Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Vascular endothelial growth factor (VEGF) is an angiogenic factor with neurotrophic effects in the peripheral nervous system. To determine if VEGF can also promote the survival of central neurons, we examined its effect on HN33 (mouse hippocampal neuron x neuroblastoma) cells deprived of serum. Serum-deprived HN33 cells expressed VEGFR-2 receptors, which, in the presence of VEGF, interacted with the downstream signaling molecules phosphatidylinositol 3'-kinase and phospho-Akt, as demonstrated by immunoprecipitation and Western blotting. Treatment of serum-deprived HN33 cells with VEGF also stimulated the phosphorylation of IkappaB-alpha and nuclear translocation of the transcription factor NF-kappaB. Withdrawal of serum for 24 h reduced HN33 cell viability by approximately 50% in the absence of VEGF, but by only approximately 20% in the presence of 100 ng/mL of VEGF. These findings support a neurotrophic role for VEGF in the central nervous system, which may be mediated through VEGFR-2 receptors, the protein kinases phosphatidylinositol 3'-kinase and Akt, and the transcription factor NK-kappaB. Thus, VEGF, like other neurotrophic factors, could exert protective effects in acute or chronic neurodegenerative disorders.
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PMID:Vascular endothelial growth factor rescues HN33 neural cells from death induced by serum withdrawal. 1098 96

Vascular endothelial growth factor (VEGF) plays a key role in human tumor angiogenesis. We compared the effects of inhibitors of VEGF with different specificities in a xenograft model of neuroblastoma. Cultured human neuroblastoma NGP-GFP cells were implanted intrarenally in nude mice. Three anti-VEGF agents were tested: an anti-human VEGF(165) RNA-based fluoropyrimidine aptamer; a monoclonal anti-human VEGF antibody; and VEGF-Trap, a composite decoy receptor based on VEGFR-1 and VEGFR-2 fused to an Fc segment of IgG1. A wide range of efficacy was observed, with high-dose VEGF-Trap causing the greatest inhibition of tumor growth (81% compared with controls). We examined tumor angiogenesis and found that early in tumor formation, cooption of host vasculature occurs. We postulate that this coopted vasculature serves as a source of blood supply during the initial phase of tumor growth. Subsequently, control tumors undergo vigorous growth and remodeling of vascular networks, which results in disappearance of the coopted vessels. However, if VEGF function is blocked, cooption of host vessels may persist. Persistent cooption, therefore, may represent a novel mechanism by which neuroblastoma can partly evade antiangiogenic therapy and may explain why experimental neuroblastoma is less susceptible to VEGF blockade than a parallel model of Wilms tumor. However, more effective VEGF blockade, as achieved by high doses of VEGF-Trap, can lead to regression of coopted vascular structures. These results demonstrate that cooption of host vasculature is an early event in tumor formation, and that persistence of this effect is related to the degree of blockade of VEGF activity.
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PMID:Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma. 1217 46

Human neuroblastoma (NB) is a highly heterogeneous childhood cancer secreting a high level of vascular endothelial growth factor (VEGF). Its vascularization has been clearly correlated with metastatic progression and poor outcome. Thus, molecules that target the vascular endothelium are regarded as new therapeutics of clinical interest. Angiostatin, an internal fragment of plasminogen containing the first four kringle structures, has been described as a powerful angiogenic inhibitor. We used a recombinant adenovirus encoding the human angiostatin kringle 1-3 directly fused to human serum albumin HSA (AdK3-HSA). Coupling to HSA has been previously shown to increase the in vivo half-life of this angiostatic factor, and to lead to tumor growth inhibition in the MDA-MB-231 carcinoma model. For the assessment of antiangiogenic gene therapy in the human NB IGR-N835 tumor model, 5 x 10(9) PFU of AdK3-HSA were intravenously injected in tumor-bearing athymic mice presenting either of the following experimental settings: early stage, established, and minimal residual tumors. No delay in tumor growth was observed in animals treated with AdK3-HSA as compared to those treated with the empty virus AdCO1. In early-stage tumors, kinetics of tumor occurrence and tumor growth were similar in AdK3-HSA- and AdCO1-treated animals. K3-HSA was found to be expressed at high levels (the mean value for the three experiments being 19.4+/-15.9 microg/ml) in the circulation of all animals up to 21-35 days after virus injection. In addition, IGR-N835 tumors were found to be highly vascularized and to release high amounts of angiogenic factors, in particular VEGF (665+/-370 pg/mg total protein). Thus, in spite of high circulating levels, K3-HSA may be unable to displace the NB proangiogenic switch. In this regard, a more promising target to inhibit NB angiogenesis seems to be the VEGF/VEGFR system.
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PMID:High level of stabilized angiostatin mediated by adenovirus delivery does not impair the growth of human neuroblastoma xenografts. 1460 72

