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:C0017636 (glioblastoma)
18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuropilin-1 is a VEGF165- and semaphorin receptor expressed by endothelial cells and tumor cells. The specific function of neuropilin-1 is not fully known, but in the developing nervous system neuropilin, as a semaphorin receptor, has been shown to influence neuronal guidance. The expression of neuropilin-1 was studied in low-grade and high-grade astrocytic tumors, the latter characterized by extensive angiogenesis. We examined 20 low-grade astrocytomas (WHO grade II) and 46 glioblastomas (WHO grade IV) immunohistochemically for neuropilin-1, p53 and EGFR. The glioblastomas were according to the p53 and EGFR expression classified as 35 primary--de novo--glioblastomas, 9 secondary glioblastomas, and 2 uncertain cases. Furthermore, the presence of mast cells was evaluated to search for any potential function in angiogenesis. The glioblastomas expressed neuropilin-1 in the endothelial cells of the proliferating vessels and the majority of the glioblastomas had immunoreactive neoplastic astrocytes, with no difference between the glioblastoma subgroups. Six out of twenty of the low-grade astrocytomas were negative in the endothelial cells and 8 out of 20 in the tumor cells for neuropilin-1. Mast cells were observed in the collagen matrix around larger vessels in the leptomeninges, but not adjacent to malignant tumor vessels or as part of the tumor process itself. Increased expression of neuropilin-1 is shown in endothelial cells and in neoplastic astrocytes of glioblastomas. Less neuropilin-1 expression is found in about half of the low-grade astrocytomas in both neoplastic astrocytes and endothelial cells. The results suggest a correlation between neuropilin-1 and vascularity in human astrocytic tumors and a possible role for neuropilin-1 as a receptor for VEGF-induced angiogenesis.
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PMID:Vascular endothelial growth factor (VEGF) receptor neuropilin-1's distribution in astrocytic tumors. 1523 40

Vascular endothelial growth factor (VEGF) is abundantly produced by glioma cells especially glioblastoma, the most malignant form of astrocytoma. VEGF, a well known angiogenic factor, acts in a paracrine fashion on endothelial cells to develop tumor vasculature. However, recent studies have found that several tumor cells express VEGF receptors, and an autocrine action of VEGF on tumor cells has been suggested. To test this hypothesis, three human glioma cell lines (U251n, U87 and A172) were checked for VEGF and VEGFR expression. These cells express 0.1-0.6 ng/ml VEGF165 in cell culture medium within 24 hours. Western blot analysis showed that these cells express all of the VEGF receptors, VEGFR-1/Flt-1, VEGFR-2/KDR, Neuropilin-1 (NRP-1) and Neuropilin-2(NRP-2), even though tyrosine kinase receptor VEGFR-2/KDR exhibited baseline levels of expression. VEGF expression was significantly down regulated by phosphorothioate oligodeoxynucleotide (PS-ODN) and VEGF RNAi transfection. However, VEGF RNAi transfection as well as VEGF and VEGFR2 neutralization antibody treatment did not decrease cell proliferation detected by MTT and CyQuant NF proliferation assay except that PS-ODN transfection caused a non-specific decrease on cell proliferation. VEGF RNAi transfection did not alter cell invasion, as demonstrated in a matrigel invasion assay. Matrix metalloproteinase-2 (MMP-2) and MMP-9, facilitating cell invasion and over expressed in glioma cells, were not altered by VEGF RNAi transfection, as shown by zymographic assays. Our data indicate that the decrease of endogenous VEGF expression may not affect glioma cell proliferation and invasion.
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PMID:Decrease of endogenous vascular endothelial growth factor may not affect glioma cell proliferation and invasion. 1755 62

