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 A (VEGF-A) and its receptor tyrosine kinases located on endothelial cells seem to play an important role in the multistep pathway of angiogenesis. SU5416 is a small molecule which inhibits angiogenesis by acting as an inhibitor of VEGF receptor-2 tyrosine kinase. We have developed a reproducible murine model for neuroblastoma, a childhood cancer, based on s.c. xenotransplantation of SH-SY5Y neuroblastoma cells. We found that SH-SY5Y cells expressed VEGF-A on both the mRNA and protein levels, that plasma concentrations of VEGF-A were significantly elevated in animals with neuroblastoma with a volume > 1.4 ml, and that there was a correlation between VEGF-A levels in plasma and tumor size in untreated tumor-bearing animals. Treatment with SU5416 reduced the growth of neuroblastoma tumors by 65% without apparent toxicity. SU5416 treatment also suppressed tumor angiogenesis, despite an increase in plasma VEGF-A levels per ml tumor volume during therapy. Our experimental data suggest that the angiogenesis inhibitor SU5416 may be beneficial in the treatment of solid tumors of childhood such as neuroblastoma.
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PMID:Importance of vascular endothelial growth factor A in the progression of experimental neuroblastoma. 1290 18

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Understanding the mechanisms regulating VEGF expression in neuroblastoma cells provides additional therapeutic options to control neuroblastoma tumor growth. VEGF mRNA is controlled by growth factors and hypoxia via the transcription factor hypoxia-inducible factor (HIF-1alpha). HIF-1alpha protein levels are regulated by the von Hippel Lindau tumor suppressor gene, VHL, which targets HIF-1alpha degradation. To determine whether the levels of VEGF in neuroblastomas are due to mutations in VHL, we evaluated genomic DNA from 15 neuroblastoma cell lines using PCR. We found no mutations in exons 1, 2, or 3 of the VHL gene. VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor. Serum/IGF-I induced increases in HIF-1alpha protein that temporally paralleled increases in VEGF mRNA, whereas HIF-1beta levels were unaffected. VEGF and HIF-1alpha levels were blocked by inhibitors of phosphatidylinositol 3-kinase and mammalian target of rapamycin. Furthermore, we confirmed that HIF-1alpha mediates approximately 40% of the growth factor activity stimulating VEGF protein expression. Topotecan blocked the IGF-I-stimulated increase in HIF-1alpha but not HIF-1beta, and this resulted in a decrease in VEGF in four neuroblastoma cell lines tested. These data indicate that growth factors in an autocrine or paracrine manner play a major role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to phosphatidylinositol 3-kinase, mammalian target of rapamycin, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Topotecan blocks hypoxia-inducible factor-1alpha and vascular endothelial growth factor expression induced by insulin-like growth factor-I in neuroblastoma cells. 1593 Feb 97

The extent of angiogenesis and/or vascular endothelial growth factor (VEGF) expression in neuroblastoma tumors correlates with metastases, N-myc amplification, and poor clinical outcome. Recently, we have shown that insulin-like growth factor-I and serum-derived growth factors stimulate VEGF expression in neuroblastoma cells via induction of hypoxia-inducible factor-1alpha (HIF-1alpha). Because another marker of poor prognosis in neuroblastoma tumors is high expression of brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor, TrkB, we sought to evaluate the involvement of BDNF and TrkB in the regulation of VEGF expression. VEGF mRNA levels in neuroblastoma cells cultured in serum-free media increased after 8 to 16 hours in BDNF. BDNF induced increases in VEGF and HIF-1alpha protein, whereas HIF-1beta levels were unaffected. BDNF induced a 2- to 4-fold increase in VEGF promoter activity, which could be abrogated if the hypoxia response element in the VEGF promoter was mutated. Transfection of HIF-1alpha small interfering RNA blocked BDNF-stimulated increases in VEGF promoter activity and VEGF protein expression. The BDNF-stimulated increases in HIF-1alpha and VEGF expression required TrkB tyrosine kinase activity and were completely blocked by inhibitors of phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) pathways. These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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PMID:Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. 1661 48

Mammalian target of rapamycin (mTOR) has been shown to play an important function in cell proliferation, metabolism and tumorigenesis, and proteins that regulate signaling through mTOR are frequently altered in human cancers. In this study we investigated the phosphorylation status of key proteins in the PI3K/AKT/mTOR pathway and the effects of the mTOR inhibitors rapamycin and CCI-779 on neuroblastoma tumorigenesis. Significant expression of activated AKT and mTOR were detected in all primary neuroblastoma tissue samples investigated, but not in non-malignant adrenal medullas. mTOR inhibitors showed antiproliferative effects on neuroblastoma cells in vitro. Neuroblastoma cell lines expressing high levels of MYCN were significantly more sensitive to mTOR inhibitors compared to cell lines expressing low MYCN levels. Established neuroblastoma tumors treated with mTOR inhibitors in vivo showed increased apoptosis, decreased proliferation and inhibition of angiogenesis. Importantly, mTOR inhibitors induced downregulation of vascular endothelial growth factor A (VEGF-A) secretion, cyclin D1 and MYCN protein expression in vitro and in vivo. Our data suggest that mTOR inhibitors have therapeutic efficacy on aggressive MYCN amplified neuroblastomas.
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PMID:Inhibitors of mammalian target of rapamycin downregulate MYCN protein expression and inhibit neuroblastoma growth in vitro and in vivo. 1802 38

