UMLS:C0027819 - FACTA Search

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Query: UMLS:C0027819 (neuroblastoma)
27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To infect target cells, the human immunodeficiency virus (HIV) type I (HIV-1) must engage not only the well-known CD4 molecule, but it also requires one of several recently described coreceptors. In particular, the CXCR4 (LESTR/fusin) receptor allows fusion and entry of T-tropic strains of HIV, whereas CCR5 is the major coreceptor used by primary HIV-1 strains that infect macrophages and CD4(+) T-helper cells (M-tropic viruses). In addition, the alpha chemokine SDF1alpha and the beta chemokines MIP1alpha, MIP1beta, and RANTES, natural ligands of CXCR4 and CCR5, respectively, are potent soluble inhibitors of HIV infection by blocking the binding between the viral envelope glycoprotein gp120 and the coreceptors. Approximately two-thirds of individuals with acquired immunodeficiency syndrome (AIDS) show neurologic complications, which are referred to a syndrome called AIDS dementia complex or HIV-1-associated cognitive/motor complex. The HIV-1 coat glycoprotein gp120 has been proposed as the major etiologic agent for neuronal damage, mediating both direct and indirect effects on the CNS. Furthermore, recent findings showing the presence of chemokine receptors on the surface of different cell types resident in the CNS raise the possibility that the association of gp120 with these receptors may contribute to the pathogenesis of neurological dysfunction. Here, we address the possible role of alpha and beta chemokines in inhibiting gp120-mediated neurotoxicity using the human neuroblastoma CHP100 cell line as an experimental model. We have previously shown that, in CHP100 cells, picomolar concentrations of gp120 produce a significant increase in cell death, which seems to proceed through a Ca(2+) - and NMDA receptor-dependent cascade. In this study, we gained insight into the mechanism(s) of neurotoxicity elicited by the viral glycoprotein. We found that CHP100 cells constitutively express both CXCR4 and CCR5 receptors and that stimulation with phorbol 12-myristate 13-acetate down-regulates their expression, thus preventing gp120-induced cell death. Furthermore, all the natural ligands of these receptors exerted protective effects against gp120-mediated neuronal damage, although with different efficiencies. These findings, together with our previous reports, suggest that the neuronal injury observed in HIV-1 infection could be due to direct (or indirect) interactions between the viral protein gp120 and chemokine and/or NMDA receptors.
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PMID:gp120 induces cell death in human neuroblastoma cells through the CXCR4 and CCR5 chemokine receptors. 1082 Jan 98

Stromal cell-Derived Factor-1 (SDF-1alpha), binds to the seven-transmembrane G protein-coupled CXCR4 receptor and modulates cell migration, differentiation, and proliferation. CXCR4 has been reported to be expressed in various tissues including brain. Moreover, CXCR4 has recently been shown to be one of the coreceptors for HIV-1 infection which could be implicated in HIV encephalitis. In the present study, the binding properties and autoradiographic distribution of [125I]SDF-1alpha binding to CXCR4 were characterized in the adult rat brain. SDF-1alpha binding and CXCR4 coupling system were also studied in human neuroblastoma cell line SK-N-SH. The binding of [125I]SDF-1alpha on rat brain sections was specific, time-dependent and reversible. The highest densities of CXCR4 were detected in the choroid plexus of the lateral and the dorsal third ventricle. Lower densities of [125I]SDF-1alpha binding sites were observed in various brain regions including cerebral cortex, anterior olfactory nuclei, hippocampal formation, thalamic nuclei, blood vessels and pituitary gland. In the choroid plexus, the IC(50) and K(d) of [125I]SDF-1alpha binding were respectively 0.6 nM and 0. 36 nM. Similar IC(50) values were obtained in other brain structures. A CXCR4 antagonist, bicyclam, competed with SDF-1alpha binding (30% inhibition at 10(-6) M). In SK-N-SH cells, [125I]SDF-1alpha bound to CXCR4 with a K(d) of 5.0 nM and a maximal binding capacity of 460 fmol/mg of protein. SDF-1alpha induced a rapid and transient intracellular calcium increase in SK-N-SH cells. These findings suggest that CXCR4 is highly expressed in some brain structures and have a regulatory role in the nervous system. The significance of this expression in the brain parenchyma and more specifically in the choroid plexus remains to be clarified in the normal as well as in the infected brain.
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PMID:Characterization and visualization of [125I] stromal cell-derived factor-1alpha binding to CXCR4 receptors in rat brain and human neuroblastoma cells. 1102 45

