Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027819 (neuroblastoma)
 27,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte macrophage colony-stimulating factor (GM-CSF)-transduced autologous tumor cells form the basis of many immunotherapeutic strategies. We tested whether combining this approach with T-helper 1 (Th-1)-like immunostimulatory CpG oligodeoxynucleotides (CpG ODNs) would improve therapeutic efficacy in an established model of murine neuroblastoma. The weakly immunogenic Neuro-2a cell line was used in syngeneic A/J mice. CpG 1826 was tested for its antitumor effect alone and as an adjuvant to Neuro-2a cells retrovirally transduced to express murine GM-CSF (GM/Neuro-2a). Three days after wild-type (WT) tumor cell inoculation, mice in different groups were s.c. vaccinated in the opposite leg with combinations of WT neuro2a, irradiated (15 Gy) WT or GM/Neuro-2a transfectants with or without CpG 1826 (200 micro g). To test for the induction of memory responses, mice that rejected their tumor were rechallenged with WT Neuro-2a (1 x 10(6)) 7 weeks after vaccination. All of the mice in the control (unvaccinated) group died within 3 weeks after Neuro-2a inoculation. Most of the vaccinated groups had only minimal-to-modest antitumor responses, and the mice succumbed to tumor. Tumor growth was remarkably inhibited in the group of mice that received irradiated GM/Neuro-2a plus CpG and four (50%) of eight mice in this group survived tumor free. Tumor-free mice were resistant to further WT tumor cell challenge, indicating a memory response. Mechanistic studies showed that CpG alone induced a favorable Th-1-like cytokine immune response and vaccine-induced tumor cell killing was dependent on both CD4 and CD8 T cells that killed tumor cell targets by apoptosis. These results demonstrate that CpG ODNs enhanced the antitumor effect of irradiated GM-CSF secreting Neuro-2a cells. This vaccine strategy elicits a potent tumor antigen-specific immune response against established murine neuroblastoma and generates systemic neuroblastoma-specific immunity.
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PMID:CpG oligonucleotides enhance the tumor antigen-specific immune response of a granulocyte macrophage colony-stimulating factor-based vaccine strategy in neuroblastoma. 1254 93

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

Human gammadelta T cells are a small fraction of T cells that have been shown to exert major histocompatibility (MHC)-unrestricted natural cytotoxicity against a variety of solid tumors and some subsets of leukemias and lymphomas. They are also involved in the immune response to certain bacterial, viral, and parasitic infections and expand significantly in CMV- or HSV-infected organ allografts. They are able to mediate antibody-dependent cytotoxicity and are not alloreactive, which makes them attractive candidates for cell-based immunotherapy. However, their frequency in peripheral blood is low and ex vivo expansion of gammadelta T cells is labor-extensive, does not always yield cells with full innate cytotoxic power, and has the potential for microbial contamination. Therefore, the authors developed a clinical-scale, automated cell purification method for the efficient enrichment of gammadelta T cells from leukapheresis products. Six leukapheresis products were purified for gammadelta T cells using a single-step immunomagnetic method. Purity and phenotype were assessed by flow cytometry. A standard Europium release assay was performed to determine the cytotoxic capacity of the cells. Cytokine production was measured using a multiplex sandwich immunoassay. The mean percentage of gammadelta T cells in the final product was 91%, with an average recovery of 63%. The cells showed a high co-expression of CD8, CD56, CD28, and CD11b/CD18. In some products an unusually high proportion of Vgamma9Vdelta1 T cells was found. The isolated cells were cytotoxic against the neuroblastoma cell line NB1691 and the erythroleukemic line K562 in vitro. They were able to produce a variety of immunomodulatory cytokines such as IFNgamma, TNFalpha, and MIP-1beta, but also GM-CSF and G-CSF when co-incubated in culture with and without various stimuli. In summary, the authors describe a rapid, automated, and efficient method for the large-scale enrichment of human gammadelta T cells. The cytotoxic properties of the cells were preserved. This method yields sufficient purified gammadelta T cells for use in adoptive immunotherapy as well as laboratory investigations and animal studies.
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PMID:Human gammadelta T cells from G-CSF-mobilized donors retain strong tumoricidal activity and produce immunomodulatory cytokines after clinical-scale isolation. 1561 47