In addition to their inhibitory effects, cannabinoids also exert stimulatory activity which can be detected at the cellular level. In a previous study, we demonstrated a stimulatory effect of the synthetic cannabinoid receptor agonist desacetyllevonantradol (DALN) on Ca(2+) flux into N18TG2 neuroblastoma cells, and suggested a dual mechanism: one pathway mediated by PKA and the other one by protein kinase C (PKC). Here we studied the PKC-mediated effect of DALN on Ca(2+) influx. The stimulatory effect of DALN on Ca(2+) influx was partially blocked by the PKC inhibitor chelerythrine, by the metalloprotease inhibitor o-phenanthroline and by the MEK (mitogen-activated protein-kinase kinase, MAPK kinase) inhibitor PD98059. Immunobloting of ERK1/2 MAPK demonstrated phosphorylation by DALN, and indicated the involvement of vascular endothelial growth factor (VEGF) receptor tyrosin kinases (RTKs) in MAPK activation as it was blocked by oxindole-1. Transactivation of the VEGFR-MAPK cascade by DALN involved CB1 cannabinoid receptors coupled to Gi/Go GTP-binding proteins as it was blocked by SR141716A and by pertussis toxin (PTX). The pharmacological implications of this novel mechanism of cannabinoid activity are discussed.
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PMID:The involvement of VEGF receptors and MAPK in the cannabinoid potentiation of Ca2+ flux into N18TG2 neuroblastoma cells. 1474 3

Vascular endothelial growth factor (VEGF), the most potent angiogenic peptide, protects the neurons against experimental ischemia. However, its neuroprotective effect on human brain is unknown. The present study attempted to determine whether VEGF can protect human cerebral neurons in vitro. A1 human hybrid clonal neurons (human cerebral neuron + neuroblastoma cell) were exposed to hypoxia with glucose deprivation. Pretreatment with VEGF reduced the A1 cell death, and VEGFR-2/Flk-1 and VEGF increased with a neuroprotective effect. However, the human neuroblastoma or neuroglioma cells failed to show these findings. Our results suggest that VEGF can protect human cerebral neurons from cell death after an ischemic insult in vitro, which is correlated to both increased expression of VEGFR-2/Flk-1 and VEGF within the cells.
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PMID:VEGF protects human cerebral hybrid neurons from in vitro ischemia. 1507 28

Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) and their cognate receptor tyrosine kinases are strongly implicated in angiogenesis associated with solid tumors. SU11657 (SUGEN) is a selective multitargeted tyrosine kinase inhibitor with antitumor and antiangiogenic activity exerted by targeting PDGF receptors (PDGFR), VEGF receptors (VEGFR), stem cell factor receptor (c-KIT), and FMS-related tyrosine kinase 3. Oral administration of SU11657 at 40 mg x kg(-1) x d(-1) to athymic mice resulted in significant growth inhibition of a panel of s.c. human neuroblastoma xenografts, namely, fast-growing SK-N-AS, MYCN- amplified IMR-32, and SH-SY5Y, by 90, 93.8, and 88%, respectively, and was well tolerated. All of the cell lines expressed VEGFR-2, PDGFR-beta, and c-KIT protein in the tumor cell and endothelial cell compartment by immunohistochemistry, and the expression decreased during therapy. Plasma concentrations of VEGF-A, PDGF-BB, and stem cell factor increased per milliliter of tumor volume at days 10, 18, and 20 of therapy. Furthermore, SU11657 reduced tumor angiogenesis by 63-96%. Our experimental data suggest that the angiogenesis inhibitor SU11657 may be beneficial in the treatment of rapidly growing and highly vascularized solid tumors of childhood, such as neuroblastoma. In summary, the class III/V receptor tyrosine kinases and their ligands are implicated in angiogenesis, tumor cell proliferation, and cell survival, and it seems reasonable to determine whether interference with these pathways can suppress neuroblastoma growth or not.
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PMID:The selective class III/V receptor tyrosine kinase inhibitor SU11657 inhibits tumor growth and angiogenesis in experimental neuroblastomas grown in mice. 1571 57