Angiogenesis in neuroblastoma (NB) correlates with increased expression of vascular endothelial growth factor (VEGF) and a worse clinical outcome. Other cellular markers, such as Akt activation and MYCN amplification, are also associated with poor prognosis in NB; therefore, we sought to determine the role of N-myc in the regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt/VEGF pathway. PI3K inhibition, using small-molecule inhibitors or phosphatase and tensin homolog adenovirus, led to decreased levels of VEGF mRNA and/or protein by reducing phosphorylation of Akt and mammalian target of rapamycin (mTOR), and attenuating hypoxia-inducible factor 1alpha expression. Moreover, PI3K inhibition decreased levels of N-myc expression in MYCN-amplified cells. To further clarify the importance of N-myc as a target of PI3K in VEGF regulation, we inhibited N-myc expression by siRNA transfection. MYCN siRNA significantly blocked VEGF secretion, irrespective of serum conditions, in MYCN-amplified NB cells; this effect was enhanced when combined with rapamycin, an mTOR inhibitor. Interestingly, in cells with low-N-myc expression, MYCN siRNA reduction of VEGF secretion was only effective with MYCN overexpression or insulin-like growth factor-1 stimulation. Our results show that N-myc plays an important role in the PI3K-mediated VEGF regulation in NB cells. Targeting MYCN, as a novel effector of PI3K-mediated angiogenesis, has significant potential for the treatment of highly vascularized, malignant NB.
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PMID:N-myc is a novel regulator of PI3K-mediated VEGF expression in neuroblastoma. 1827 68

The purpose of the study was to investigate the antitumor effects of Isatin and the related mechanism. Human neuroblastoma cells (SH-SY5Y) were exposed to Isatin at different concentrations for 48 h. Apoptotic features were demonstrated by means of nuclei staining with Hoechst 33258 and flow cytometry with propidium iodide (PI). Expressions of Bcl-2, Bax and vascular endothelial growth factor (VEGF) mRNA were analyzed via RT-PCR. Expressions of Bcl-2, Bax proteins and phosphorylated extracellular signal regulated protein kinases (ERKs, p42/p44) were analyzed via Western blot. Activation of caspase-3 was assayed by flow cytometry with anti-active caspase-3-McAb-PE. VEGF protein was determined by ELISA kits. And the results showed that apoptosis of SH-SY5Y cells were induced by Isatin in a dose-dependent manner. Expressions of Bcl-2, VEGF mRNA and Bcl-2, VEGF proteins were down-regulated, while expressions of Bax mRNA and Bax protein were not changed obviously. Expression of phosphorylated ERKs decreased, but the level of activated caspase-3 increased after treatment of Isatin. These results suggest that Isatin promotes the apoptosis of neuroblastoma cells, therefore, it might be a potential candidate for the treatment of neuroblastoma.
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PMID:Antitumor effects of Isatin on human neuroblastoma cell line (SH-SY5Y) and the related mechanism. 1856 13

Differential regulation as well as target gene specificity of the two hypoxia-inducible factor (HIF)-alpha subunits HIF-1alpha and HIF-2alpha in various tumors and cell lines have been suggested. In breast cancer, the prognostic significance of HIF-1alpha is not clear-cut and that of HIF-2alpha is largely unknown. Using IHC analyses of HIF-1alpha, HIF-2alpha, and vascular endothelial growth factor (VEGF) expression in a tissue microarray of invasive breast cancer specimens from 512 patients, we investigated the expression patterns of the 2 HIF-alpha subunits in relation to established clinicopathologic variables, VEGF expression, and survival. HIF-1alpha and HIF-2alpha protein levels and their effect on survival were additionally analyzed in a second cohort of 179 patients. To evaluate the individual role of each subunit in the hypoxic response and induction of VEGF, HIF-alpha protein and HIF-alpha and VEGF mRNA levels were further studied in cultured breast cancer cells after hypoxic induction and/or knockdown of HIF-alpha subunits by siRNA by Western blot and Quantitative Real-Time PCR techniques. We showed that although HIF-1alpha and HIF-2alpha protein levels in breast cancer specimens were not interrelated, high levels of both HIF-1alpha and HIF-2alpha associated to high VEGF expression. HIF-2alpha expression was an independent prognostic factor associated to reduced recurrence-free and breast cancer-specific survival, whereas HIF-1alpha did not exhibit these correlations. In cultured cells, acute hypoxia induced both HIF-proteins. At prolonged hypoxia, HIF-2alpha remained accumulated, whereas HIF-1alpha protein levels decreased, in agreement with the oxygen level and time-dependent induction of HIFs recently reported in neuroblastoma.
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PMID:Hypoxia-inducible factor-2alpha correlates to distant recurrence and poor outcome in invasive breast cancer. 1901 Aug 93

