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)

Vascular endothelial growth factor (VEGF) is known to play a predominant role in tumor angiogenesis and metastasis formation that is mediated by its interactions with two tyrosine kinase receptors, VEGFRI (Flt-1) and VEGFRII (KDR). Inhibition of VEGF-dependent events in tumor tissues is known to enhance apoptosis and to suppress tumor growth. A novel peptide, SP5.2, which selectively binds Flt-1 and inhibits a broad range of VEGF-mediated events, was identified using a phage-display library screening. The fluorescein-labeled SP5.2 specifically bound to VEGF-stimulated primary human cerebral endothelial cells (HCECs), whereas non-stimulated HCECs, as well as human neuroblastoma cells (ShyY) did not show any interaction with the peptide. SP5.2 prevented proliferation of cultured primary human umbilical vein endothelial cells induced by recombinant human VEGF165 with an IC50 of 5 microm. SP5.2 was also shown to antagonize VEGF- and PLGF-induced, but not basic fibroblast growth factor-induced proliferation of HCECs. In contrast to "scrambled" peptide, SP5.2 was also found to selectively inhibit VEGF-stimulated migration of HCECs. The in vitro analysis of antiangiogenic activity of SP5.2 using a capillary-like tube formation assay showed that VEGF-induced angiogenesis of HCECs grown on Matrigel was completely inhibited in the presence of 10 microm SP5.2. Further studies demonstrated that SP5.2 prevented VEGF-induced permeability increase in HCECs monolayers. To explore whether SP5.2 can be used as a targeting agent, chemical and recombinant conjugates of SP5.2 with reporter proteins (peroxidase and beta-galactosidase) were produced. The resulting products showed significant increases (200-fold for SP5.2-beta-gal and 400-fold for SP5.2-peroxidase) in binding affinity to recombinant Flt-1 compared with the original synthetic SP5.2, suggesting that conjugate with therapeutic activity in nanomolar range could potentially be developed based on SP5.2 structure.
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PMID:A vascular endothelial growth factor high affinity receptor 1-specific peptide with antiangiogenic activity identified using a phage display peptide library. 1295 24

Advanced stages of neuroblastoma show increased expression of matrix metalloproteinases MMP-2 and MMP-9, that have been implicated in many steps of tumor progression, suggesting that they play a contributory role. Using pharmacological and genetic approaches, we have examined the role of these MMPs in progression of SK-N-BE (2).10 human neuroblastoma tumors orthotopically xenotransplanted into immunodeficient mice. Mice treated with Prinomastat, a synthetic inhibitor of MMPs, showed an inhibition of tumor cell proliferation in implanted tumors and a prolonged survival (50 versus 39 days in control group, P < 0.035). Treatment with Prinomastat did not affect formation of liver metastases (P = 0.52) but inhibited intravascular colonization by the tumor cells in the lung by 73.8% (P = 0.03) and angiogenesis in both primary tumors and experimental liver metastases. The primary tumors from Prinomastat-treated mice showed a 39.3% reduction in endothelial area detected by PECAM/CD31 staining in tumor sections (P < 0.001), primarily due to the presence of smaller vessels (P = 0.004). MMP-2 is expressed by neuroblastoma tumor cells and stromal cells, whereas MMP-9 is exclusively expressed by stromal cells, particularly vascular cells. To examine the contribution of MMP-9 to tumor angiogenesis, we generated RAG1/MMP-9 double-deficient mice. We observed a significant inhibition of angiogenesis in the immunodeficient RAG1/MMP-9 double-deficient mice orthotopically implanted with tumor cells (P = 0.043) or implanted s.c. with a mixture of tumor cells and Matrigel (P < 0.001). Using an FITC-labeled lectin, we demonstrated an inhibition in the architecture of the tumor vasculature in MMP-9-deficient mice, resulting in fewer and smaller blood vessels. These changes were associated with a 48% decrease in pericytes present along microvessels. Taken together, the data demonstrate that in neuroblastoma, stromally derived MMP-9 contributes to angiogenesis by promoting blood vessel morphogenesis and pericyte recruitment.
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PMID:Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. 1499 27