We have prepared the map of regional distribution of cervical cancer in Hungary. Serial HPV genotyping of sexual partners provided evidence for the sexually transmitted infections. Molecular epidemiology studies revealed activating c-kit mutation in bilateral testicular cancers. A cost-effective molecular staging method was introduced to the management of breast cancer patients. Genomic profiling identified the gene signature of Herceptin and taxane sensitivity of breast cancer. In colon cancer patients we have determined the mutational spectrum of hMLH1 and hMSH2 genes in Hungary. The prognostic power of SHMT and MTHFR polymorphism was determined in colorectal cancer patients. In head and neck cancer the gene signature of cisplatin sensitivity and the EGFR polymorphism was determined. We have introduced a cost-effective in vitro assay to determine the drug resistance of pediatric leukemias. The prognostic power of N-myc genotyping was determined in neuroblastoma patients. A phase I trial for gene therapy of brain cancer was started by using a GM-CSF adenoviral vector system. Using global genomic approaches the gene signature of malignant melanoma and its metastatic disease was determined. We have found that Ca-channel blockers and EGFR tyrosine kinase inhibitors are effective in preclinical human melanoma models in breaking the apoptosis resistance of this tumor.
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PMID:[Activity of the National Oncology R&D Consortium in 2004]. 1590 26

Polysialic acid (PSA) is highly expressed in many human cancers, including neuroblastoma (NB), and is critical for cellular adhesion, neuronal migration and tumor metastasis. The key enzyme responsible for PSA synthesis is sialyltransferase STX (ST8SiaII). Using quantitative RT-PCR we (i) studied STX expression in 39 NB tumors and 8 cell lines and (ii) examined its potential clinical utility as an early response marker in the bone marrows of the entire cohort of 136 high-risk NB patients treated with an immunotherapy protocol utilizing anti-GD2 antibody 3F8 and GM-CSF. Based on the quantitation of 24 normal marrow and peripheral blood samples, a normalized STX transcript value below the mean + 2SD was defined as negative. Sensitivity of this assay was 1 NB cell in 10(6) normal mononuclear cells. STX expression was high among NB tumors of all stages, as well as NB cell lines of different phenotypes. Evaluation for early (2.5 months from protocol entry) marrow response by univariate Cox model indicated that STX marker status (positive versus negative) was strongly associated with both progression-free and overall survival (p < 0.0005 for both). Similarly, the STX transcript level of posttreatment marrows was also highly prognostic of outcome (PFS, p = 0.001; OS, p < 0.0005). We conclude that STX mRNA has potential clinical utility as a molecular marker of metastatic NB.
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PMID:Sialyltransferase STX (ST8SiaII): a novel molecular marker of metastatic neuroblastoma. 1645 Mar 93