The homing of hemopoietic stem cells to the bone marrow is mediated by specific interactions occurring between CXCR4, which is expressed on hemopoietic stem cells, and its ligand, stromal cell-derived factor-1 (SDF-1), a CXC chemokine secreted by bone marrow stromal cells. In the present study we evaluated the possibility that neuroblastoma cells use a mechanism similar to that used by hemopoietic stem cells to home to the bone marrow and adhere to bone marrow stromal cells. Our study suggests that CXCR4 expression may be a general characteristic of neuroblastoma cells. SH-SY5Y neuroblastoma cells express not only CXCR4, but also its ligand, SDF-1. CXCR4 expression on SH-SY5Y neuroblastoma cells is tightly regulated by tumor cell-derived SDF-1, as demonstrated by the ability of neutralizing Abs against human SDF-1alpha to up-regulate CXCR4 expression on the tumor cells. The reduction in CXCR4 expression following short term exposure to recombinant human SDF-1alpha can be recovered as a result of de novo receptor synthesis. Recombinant human SDF-1alpha induces the migration of CXCR4-expressing SH-SY5Y neuroblastoma cells in CXCR4- and heterotrimeric G protein-dependent manners. Furthermore, SH-SY5Y cells interact at multiple levels with bone marrow components, as evidenced by the fact that bone marrow-derived constituents promote SH-SY5Y cell migration, adhesion to bone marrow stromal cells, and proliferation. These results suggest that SH-SY5Y neuroblastoma cells are equipped with adequate machinery to support their homing to the bone marrow. Therefore, the ability of neuroblastoma tumors to preferentially form metastases in the bone marrow may be influenced by a set of complex CXCR4-SDF-1 interactions.
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PMID:A possible role for CXCR4 and its ligand, the CXC chemokine stromal cell-derived factor-1, in the development of bone marrow metastases in neuroblastoma. 1159 6

The human immunodeficiency virus type 1 (HIV-1) coat glycoprotein gp120 binds to its (co)receptors and orchestrates cell entry by the direct fusion of viral and target cell membranes. Here, we modulated membrane fluidity of human neuroblastoma CHP100 cells by modulating their cholesterol content, and investigated the ability of gp120 to induce cell death in comparison with the untreated cells. We show that in normal CHP100 cells gp120 induces necrosis by: (i) increased cyclooxygenase and 5-lipoxygenase activity, and metabolites generated thereof (prostaglandin E2 and leukotriene B4, respectively); (ii) increased membrane lipoperoxidation; and (iii) increased mitochondrial uncoupling. These events were triggered by a rapid increase in intracellular calcium, and in cholesterol-depleted cells engaged CXCR4 chemokine receptors. The intracellular calcium chelator EGTA-AM protected CHP100 cells almost completely against the toxic effects of gp120. However, gp120-induced necrosis and related biochemical changes were negligible in cholesterol-enriched, and significantly enhanced in cholesterol-depleted, CHP100 cells exposed to the viral glycoprotein under the same experimental conditions. Taken together, these results suggest that membrane fluidity may control the neurotoxic effects of HIV-1 glycoprotein gp120.
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PMID:Cholesterol-dependent modulation of the toxicity of HIV-1 coat protein gp120 in human neuroblastoma cells. 1235 92