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

Angiogenesis plays a critical role in tumor progression in various cancers, including neuroblastoma. We have previously shown that gastrin-releasing peptide (GRP) stimulates neuroblastoma growth and that its cell surface receptors, gastrin-releasing peptide receptors (GRP-R), are overexpressed in advanced-stage human neuroblastomas; however, the effects of GRP on angiogenesis are not clearly elucidated. Interleukin (IL) 8, a proinflammatory chemokine, plays an important role during tumor angiogenesis. Ets transcription factors, such as oncoproteins, cause tumor development and are also known to induce IL-8 expression. In the present study, we found an increased expression of Ets1 in more undifferentiated human neuroblastomas. Stable transfection of SK-N-SH human neuroblastoma cells with Ets1 plasmid resulted in increased IL-8 luciferase activity and IL-8 secretion into cell culture media. Conversely, silencing of Ets1 resulted in a significant decrease in IL-8 secretion in SK-N-SH cells. Moreover, exogenous GRP treatment increased Ets1 (T38) phosphorylation and Ets1 nuclear accumulation, and enhanced Ets1 binding to its DNA consensus sequence, resulting in the stimulation of IL-8 mRNA expression and protein secretion. Our findings demonstrate that GRP upregulates proangiogenic IL-8 expression in an Ets1-dependent manner, suggesting a critical role of this process during GRP-induced neuroblastoma angiogenesis and metastasis.
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PMID:Ets1 transcription factor mediates gastrin-releasing peptide-induced IL-8 regulation in neuroblastoma cells. 1740 58

The biologic behavior of neuroblastoma (NB) is extremely variable; therefore, the clinical behavior may be reliably predicted based on the analysis of a panel of prognostic parameters. High vascular density has been correlated with aggressive tumor progression in many types of cancers. The goal of this study was to correlate the tumor vascularity in NB with status of MYCN and the short arm of chromosome 1 (1p) to address the association between angiogenesis and genetic markers of prognostic significance. The study population consisted of 33 patients with histologically proven diagnosis of primary NB and no history of previous chemotherapy. Histologic quantitation of tumor angiogenesis was performed using 3 different methods: microvessel density, vascular grading, and Chalkley counting. MYCN amplification and 1p deletion were determined by using fluorescence in situ hybridization technique. The differentiation and mitosis-karyorrhexis index of tumor cells were also assessed using the Shimada System. MYCN amplification was present in 12 cases (36.3%), and 1p deletion in 16 (48.5%). Both genetic changes significantly correlated with increased tumor vascularity. In addition, tumor vascularity was significantly increased in tumors with high mitosis-karyorrhexis index or of undifferentiated histology. We conclude that angiogenesis shows close association with histologic and genetic prognosticators in NB. Our data support the validity of recent applications of antiangiogenic agents which interfere or block NB progression.
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PMID:Association of MYCN amplification and 1p deletion in neuroblastomas with high tumor vascularity. 1752 31

Targeted expression of MYCN to the neural crest [under control of the rat tyrosine hydroxylase (TH) promoter] causes neuroblastoma in transgenic mice (TH-MYCN) and is a well-established model for this disease. Because high levels of MYCN are associated with enhanced tumor angiogenesis and poor clinical outcome in neuroblastoma, we serially characterized malignant progression, angiogenesis, and sensitivity to angiogenic blockade in tumors from these animals. Tumor cells were proliferative, secreted high levels of the angiogenic ligand vascular endothelial growth factor (VEGF), and recruited a complex vasculature expressing the angiogenic markers VEGF-R2, alpha-SMA, and matrix metalloproteinases MMP-2 and MMP-9, all of which are also expressed in human disease. Treatment of established murine tumors with the angiogenesis inhibitor TNP-470 caused near-complete ablation, with reduced proliferation, enhanced apoptosis, and vasculature disruption. Because TNP-470 has been associated with neurotoxicity, we tested the recently described water-soluble HPMA copolymer-TNP-470 conjugate (caplostatin), which showed comparable efficacy and was well tolerated without weight loss or neurotoxicity as measured by rotarod testing. This study highlights the importance of angiogenesis inhibition in a spontaneous murine tumor with native tumor-microenvironment interactions, validates the use of mice transgenic for TH-MYCN as a model for therapy in this common pediatric tumor, and supports further clinical development of caplostatin as an antiangiogenic therapy in childhood neuroblastoma.
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PMID:Malignant progression and blockade of angiogenesis in a murine transgenic model of neuroblastoma. 1790 53

The chick embryo chorioallantoic membrane (CAM) is commonly used as an experimental in vivo assay to study both angiogenesis and antiangiogenesis in response to tissues, cells or soluble factors. This article summarizes literature data about the use of the CAM in the study of tumor angiogenesis and particularly our experimental data concerning the study of angiogenesis in multiple myeloma and in neuroblastoma.
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PMID:The chick embryo chorioallantoic membrane in the study of tumor angiogenesis. 1851 17

