloroethyl)-3-nitrosoure a (ACNU), 50 micrograms/ml cisplatin, 1 microgram/ml vincristine, or combinations of these chemotherapeutic agents. Primary chemoresistance was observed in 87% of tumors for ACNU, in 87% for cisplatin, and in 83% for vincristine. All tumors were examined for expression of multidrug-resistant p-glycoprotein, a transport protein of 170,000 D, by means of immunohistochemical staining with the JSB-1 antibody on paraffinized tumor sections. Eight of 15 specimens (53%) showed positive staining for the monoclonal antibody. Primary chemoresistance was overcome by addition of the calcium antagonists verapamil or nimodipine to the cultures if the original tumor expressed p-glycoprotein (p < 0.01 for verapamil, p < 0.05 for nimodipine). In tumors not expressing p-glycoprotein, addition of calcium antagonists to the cell cultures did not influence primary chemoresistance. It is concluded from these data that addition of calcium antagonists to the adjuvant chemotherapy of malignant gliomas might overcome primary chemoresistance in tumors expressing the multidrug-resistant phenotype.
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PMID:Reversal of chemoresistance in malignant gliomas by calcium antagonists: correlation with the expression of multidrug-resistant p-glycoprotein. 793 93

Previously we found that ethanol increases expression of the constitutive 70-kDa heat shock protein (Hsc70) in NG108-15 neuroblastoma x glioma cells. We suggested that known ethanol actions on cellular protein trafficking may relate to Hsc70 induction because Hsc70 functions as a molecular chaperone. Here we use a subtractive hybridization protocol to isolate ethanol-responsive genes (EtRGs). Northern blot hybridization verified ethanol-induced increases in mRNA abundance for five cDNA clones isolated from ethanol-treated NG108-15 neuroblastoma x glioma cells. DNA sequence analysis identified one EtRG as 94-kDa glucose-regulated protein (GRP94), a member of the "glucose-responsive" subgroup of stress proteins. Other identified EtRGs included an insulin-induced growth-response protein gene and an intracisternal A-type particle gene. Sequence analysis of the remaining two EtRGs showed no homology in DNA sequence databases. All EtRGs showed wide tissue expression, except SL64, which was not detected in Northern blot analyses of adult mouse or rat tissues. Ethanol also increased mRNA abundance for 78-kDa glucose-regulated protein (GRP78), a molecular chaperone known to function in glycoprotein trafficking and usually coordinately regulated with GRP94. However, ethanol induced GRP94 more than GRP78, a pattern distinct from those of other inducers of these genes. All EtRGs, including GRP94 and GRP78, showed similar ethanol concentration-dependent increases in mRNA abundance. In contrast, thapsigargin and other inducers of glucose-responsive proteins increased GRP94 and GRP78 mRNA levels without altering expression of other EtRGs. Our studies demonstrate that several molecular chaperones constitute a subset of EtRGs. Ethanol appears to regulate these EtRGs by a unique mechanism, rather than one shared by classical inducers of stress proteins.
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PMID:Ethanol-responsive genes in neural cells include the 78-kilodalton glucose-regulated protein (GRP78) and 94-kilodalton glucose-regulated protein (GRP94) molecular chaperones. 796 74

Our studies in the NG108-15 neuroblastoma x glioma cell line previously showed that the molecular chaperonin, Hsc70, is an ethanol-responsive gene (EtRG) regulated at the level of transcription by ethanol. We recently identified two related molecular chaperonins, GRP94 and GRP78, as EtRGs with GRP94 mRNA abundance being induced by ethanol more than three-fold vs. control. Stable transfection studies show that GRP78 transcription is also regulated by ethanol and that ethanol also potentiates GRP78 induction by classical inducing agents such as tunicamycin. Recently, we have found that ethanol induction of Hsc70 may require cis-acting promoter sequences recognized by the DNA-binding protein Sp1. Chronic ethanol exposure does not alter Sp1 DNA-binding activity, thus suggesting a possible ethanol-induced post-translational modification that activates Sp1 function. We predict that the molecular mechanisms underlying ethanol regulation of Hsc70, GRP94 and GRP78 may be similar since they have related functions. GRP94 and GRP78 (GRP94/78) are known to be induced by agents which inhibit glycoprotein processing or deplete endoplasmic reticulum stores of calcium. In turn, induction of GRP78 expression is known to selectively alter the transport of glycoproteins and produce "tolerance" to depletion of sequestered intracellular calcium. The regulation of these genes by ethanol could thus relate to the known effects of ethanol on calcium homeostasis and protein trafficking. The actions of ethanol on chaperonin gene expression may have important mechanistic implications for CNS adaptation to ethanol, particularly if other EtRGs share the same regulatory mechanisms.
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PMID:Effects of alcohol on gene expression in neural cells. 803 72