Flt1, an "fms-like tyrosine kinase" receptor, has been suggested to play an active role in vascular endothelial growth factor (VEGF)-mediated autocrine signaling of tumor growth and angiogenesis. Here, we used a neuroblastoma model to investigate the role of VEGF/Flt1 signaling in hypoxia-mediated tumor cell survival, drug resistance, and in vivo angiogenesis. SK-N-BE2, a highly malignant neuroblastoma cell line resistant to hypoxia-induced apoptosis expresses active Flt1 but lacks VEGFR2 expression. We found that 24-hour hypoxia (<0.1% O2) alone (no serum deprivation) showed sustained activation of extracellular signal-regulated kinase 1/2 (ERK1/2) associated with bcl-2 up-regulation and resistance to etoposide-induced (5 mumol/L) apoptosis. Treatment with anti-VEGF and anti-Flt1 antibodies inhibited ERK1/2 activation, down-regulated bcl-2, and reversed the hypoxia-mediated drug resistance to etoposide. Similar results were obtained with U0126 and ursolic acid, specific and nonspecific inhibitors of ERK1/2, respectively. We confirmed the protective role of Flt1 receptor by small interfering RNA knockout and Flt1 overexpression studies. Subsequently, we found that inhibition of VEGF/Flt1 autocrine signaling led to reduced hypoxia-inducible factor-1alpha (HIF-1alpha) phosphorylation. Furthermore, the reduced phosphorylation was associated with down-regulation of basic fibroblast growth factor, a downstream target of the HIF-1alpha and VEGF pathways. Our findings suggested an expanded autocrine loop between VEGF/Flt1 signaling and HIF-1alpha. We investigated the angiogenic activity of the loop in an in vivo Matrigel plug assay. The hypoxia-treated conditioned medium induced a strong angiogenic response, as well as the cooption of surrounding vessels into the plugs; ursolic acid inhibited the angiogenesis process. We also found that three other Flt1-expressing neuroblastoma cell lines show hypoxia-mediated drug resistance to etoposide, melphalan, doxorubicin, and cyclophosphamide. Taken together, we conclude that a hypoxia-driven VEGF/Flt1 autocrine loop interacts with HIF-1alpha through a mitogen-activated protein kinase/ERK1/2 pathway in neuroblastoma. The interaction, in the form of an autocrine loop, is required for the hypoxia-driven cell survival, drug resistance, and angiogenesis in neuroblastoma.
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PMID:A hypoxia-driven vascular endothelial growth factor/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 pathway in neuroblastoma. 1610 78