To study the mechanism by which HIV-1 infects neurons we have used human neuroblastoma cell lines (NB). NB (SK-N-SH and SK-N-MC) were found to be susceptible to productive infection by X4 or R5 HIV-1, as detected by viral load and Ag-p24. To identify the putative receptor, we tested the cell surface expression of previously described receptors such as CD4, nucleolin, galactosylceramide, and CCR1, CCR5, and CXCR4 by cytometry and RT-PCR. NB express no CD4 and low levels of galactosylceramide or nucleolin. Furthermore, antibodies to any of these molecules did not affect NB infection. NB express variable levels of CCR5, CCR1, and CXCR4. Interestingly, exogenous heparan sulfate alone was able to substantially inhibit HIV-1 infection, an effect which was potentiated by RANTES or SDF-1 in the HIV-1-infection with R5 or X4 isolates. Besides, anti-CCR5 and anti-CXCR4 significantly blocked HIV-1 infection of R5 and X4 isolates. Our results suggest that HIV-1 entry involves a chemokine-receptor-dependent but CD4-independent entry in neural cells.
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PMID:A new possible mechanism of human immunodeficiency virus type 1 infection of neural cells. 1258 55

Human immunodeficiency virus type 1 (HIV-1)-associated central nervous system disorders, including encephalopathy, often occur in the late stage of HIV-1 infection. Some inflammatory cytokines and HIV-1 antigens released from infected microglia or brain macrophages are considered to play an important role in neuropathogenesis. In this study, an in vitro assay system has been established for the evaluation of neural cell death, which would be predictive of the pathogenesis of neural cell death in vivo. The human neuroblastoma cell line SK-N-SH was differentiated to a neural phenotype with retinoic acid, while the promyelocytic cell line HL-60 and its HIV-1-infected clone OM-10.1 were differentiated to macrophages with phorbol myristate acetate. When neural (differentiated SK-N-SH) cells were cocultured with either uninfected or HIV-1-infected macrophages (differentiated HL-60 or OM-10.1 cells, respectively) for 3-5 days, significant neural cell death was observed in the cells cocultured with infected macrophages. Direct contact with macrophages was not necessary for the induction of neural cell death, since indirect coculture or coculture supernatants could also induce neural cell death. Large amounts of cytokines and chemokines were released in the coculture supernatants. The CXCR4 antagonist AMD3100 and the HIV-1 transcription inhibitor K-37 partially inhibited neural cell death. These results indicate that this system seems to be a useful tool for the evaluation of compounds against HIV-1-induced neural cell death.
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PMID:Establishment of an in vitro assay system mimicking human immunodeficiency virus type 1-induced neural cell death and evaluation of inhibitors thereof. 1260 87

Several patients with acquired immunodeficiency syndrome (AIDS) develop neurological complications, which are referred to as human immunodeficiency virus (HIV)-associated dementia (HAD). The HIV-1 coat glycoprotein gp-120 has been proposed as the major etiologic agent for neuronal loss reported postmortem in the brain of AIDS patients. Chemokine receptors may play a role in gp-120-triggered neurotoxicity, both in vitro and in vivo, thus being an intriguing target for developing therapeutic strategies aimed to prevent or reduce neuronal damage occurring during HIV infection. We have previously shown that human CHP100 neuroblastoma cells express CXCR4 and CCR5 chemokine receptors and that interaction between gp-120 and these receptors contributes to cytotoxicity elicited by the protein. Here, we examined the neuroprotective potential of neomycin B hexa-arginine conjugate (NeoR), a recently synthesized compound with anti-HIV activity. We found that gp-120-triggered death is significantly reduced by NeoR, and this protective effect seems related to the ability of NeoR to interact with CXCR4 receptors. The ability of NeoR to cross the blood-brain barrier, as demonstrated in mice by systemic administration of the fluorescein conjugate drug, makes this compound a powerful and attractive therapeutic agent.
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PMID:The Tat antagonist neomycin B hexa-arginine conjugate inhibits gp-120-induced death of human neuroblastoma cells. 1261 24