The incurability of malignant glioblastomas is mainly attributed to their highly invasive nature coupled with resistance to chemo- and radiation therapy. Because invasiveness is partially dictated by the proteins these tumors secrete we used SILAC to characterize the secretomes of four glioblastoma cell lines (LN18, T98, U118 and U87). Although U87 and U118 cells both secreted high levels of well-known invasion promoting proteins, a Matrigel invasion assay showed U87 cells to be eight times more invasive than U118 cells, suggesting that additional proteins secreted by U87 cells may contribute to the highly invasive phenotype. Indeed, we identified a number of proteins highly or exclusively expressed by U87 cells as compared to the less invasive cell lines. The most striking of these include ADAM9, ADAM10, cathepsin B, cathepsin L1, osteopontin, neuropilin-1, semaphorin-7A, suprabasin, and chitinase-3-like protein 1. U87 cells also expressed significantly low levels of some cell adhesion proteins such as periostin and EMILIN-1. Correlation of secretome profiles with relative levels of invasiveness using Pavlidis template matching further indicated potential roles for these proteins in U87 glioblastoma invasion. Antibody inhibition of CH3L1 reduced U87 cell invasiveness by 30%.
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PMID:Secretome signature of invasive glioblastoma multiforme. 2157 46

Neuropilin-1 (NRP-1) is a non-tyrosine kinase receptor for vascular endothelial growth factor (VEGF) that was recently found to play a role in tumor functions. Previous studies demonstrated that NRP-1 was overexpressed in a number of human tumors, including glioblastoma (GBM). However, the role of NRP-1 in glioma progression has yet to be adequately elucidated. Thus, we examined the expression of NRP-1 in human glioma cell lines using Western blotting, and cell cycle distribution and proliferation by transfection of the U373 cell line with NRP-1 short interference RNA (siRNA). Results showed NRP-1 siRNA to significantly reduce NRP-1 gene expression, decrease in vitro cell proliferation and induce cell apoptosis in cultured glioma cells, along with the accumulation of cells in the G1 phase and a decrease in cells in the S phase. Our results further revealed that NRP-1 knockdown decreased the expression levels of Bcl-2 family proteins and deactivated extracellular signal-regulated kinase (ERK) and c-Jun-N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signaling pathways, closely associated with cancer progression. Thus, our results provide a molecular mechanism for the effect of NRP-1 in tumors, rendering NRP-1 an attractive candidate as a therapeutic target in certain types of cancer, such as GBM.
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PMID:RNA interference targeting NRP-1 inhibits human glioma cell proliferation and enhances cell apoptosis. 2184 23

Photodynamic therapy (PDT) is an emerging theranostic modality for various cancer as well as non-cancer diseases. Its efficiency is mainly based on a selective accumulation of PDT and imaging agents in tumor tissue. The vascular effect is widely accepted to play a major role in tumor eradication by PDT. To promote this vascular effect, we previously demonstrated the interest of using an active- targeting strategy targeting neuropilin-1 (NRP-1), mainly over-expressed by tumor angiogenic vessels. For an integrated vascular-targeted PDT with magnetic resonance imaging (MRI) of cancer, we developed multifunctional gadolinium-based nanoparticles consisting of a surface-localized tumor vasculature targeting NRP-1 peptide and polysiloxane nanoparticles with gadolinium chelated by DOTA derivatives on the surface and a chlorin as photosensitizer. The nanoparticles were surface-functionalized with hydrophilic DOTA chelates and also used as a scaffold for the targeting peptide grafting. In vitro investigations demonstrated the ability of multifunctional nanoparticles to preserve the photophysical properties of the encapsulated photosensitizer and to confer photosensitivity to MDA-MB-231 cancer cells related to photosensitizer concentration and light dose. Using binding test, we revealed the ability of peptide-functionalized nanoparticles to target NRP-1 recombinant protein. Importantly, after intravenous injection of the multifunctional nanoparticles in rats bearing intracranial U87 glioblastoma, a positive MRI contrast enhancement was specifically observed in tumor tissue. Real-time MRI analysis revealed the ability of the targeting peptide to confer specific intratumoral retention of the multifunctional nanoparticles.
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PMID:Multifunctional Peptide-conjugated hybrid silica nanoparticles for photodynamic therapy and MRI. 2308 1