VEGF, Hedgehog, FGF, Notch, and WNT signaling pathways network together for vascular remodeling during embryogenesis, tissue regeneration, and carcinogenesis. VEGFA (VEGF), VEGFB, VEGFC, VEGFD (FIGF) and PGF (PlGF) are VEGF family ligands for receptor tyrosine kinases, including VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4). Bevacizumab (Avastin), Sunitinib (Sutent) and Sorafenib (Nexavar) are anti-cancer drugs targeted to VEGF signaling pathway. TCF/LEF binding sites within the promoter region of human VEGF family members were searched for by using bioinformatics and human intelligence (Humint). Because four TCF/LEF-binding sites were identified within the 5'-promoter region of human VEGFD gene within AC095351.5 genome sequence, comparative genomics analyses on VEGFD orthologs were further performed. ASB9-ASB11-VEGFD locus at human chromosome Xp22.2 and ASB5-VEGFC locus at human chromosome 4q34 were paralogous regions within the human genome. Human VEGFD mRNA was expressed in lung, small intestine, uterus, breast, neural tissues, and neuroblastoma. Mouse Vegfd mRNA was expressed in kidney, pregnant oviduct, and neural tissues. Chimpanzee VEGFD promoter, cow Vegfd promoter, mouse Vegfd promoter and rat Vegfd promoter were identified within NW_121675.1, AC161065.2, AL732475.6 and AC130036.3 genome sequences, respectively. Three out of four TCF/LEF-binding sites within human VEGFD promoter were conserved in chimpanzee VEGFD promoter, and one in cow Vegfd promoter. TCF/LEF-binding site, not conserved in human VEGFD promoter, occurred in cow, mouse and rat Vegfd promoters. At least five out of six bHLH-binding sites within human VEGFD proximal promoter region were conserved in chimpanzee VEGFD proximal promoter region, while only one in cow Vegfd proximal promoter region. Together these facts indicate that relatively significant promoter evolution occurred among mammalian VEGFD orthologs. Human VEGFD was characterized as a potent target gene of WNT/beta-catenin signaling pathway. VEGFD, implicated in angiogenesis and lymphatic metastasis, is a pharmacogenomics target in the field of oncology.
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PMID:Comparative integromics on VEGF family members. 1668 60

For the first time, we could detect lymph vessels in neuroblastoma (NB) by immunohistochemistry with the antibody D2_40. Furthermore, we demonstrate expression of the lymphangiogenic factors VEGF-C and VEGF-D and their receptors VEGFR-2 and VEGFR-3 in NB in vitro and in vivo by RT-PCR. However, addition of recombinant human VEGF-C or -D results in the absence of autocrine growth stimulus in NB cells. Treatment of NB cells with retinoic acid did not lead to a change in VEGF-C or VEGF-D mRNA expression. Incubation of the NB cells Lan-5 with 5-Aza-2'-deoxycytidine led to the up-regulation of VEGF-C mRNA expression, suggesting that the promotor of VEGF-C is methylated. Finally, VEGF-C mRNA expression could be effectively down-regulated by transfection with a specific siRNA in the NB cells Kelly. We conclude that lymphangiogenesis is involved in NB biology and that siRNA directed against VEGF-C may have a future role in anti-lymphangiogenic strategies in NB.
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PMID:Lymphangiogenesis and its regulation in human neuroblastoma. 1714 May 47

Evidence suggests that vascular endothelial growth factor (VEGF) mediates neuroprotection to prevent an apoptotic cell death. The p38 mitogen-activated protein kinase (MAPK) pathway is implicated as an important mediator of neuronal apoptosis but its role in VEGF-mediated neuroprotection is unclear. Herein, we show that treatments with the p38 MAPK inhibitor, SB202190, enhanced VEGF-mediated survival in serum deprived SK-N-SH neuroblastoma cells by decreasing caspase-3/7 activation while increasing the phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and Akt signaled through the VEGF receptor, VEGFR2. A blockade of VEGFR2 signaling with a selective inhibitor, SU1498 or gene silencing with VEGFR2 siRNA in SB202190 treated cells abrogated this prosurvival response and induced high activation levels of caspase-3/7. These findings suggested that the protection elicited by p38 MAPK inhibition in serum starved cells was dependent on a functional VEGF/VEGFR2 pathway. However, p38 MAPK inhibition attenuated caspase-3 cleavage in SU1498/SB202190 treated cells, indicating that p38 MAPK and caspase-3 only contributed in part to the total levels of caspase-3/7 induced by VEGFR2 inhibition. Pretreatments with the pan caspase inhibitor, z-VAD-fmk, prevented the apoptosis induced by VEGFR2 inhibition and promoted survival in serum starved cells irrespective of p38 MAPK inhibition. Collectively, our findings suggest that p38 MAPK exerts a negative effect on VEGF-mediated signaling through VEGFR2 in serum starved neuroblastoma cells. Furthermore, VEGF signals protection against a caspase-mediated cell death that is regulated by p38 MAPK-dependent and -independent mechanisms.
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PMID:p38 MAPK as a negative regulator of VEGF/VEGFR2 signaling pathway in serum deprived human SK-N-SH neuroblastoma cells. 1817 12


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