In previous studies, we demonstrated that human neuroblastoma cells are equipped with the machinery to direct their homing to bone marrow. These tumor cells express the CXCR4 receptor for the bone marrow stroma-derived chemokine CXCL12 (SDF-1) and secrete the CXCL12 ligand. The present study was undertaken to explore possible differences in gene-expression patterns between neuroblastoma variants that over-express CXCR4 (designated STH cells) and those which express very little of this receptor (STL cells). The results of the study clearly indicate that these variants show a differential gene-expression profile. They differ in expression of some integrins such as VLA2, VLA3 and VLA6, of neuroendocrine-markers such as CD56 and synaptophysin, in the expression of c-kit and in the secretion of certain cytokines and growth factors such as TNFalpha, SDF-1, VEGF, IL-8, GM-CSF and IP-10. We hypothesize that these differences are due to an autocrine SDF-1alpha-CXCR4 axis.
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PMID:The tumor microenvironment: CXCR4 is associated with distinct protein expression patterns in neuroblastoma cells. 1508 41

Neuroblastoma, a cancer of young children, is well known for its diverse pattern of presentation. Approximately one-half of children have localized tumors that can be cured with surgery alone. The remaining children have widespread metastatic disease or quite large, aggressive, localized tumors. These children have a poor long-term survival rate of approximately 30%. We review the prognostically significant histologic and molecular features of high risk neuroblastoma and propose an algorithm to dissect further the differentially expressed genes that define the phenotype of this disease. Over the past 25 years, much effort has gone into establishing reliable prognostic indicators of high risk disease. For neuroblastoma, age, stage, and histopathology have time and again correlated well with outcomes. Chromosomal number, or ploidy, and amplification of the MYCN oncogene have proved to be equally as important and are commonly used to stratify patient risk. Other potentially lucrative markers include chromosome 1p deletion, chromosome 17q gain, receptor tyrosine kinases A and B (trk-A, trk-B), CD44, CXCR4, and multidrug resistance associated protein (MRP). With the onset of new technology, expression microarrays are now being used to profile advanced-stage neuroblastoma on a larger scale. Genes particular to cell cycle control, DNA/RNA replication, ribosomal synthesis, neuronal differentiation, and intracellular/extracellular signal transduction have been identified through differential expression analysis. We present our research on the MYCN transcription factor and target gene, MCM7, to show the utility of this approach.
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PMID:Gene profiling of high risk neuroblastoma. 1570 35

Stromal cell-derived factor-1alpha (SDF-1alpha) is a chemokine whose receptor, CXCR4, is distributed in specific brain areas including hypothalamus. SDF-1alpha has recently been found to play important roles in neurons, although direct modulation of voltage-gated ionic channels has never been shown. In order to clarify this issue, we performed patch-clamp experiments in fetal mouse hypothalamic neurons in culture. SDF-1alpha (10 nm) decreased the peak and rising slope of the action potentials and spike discharge frequency in 22% of hypothalamic neurons tested. This effect was blocked by the CXCR4 antagonist AMD 3100 (1 microm) but not by the metabotropic glutamate receptor antagonist MCPG (500 microm), indicating a direct action of SDF-1alpha on its cognate receptor. This effect involved a depression of both inward and outward voltage-dependent currents of the action potential. We confirmed these effects in the human neuroblastoma cell line SH-SY5Y, which endogenously expresses CXCR4. Voltage-clamp experiments revealed that SDF-1alpha induced a 20% decrease in the peak of the tetrodotoxin-sensitive sodium current and tetraethylammonium-sensitive delayed rectifier potassium current, respectively. Both effects were concentration dependent, and blocked by AMD 3100 (200 nm). This dual effect was reduced or blocked by 0.4 mm GTPgammaS G-protein pre-activation or by pre-treatment with the G-protein inhibitor pertussis toxin (200 ng/mL), suggesting that it is mediated via activation of a G(i/o) protein. This study extends the functions of SDF-1alpha to a direct modulation of voltage-dependent membrane currents of neuronal cells.
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PMID:Stromal cell-derived factor-1alpha directly modulates voltage-dependent currents of the action potential in mammalian neuronal cells. 1585 99

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