The hematopoietic cytokine erythropoietin (Epo) exerts cytoprotective effects on several types of neuronal cells both in vivo and in culture. Detailed molecular mechanisms underlying this phenomenon have not been elucidated and even the identity of the cytoprotective Epo receptors in neuronal cells is controversial. Here we show that Epo prevents staurosporine-induced apoptosis of differentiated human neuroblastoma SH-SY5Y cells, and activates the STAT5, AKT and MAPK signaling pathways. Differentiated SH-SY5Y cells have fewer than 50 high affinity Epo surface binding sites per cell, which could not be detected by standard assays measuring binding of 125I-labeled Epo. However, by measuring endocytosis of 125I-Epo, we could reliably quantify very small numbers of high-affinity Epo surface binding sites. Using SH-SY5Y cells stably expressing an Epo receptor (EpoR) shRNA and thus lacking detectable EpoR expression, we show that high affinity binding of Epo to these neuronal cells is mediated by the hematopoietic EpoR, and that this EpoR is also essential for the antiapoptotic activity of Epo. In contrast, a mutant Epo that has an intact binding site 1 but a non-functional binding site 2 and hence binds only to one cell surface EpoR molecule ("site 2" Epo mutant) displays significantly lower antiapoptotic activity than wild-type Epo. Furthermore, expression of the GM-CSF/IL-3/IL-5 receptor common beta chain, which was proposed to be responsible for the cytoprotective activity of Epo on certain types of neuronal cells, was undetectable in differentiated SH-SY5Y cells. Epo also alleviated staurosporine-induced apoptosis of rat PC-12 pheochromocytoma cells while the R103A "site 2" Epo mutant did not, and we could not detect expression of the common beta chain in PC-12 cells. Together our results indicate that Epo exerts its antiapoptotic effects on differentiated SH-SY5Y and PC-12 cells through the standard stoichiometry of one molecule of Epo binding to two EpoR subunits, comprising the "classical" Epo receptor signaling complex.
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PMID:A "classical" homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells. 1704 82

Recently, we reported that GM-CSF showed therapeutic effects on the spinal cord injury (SCI) in rat model possibly via its anti-apoptotic activity in the nervous system. This study investigated the molecular mechanism of its anti-apoptotic and neuroprotective effects in N2a neuroblastoma cells and in rat SCI model. GM-CSF inhibited staurosporine-induced cytotoxicity and apoptosis of N2a cells. Single administration of GM-CSF either intraperitoneally or locally using a gelfoam, clearly reduced the apoptotic events in the surrounding region of the injury site in rat SCI model. Immunohistochemical analysis showed that apoptosis of cells occurred mainly in the neurons, but not significantly in the astrocytes in the surrounding regions. In both N2a cells and in rat SCI model, GM-CSF actually reduced the expression of pro-apoptotic proteins (p53, p21(WAF1/CIP1) and Bax), while further induced that of an anti-apoptotic protein (Bcl-2). In the Basso-Beattie-Bresnahan (BBB) locomotor test, the single GM-CSF administration showed better behavioral recovery than the untreated control only at early times within 1 week after injury. Overall, GM-CSF was shown to exert its neuroprotective effect on the neural injury by regulating the expression of apoptosis related genes, providing the molecular basis on its anti-apoptotic activity. Longer administration of GM-CSF appeared to be necessary for the sustained functional recovery from SCI.
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PMID:GM-CSF inhibits apoptosis of neural cells via regulating the expression of apoptosis-related proteins. 1733 4

GM-CSF is recently being suggested to play important role(s) in the nervous system. Present study was intended to understand signal transduction pathways of GM-CSF in human neuroblastoma (SK-N-(BE)2) and glioblastoma (A172) cell lines. The expression of GM-CSF receptors on the surface of these cells was confirmed by immunocytochemistry, Western blot analysis and RT-PCR. When treated for 10min, GM-CSF activated the signal transducer and activator of transcription 5 (STAT5) and extracellular signal regulated kinase (ERK) in both cell lines. However, Janus kinase 2 (JAK2) was activated only in A172 cells but not in SK-N-(BE)2 cells by GM-CSF. The GM-CSF-activated cellular signal pathways were specifically inhibited by the pretreatment of GM-CSF receptor alpha antibody, suggesting the specificity of the signal activation. The experiment using specific inhibitors (AG490) to the JAK/STAT pathway showed that JAK2/STAT5 cascade was well preserved and activated by GM-CSF in A172 cells, while STAT5 was activated by GM-CSF without JAK2 activation in SK-N-(EB)2 cells. The ERK pathway was activated by GM-CSF independently of JAK2 in both cell lines. Finally, GM-CSF showed cytoprotective effect on these cell lines by inhibiting cytotoxicity of saturosporine. The results revealed the signal transduction pathways activated by GM-CSF in neural cells and suggested that GM-CSF might affect the neural functions via these signal pathways.
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PMID:Signal transduction pathways of GM-CSF in neural cell lines. 1755 97