The targeted therapeutic effect of nano drug delivery system for glioblastoma has been hampered by the weak enhanced permeability and retention (EPR) effect of glioblastoma and the low delivering efficiency of NDDS in glioblastoma tissue. In this study, a tumor-penetrating peptide (RGERPPR), the specific ligand of neuropilin-1 overexpressed on glioblastoma and endothelial cells, was used as a targeting moiety to enhance the anti-glioblastoma effect of doxorubicin liposomes. Firstly, RGERPPR-PEG-DSPE was synthesized and used to prepare the RGERPPR peptide-functionalized liposomes (RGE-LS), which showed vesicle sizes of around 90 nm and narrow size distributions. The cellular uptake and in vivo near-infrared fluorescence imaging test displayed that RGE-LS exhibited increased uptake by glioblastoma cells and intracranial glioblastoma tissues. The cytotoxicity assay and anti-glioblastoma study proved that RGERPPR functionalization significantly enhanced the in vitro inhibitory effect of doxorubicin liposomes on glioblastoma cells and prolonged the median survival time of nude mice bearing intracranial glioblastoma. Finally, the immunofluorescence analysis evidenced that RGE-LS were able to penetrate through tumor vessels and stroma and deep into the whole tumor tissue. The results indicated that tumor-penetrating peptide functionalization is an effective strategy for enhancing the anti-glioblastoma effect of doxorubicin liposomes.
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PMID:Tumor-penetrating peptide functionalization enhances the anti-glioblastoma effect of doxorubicin liposomes. 2402 87

Safe and efficient systems capable of specifically targeting brain tumour cells represent a promising approach for the treatment glioblastoma multiforme. Neuropilin-1 (NRP-1) is over-expressed in U87 glioma cells. In the current study, the tumour specific peptide RGERPPR, which binds specifically to NRP-1, was used as a targeting ligand in a gene delivery strategy for glioblastoma. The RGERPPR peptide was coupled to branched polyethylenimine (PEI, 25kDa) using heterobifunctional Mal-PEG-NHS, resulting in a novel gene delivery polymer. Polymer/plasmid DNA (pDNA) complexes were formed and their sizes and zeta potentials were measured. Compared with the unmodified mPEG-PEI/pDNA complexes, the RGERPPR-PEG-PEI/pDNA complex led to a significant enhancement in intracellular gene uptake and tumour spheroid penetration. Furthermore, the RGERPPR-PEG-PEI/pDNA complex facilitated enhanced transfection efficiency levels, as well as a reduction in cytotoxicity when tested in U87 glioma cells in vitro. Most significantly of all, when complexes formed with pDsRED-N1 were injected into the tail vein of intracranial U87 tumour-bearing nude mice, the RGERPPR-PEG-PEI complexes led to improved levels of red fluorescence protein expression in the brain tissue. Taken together, the results show that RGERPPR-PEG-PEI could be used as a safe and efficient gene delivery vehicle with potential applications in glioblastoma gene delivery.
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PMID:Targeted gene delivery to glioblastoma using a C-end rule RGERPPR peptide-functionalised polyethylenimine complex. 2414 51

The development of nonviral gene delivery vectors offers the potential to provide effective treatment for glioblastoma in the form of gene therapy. Here, we report the use of retro-inverso C-end rule (CendR) peptide D(RPPREGR) as a targeting ligand to prepare a D(RPPREGR)-PEG-PEI gene vector. D(RPPREGR) peptide specifically recognized the neuropilin-1 receptor that was overexpressed on U87 glioma cells, and showed enhanced tumor spheroid penetration ability. Compared with parental RGERPPR, D(RPPREGR) possessed improved biological stability and had a higher affinity for U87 glioma cells; it also showed enhanced penetration of the tumor spheroid. mPEG-PEI/pDNA and D(RPPREGR)-PEG-PEI/pDNA complexes were prepared and MTT assay results revealed that the cytotoxicity of D(RPPREGR)-PEG-PEI complexes was significantly lower than that of PEI complexes, with cell survival rates above 80%. Qualitative and quantitative in vitro transfection results revealed that D(RPPREGR)-PEG-PEI complex transfection efficiencies were 1.9 times higher than those of mPEG-PEI. Fluorescent imaging and frozen sections of brain tissue demonstrated that the D(RPPREGR) modification improved the in vivo transfection efficiency of mPEG-PEI in nude mice bearing U87 gliomas. An antiglioblastoma assay revealed that D(RPPREGR)-PEG-PEI carrying the therapeutic gene pORF-hTRAIL significantly prolonged the survival time of intracranial U87 glioma-bearing mice from 25 to 30 days. Therefore, D(RPPREGR)-PEG-PEI appears to be suitable for use as a safe and efficient gene delivery vehicle with potential applications in glioblastoma gene therapy.
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PMID:Retro-inverso CendR peptide-mediated polyethyleneimine for intracranial glioblastoma-targeting gene therapy. 2450 88