Among the most specific markers of the blood-brain barrier phenotype of endothelial cells are the well-characterized immunoglobulin-like surface glycoprotein HT7 and the probably related or identical glycoprotein neurothelin. Both can be induced in chorioallantoic vessels by transplants of embryonic mouse brain. Other blood-brain barrier markers have been shown to be inducible by type-1 astrocytes in endothelial cells of non-neural origin. In the present work we tested the hypothesis that this cellular interaction between astrocytes and endothelial cells is mediated by a soluble factor(s). Chorioallantoic vessels of embryonic day 9 chick embryos were exposed for 4 or 10 days to a constant and localized delivery of astrocyte-conditioned medium by using a piece of gelfoam posed onto the chorioallantoic membrane, as a localized reservoir, which was connected to a miniosmotic pump system delivering astrocyte-conditioned medium at a steady rate. We found that in a significant number of chorioallantoic vessels located near the gelfoam, endothelial cells exposed to astrocyte-conditioned medium for a period of 4 or 10 days, but not to glioma-, fibroblast- or endothelial cell-derived conditioned medium, expressed the HT7 antigen and neurothelin. These results provide evidence that type-1-astrocytes are capable of inducing blood-brain barrier related properties in endothelial cells of non-neural origin through a soluble factor(s).
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PMID:Astrocytes secrete a factor inducing the expression of HT7-protein and neurothelin in endothelial cells of chorioallantoic vessels. 833 36

The C6 rat glioma cell line is response to glucocorticoid hormones. C6 variants that are hyper-responsive (ST1) and resistant (P7) to hormone treatment have been derived previously. Glucocorticoid treatment of ST1 cells leads to complete reversion of the transformed phenotype and loss of tumorigenic potential. Production of C type retrovirus particles is also induced by glucocorticoids in ST1 cells. Cloning of the genes regulated by glucocorticoids in this cell system was used here as a strategy to uncover the gene products involved in the transformed-to-normal phenotypic change. Construction of a cDNA library from glucocorticoid-treated ST1 cells and screening by differential hybridization resulted in the isolation of three cellular sequences that code for rat metallothioneins (C27 and C41) and alpha 1-acid glycoprotein (C36). Northern blot analysis revealed that expression of these genes was dramatically induced by hydrocortisone in ST1 but not in P7 cells. Viral genomic RNA was used to isolate and characterize retrovirus-related sequences that could also be responsible for the phenotypic reversion phenomenon.
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PMID:Cloning of glucocorticoid-regulated genes in C6/ST1 rat glioma phenotypic reversion. 856 57

GRP78, a molecular chaperone expressed in the endoplasmic reticulum, is a "glucose-regulated protein" induced by stress responses that deplete glucose or intracisternal calcium or otherwise disrupt glycoprotein trafficking. Previously we showed that chronic ethanol exposure increases the expression of GRP78. To further understand the mechanism underlying ethanol regulation of GRP78 expression, we studied the interaction between ethanol and classical modulators of GRP78 expression in NG108-15 neuroblastoma x glioma cells. We found that, in addition to increasing basal levels of GRP78 mRNA ("induction"), ethanol produced greater than additive increases in the induction of GRP78 mRNA by the "classical" GRP inducers A23187, brefeldin A, and thapsigargin ("potentiation"). Both the ethanol induction and potentiation responses modulated grp78 gene transcription as determined by stable transfection analyses with the rat grp78 promoter. Ethanol potentiated the action of all classical inducers of grp78 transcription that were studied. In contrast, co-treatment with the classical GRP inducers thapsigargin and tunicamycin produced only simple additive increases in grp78 promoter activity. Transient transfection studies with deletion mutants of the rat grp78 promoter showed that cis-acting promoter sequences required for ethanol induction differ from those mediating responses to classical GRP inducers. Furthermore, linker-scanning mutations of the grp78 promoter suggested that the ethanol potentiation response required a cis-acting promoter element different from those involved in induction by ethanol or classical inducing agents. While the ethanol induction response required 16-24 h to be detectable, ethanol potentiation of thapsigargin occurred within 6 h. The potentiation response also decayed rapidly after ethanol removal. In addition, the protein kinase A inhibitor Rp-cAMPS and protein phosphatase inhibitor okadaic acid both increased ethanol potentiation of thapsigargin while Sp-cAMPS, an activator of protein kinase A, decreased ethanol potentiation. Taken together, our findings suggest two mechanisms by which ethanol regulates grp78 transcription, both differing from the action of classical GRP inducers such as thapsigargin. One mechanism (potentiation) involves a protein phosphorylation cascade and potentiates the action of classical GRP inducers. In contrast, GRP78 induction by ethanol involves promoter sequences and a mechanistic pathway separate from that of the ethanol potentiation response or classical GRP78 inducers. These studies show that ethanol produces a novel and complex regulation of grp78 transcription which could be of particular importance during neuronal exposure to GRP-inducing stressors as might occur with central nervous system injury.
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PMID:Interaction of ethanol with inducers of glucose-regulated stress proteins. Ethanol potentiates inducers of grp78 transcription. 857 45


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