Metabolism of sphingolipids into downstream lipid mediators followed by signaling modulates tumor microenvironment and the cancer cells to influence tumor progression. As such, sphingolipid signaling represents a novel way to modulate tumor biology. Neuroblastoma (NB), the most common extracranial solid tumor of childhood, is highly angiogenic and often displays poor prognosis. However, the role of sphingolipid mediators is not known in NB. We found that NB expresses high levels of sphingosine kinase-2, which is essential for the formation of sphingosine-1-phosphate (S1P). S1P induced VEGF expression in SK-N-AS NB cells. The effect occurred at the transcriptional level. Hypoxia in combination with S1P had a synergistic effect on VEGF expression. Strong correlation was detected between S1P receptor-2 (S1P(2)) and VEGF mRNAs in 11 different cell lines and 17 NB tissues. Blockade of S1P(2) with the selective antagonist JTE-013 significantly inhibited S1P-induced VEGF expression. Overexpression and knockdown of S1P(2) in SK-N-AS cells increased or inhibited S1P-induced VEGF secretion, respectively. Interestingly, JTE-013 significantly inhibited tumor growth, VEGF mRNA expression, and induced apoptosis in the NB tumor xenografts. Taken together, our data suggest that enhanced formation of sphingolipid mediator S1P in NB profoundly influences tumor microenvironment by inducing VEGF expression via S1P(2). Modulation of sphingolipid signaling by inhibiting S1P(2) may constitute a novel strategy to control NB.
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PMID:Sphingolipid modulation of angiogenic factor expression in neuroblastoma. 2157 49

Expression of vascular endothelial growth factor (VEGF) increases in cancer cells during hypoxia. Herein, we report that the MDM2 oncoprotein plays a role in hypoxia-mediated VEGF upregulation. In studying the characteristics of MDM2 and VEGF expression in neuroblastoma cells, we found that hypoxia induced significantly higher upregulation of both VEGF mRNA and protein in MDM2-positive cells than in the MDM2-negative cells, even in cells without wild-type (wt) p53. We found that hypoxia induced translocation of MDM2 from the nucleus to the cytoplasm, which was associated with increased VEGF expression. Enforcing overexpression of cytoplasmic MDM2 by transfection of the mutant MDM2/166A enhanced expression of VEGF mRNA and protein production, even without hypoxia. The results of mechanistic studies demonstrated that the C-terminal RING domain of the MDM2 protein bound to the AU-rich sequence within the 3' untranslated region (3'UTR) of VEGF mRNA; this binding increased VEGF mRNA stability and translation. In addition, knockdown of MDM2 by small interfering RNA (siRNA) in MDM2-overexpressing cancer cells resulted in inhibition of VEGF protein production, cancer cell survival, and angiogenesis. Our results suggest that MDM2 plays a p53-independent role in the regulation of VEGF, which may promote tumor growth and metastasis.
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PMID:MDM2 regulates vascular endothelial growth factor mRNA stabilization in hypoxia. 2198

The potential role of osteoblasts in bone and bone marrow (BM) metastases in neuroblastoma (NBL) remains unclear. In this study, we examined the effect of NBL cells on the osteoblastic differentiation of BM-derived mesenchymal stromal cells (BMMSC). We show that the presence of NBL cells enhanced the osteoblastic differentiation of BMMSC driven by bone morphogenetic protein (BMP)-4, in the absence of any effect on NBL cell proliferation. Expression profiles of BMMSC driven toward osteoblastic differentiation revealed an increase in vascular endothelial growth factor A (Vegfa) expression in the presence of NBL cells. We demonstrated that NBL cells increased BMMSC-derived VEGFA mRNA and protein and that this was enhanced by BMP-4. However, in similar conditions, neither the addition of an mVEGFA blocking antibody nor exogenous recombinant (r) mVEGFA affected osteoblastic differentiation. In contrast, siRNA- mediated knock-down of VEGFA in BMMSC prevented osteoblastic differentiation in BMP-4-treated cocultures, an effect that was not reversed in the presence of rmVEGFA. An analysis of murine bones injected with hNBL cells revealed an increase of mVEGFA producing cells near tumor cells concomitantly with an increase in Vegfa and Runx2 mRNA. This coincided with an increase in osteoclasts, in Rankl/Opg mRNA ratio and with the formation of osteolytic lesions. Thus NBL cells promote osteoblastogenesis in the BM by increasing VEGFA expression in BMMSC. Our study provides a new insight into the role of VEGFA in NBL metastases by pointing to the role of stroma-derived intracrine VEGFA in osteoblastogenesis.
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PMID:Interaction between bone marrow stromal cells and neuroblastoma cells leads to a VEGFA-mediated osteoblastogenesis. 2564 3


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