Combinations of drugs promoting anti-angiogenesis and apoptosis effects are meaningful for cancer therapy. In the present study, dual peptides-modified liposomes were designed by attaching two receptor-specific peptides, specifically low-density lipoprotein receptor-related protein receptor (Angiopep-2) and neuropilin-1 receptor (tLyP-1) for brain tumor targeting and tumor penetration. Vascular endothelial growth factor (VEGF) siRNA and chemotherapeutic docetaxel (DTX) were chosen as the two payloads because VEGF is closely associated with angiogenesis, and DTX can kill tumor cells efficiently. Binding to glioma cells, co-delivery of siRNA and DTX in human glioblastoma cells (U87 MG) and murine brain microvascular endothelial cells (BMVEC), VEGF gene silencing, antiproliferation and anti-tumor effects of the dual peptides-modified liposomes were evaluated in vitro and in vivo. The dual peptides-modified liposomes persisted the binding ability to glioma cells, enhanced the internalization via specific receptor mediated endocytosis and tissue penetration, thus the dual peptides-modified liposomes loading VEGF siRNA and DTX possessed stimulative gene silencing and antiproliferation activity compared with non-modified and single peptide-modified liposomes. The co-delivery research revealed different intracellular behavior of hydrophilic large molecular and lipophilic small molecule, the former involves endocytosis and subsequent escape of endosome/lysosomes, while the latter experiences passive diffusion of lipophilic small drugs after its release. Furthermore, the dual peptides-modified liposomes showed superiority in anti-tumor efficacy, combination of anti-angiogenesis by VEGF siRNA and apoptosis effects by DTX, after both intratumor and system application against mice with U87 MG tumors, and the treatment did not activate system-associated toxicity or the innate immune response. Combination with the dual peptides-guided tumor homing and penetration, the dual peptides-modified liposomes provide a strategy for effective targeting delivery of siRNA and DTX into the glioma cell and inhibition of tumor growth in a synergistic manner.
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PMID:Tumor-targeting dual peptides-modified cationic liposomes for delivery of siRNA and docetaxel to gliomas. 2469 93

Tumor angiogenesis involves multiple signaling pathways that provide potential therapeutic targets to inhibit tumor growth and metastasis. Regarding the significant role of vascular endothelial growth factor (VEGF) in angiogenesis and tumor progression, VEGF sequence-specific small interfering RNA (siRNA) for anti-angiogenic tumor therapy are under development. In the present study, dual-modified liposomes (At-Lp) was designed by attaching two receptorspecific peptides, Angiopep and tLyP-1, which specifically targeting low-density lipoprotein receptor (LRP) for brain tumor targeting and neuropilin-1 receptor (NRP-1) for tumor penetration, respectively. Gene transfection and silencing, and antitumor effect of the At-Lp loaded with VEGF siRNA were evaluated in vitro and in orthotopic xenograft models of U87 MG tumor. The At-Lp significantly enhanced cellular uptake (2-fold) and down-regulated expression of VEGF in U87 MG glioblastoma cells compared with non-modified and single-modified liposomes. The internalization of the At-Lp into tumor cells was taken via the enhanced permeability and retention effect and receptor-mediated endocytosis, followed by an effective endosomal escape of loaded siRNA into the cytoplasm. The At-Lp showed great superiority in inhibition of tumor growth, anti-angiogenesis, expression of VEGF and apoptosis effect after in vivo application against nude mice bearing U87 MG glioblastoma without activation of system-associated toxicity and the innate immune response. These results demonstrated that the combination of two receptor-specific peptides-mediated liposomes presented a promising platform for effective targeting delivery of siRNA for cancer anti-angiogenic therapy.
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PMID:Dual receptor-specific peptides modified liposomes as VEGF siRNA vector for tumor-targeting therapy. 2503 17


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