Non-viral polymeric gene carriers have been widely investigated but no promising biocompatible polymer was developed for the gene therapy of neural system injuries yet. This study evaluated the potential usage of water-soluble lipopolymer (WSLP) as a gene delivery vehicle in neural lineage cells of SK-N-BE(2)C, a neuroblastoma cell line and primary culture of mouse neural progenitor cells (mNPCs). When tested with the luciferase reporter (pSV-Luc), WSLP showed higher gene transfection efficiency by more than 8-10 folds yet with lower cytotoxicity than polyethylenimine of 1800 Da (PEI1800), a parental polymer, and Lipofectamine 2000. The optimum N/P ratios were 40:1 for WSLP and 10:1 for PEI1800, respectively. The transfection efficiency for both of WSLP and PEI1800 was higher overall in SK-N-BE(2)C cells than in mNPCs. WSLP was also used successfully for the delivery and hypoxia-inducible expression of luciferase reporter plasmid containing the erythropoietin (Epo) enhancer (pEpo-SV-Luc) or RTP801 promoter (pRTP801-Luc). The hypoxia-inducible system and WSLP were then successfully applied to the delivery of granulocyte macrophage colony-stimulating factor (GM-CSF) gene that was previously shown to have neuroprotective effect on neural cell death in vitro and in rat SCI model. The hypoxia-inducible GM-CSF plasmids (pEpo-SV-GM-CSF and pRTP801-GM-CSF) showed induced expression of GM-CSF under hypoxia and decrease in the hypoxia-induced cell death in SK-N-BE(2)C cells. In conclusion, this study demonstrated that WSLP could be an efficient gene delivery carrier for neural cells and gene therapy of GM-CSF using the hypoxia-inducible system could be a potential therapeutic intervention for neural injuries. Further studies are necessary to confirm the current findings in animal models of CNS injuries.
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PMID:Gene therapy of neural cell injuries in vitro using the hypoxia-inducible GM-CSF expression plasmids and water-soluble lipopolymer (WSLP). 1893 3

Ascorbic acid (AA) is best known for its role as an essential nutrient in humans and other species. As the brain does not synthesize AA, high levels are achieved in this organ by specific uptake mechanisms, which concentrate AA from the bloodstream to the CSF and from the CSF to the intracellular compartment. Two different isoforms of sodium-vitamin C co-transporters (SVCT1 and SVCT2) have been cloned. Both SVCT proteins mediate high affinity Na(+)-dependent L-AA transport and are necessary for the uptake of vitamin C in many tissues. In the adult brain the expression of SVCT2 was observed in the hippocampus and cortical neurons by in situ hybridization; however, there is no data regarding the expression and distribution of this transporter in the fetal brain. The expression of SVCT2 in embryonal mesencephalic neurons has been shown by RT-PCR suggesting an important role for vitamin C in dopaminergic neuronal differentiation. We analyze SVCT2 expression in human and rat developing brain by RT-PCR. Additionally, we study the normal localization of SVCT2 in rat fetal brain by immunohistochemistry and in situ hybridization demonstrating that SVCT2 is highly expressed in the ventricular and subventricular area of the rat brain. SVCT2 expression and function was also confirmed in neurons isolated from brain cortex and cerebellum. The kinetic parameters associated with the transport of AA in cultured neurons and neuroblastoma cell lines were also studied. We demonstrate two different affinity transport components for AA in these cells. Finally, we show the ability of different flavonoids to inhibit AA uptake in normal or immortalized neurons. Our data demonstrates that brain cortex and cerebellar stem cells, neurons and neuroblastoma cells express SVCT2. Dose-dependent inhibition analysis showed that quercetin inhibited AA transport in cortical neurons and Neuro2a cells.
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PMID:The Na+-dependent L-ascorbic acid transporter SVCT2 expressed in brainstem cells, neurons, and neuroblastoma cells is inhibited by flavonoids. 1905 84


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