Notch signaling is required for vascular development and tumor angiogenesis. Although inhibition of the Notch ligand Delta-like 4 can restrict tumor growth and disrupt neovasculature, the effect of inhibiting Notch receptor function on angiogenesis has yet to be defined. In this study, we generated a soluble form of the Notch1 receptor (Notch1 decoy) and assessed its effect on angiogenesis in vitro and in vivo. Notch1 decoy expression reduced signaling stimulated by the binding of three distinct Notch ligands to Notch1 and inhibited morphogenesis of endothelial cells overexpressing Notch4. Thus, Notch1 decoy functioned as an antagonist of ligand-dependent Notch signaling. In mice, Notch1 decoy also inhibited vascular endothelial growth factor-induced angiogenesis in skin, establishing a role for Notch receptor function in this process. We tested the effects of Notch1 decoy on tumor angiogenesis using two models: mouse mammary Mm5MT cells overexpressing fibroblast growth factor 4 (Mm5MT-FGF4) and NGP human neuroblastoma cells. Exogenously expressed FGF4 induced Notch ligand expression in Mm5MT cells and xenografts. Notch1 decoy expression did not affect tumorigenicity of Mm5MT-FGF4 cells in vitro but restricted Mm5MT-FGF4 xenograft growth in mice while markedly impairing neoangiogenesis. Similarly, Notch1 decoy expression did not affect NGP cells in vitro but disrupted vessels and decreased tumor viability in vivo. These results strongly suggest that Notch receptor signaling is required for tumor neoangiogenesis and provides a new target for tumor therapy.
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PMID:A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. 1855 19

Neuroblastoma produce angiogenic peptides, and the extent of angiogenesis correlates with tumor progression and poor clinical outcome. Hence, angiogenic factor inhibition represents an important therapeutic option. One of the major drives to tumor angiogenesis is hypoxia, a decrease in oxygen tension that characterizes the tumor microenvironment. We investigated the effects of the topoisomerase I inhibitor, topotecan, on vascular endothelial growth factor (VEGF) induction by hypoxia in advanced-stage human neuroblastoma cells. Topotecan counteracted hypoxic induction of VEGF and decreased angiogenic activity of conditioned medium from hypoxic cultures in vivo in the chick chorioallantoic membrane. Promoter-driven reporter studies showed the role of both hypoxia-inducible factor (HIF)-1alpha and -2alpha in VEGF transcription activation by hypoxia, because (a) overexpression of either protein by cotransfection with expression vectors resulted in VEGF promoter transactivation, which was abrogated by mutation in the HIF-binding site, and (b) targeted knockdown of HIF-1alpha/2alpha by RNA interference inhibited hypoxia-stimulated VEGF transcriptional activity and protein secretion. Topotecan-inhibitory effects on VEGF induction by hypoxia were mediated through suppression of both HIF-1alpha and HIF-2alpha protein accumulation and transactivation properties, which was specific and required ongoing RNA transcription. A similar pattern of results was obtained in cells treated with the hypoxia-mimetic agent, desferrioxamine. These data provide the first evidence that topotecan is a potent inhibitor of HIF-1alpha and HIF-2alpha subunits in hypoxic neuroblastoma cells, leading to decreased VEGF expression and angiogenic activity. An important clinical implication of these findings is that therapies targeted to the HIF pathway have the potential to inhibit neuroblastoma angiogenesis and growth.
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PMID:Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1alpha and -2alpha. 1864 7

The chick embryo chorioallantoic membrane (CAM) is an extraembryonic membrane mediating gas and nutrient exchanges until hatching. Since it has a dense capillary network, it has been commonly used in vivo to study both angiogenesis and antiangiogenesis in response to normal tissues and cells, to tumor bioptic specimens and cells, or to soluble factors. During the last 8 years, this assay has been used in over 550 published works. This chapter summarizes current knowledge about the embryological origin of the CAM, morphology of its blood and lymphatic vessels, the use of CAM in the study of tumor angiogenesis and metastasis, angiogenic and antiangiogenic substances. The angiogenic response of CAM to multiple myeloma and neuroblastoma cells and bioptic specimens and their responses to antiangiogenic molecules and the role played by fibroblast growth factor-2 in CAM vascularization have been analyzed in detail. Finally, advantages and limitations of CAM as an experimental model to study angiogenesis and antiangiogenesis are discussed.
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PMID:Chick embryo chorioallantoic membrane as a useful tool to study angiogenesis. 1908 37

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