Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastomas, the most frequent primary brain tumors in adults, are characterized by a highly aggressive, inflammatory and angiogenic phenotype. Methylation of CpG islands in cancer-related genes may serve as an epigenetic biomarker for glioblastoma diagnosis and prognosis. The aim of this study was to analyze the methylation status of four critical tumor-associated genes (MGMT, RARbeta, RASSF1A, CDH13), and investigate possible links with inflammatory (interleukin [IL]-6, IL-8) and angiogenic mediators (vascular endothelial growth factor [VEGF], cyclooxygenase [COX]-2) and clinical outcome in 23 glioma samples (6 grade II astrocytomas, 17 grade IV glioblastomas). RARbeta and MGMT genes were more frequently methylated in 70.58% and 58.8% of glioblastomas, respectively. RASSF1A and CDH13 displayed a similar methylation frequency (23.52%) in glioblastomas. No gene methylation was observed in grade II astrocytomas. Tumor grade correlated positively with MGMT and RARbeta methylation (P = 0.005 and P = 0.019, respectively) and the extent of necrosis (P = 0.001 and P = 0.003). Interestingly, the marker of chronic inflammation, IL-6, was positively associated with methylation of MGMT (P = 0.004), RARbeta (P = 0.002), and RASSF1A (P = 0.0081) as well as the total number of methylated genes (P < 0.0001), indicating the important role of IL-6 in maintaining promoter methylation of these genes. VEGF expression correlated positively with MGMT and RARbeta methylation although these relationships were of marginal significance (P = 0.0679 and P = 0.0757). Kaplan-Meier univariate survival analysis indicated an unfavorable survival period in patients with MGMT methylation compared with those without methylation (P = 0.0474). Our study highlights the implication of MGMT and RARbeta methylation in the aggressive phenotype of primary glioblastomas. The association of MGMT methylation with clinical outcome indicates its potential prognostic value.
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PMID:High incidence of MGMT and RARbeta promoter methylation in primary glioblastomas: association with histopathological characteristics, inflammatory mediators and clinical outcome. 1980 23

Although significant progresses were made in the field of molecular biology of malignant cerebral gliomas, the prognostic of these tumors continues to be reserved. One of the therapeutic failure reasons is the incomplete knowledge regarding the origin of these tumors and cells features, which in fact represent an obstacle in developing a cell and molecular therapy guided against malignant cells responsible for the tumor development and for the therapeutic resistance. Initiation and characterization of glioblastoma cell lines represents an essential step in order to obtain a better in vitro and in vivo experimental model for glioblastoma. We describe here a new glioblastoma line, named T11, which was successfully isolated in our laboratories starting with a tumor sample obtained intraoperative from a 58 years-old female patient. The histopathological evaluation showed a grad IV WHO glioma (glioblastoma). The sample was prepared by manual fragmentation, followed by enzymatic digestions using different concentration of trypsin. The cell line has been cultivated for more than 150 passages. The characterization of the glioblastoma line consisted in the evaluation of cells proliferation capacity (growth curve), morphological features, karyotyping and identification of specific markers. We found that T11 expressed specific markers for glial progenitors and astrocytes (glial fibrillary acidic protein-GFAP); oligodendrocites (A2B5; O4), and microglia (CD45, CD 11b). Cells were negative for neuronal lineage markers like beta3-tubulin and NCAM. In order to evaluate the differentiation grade of T11 cell line, the presence of stem cell markers (nestin, CD133) was explored. T11l cells expressed higher level of nestin and lower level of CD133 comparing with standard glioblastoma cell line U87. T11 cell line expressed VEGF and Bcl-2, but not EGFR and Mdrl and Bax. This new line has distinct and unique characteristics when compared with standard glioblastoma cell line (e.g., U87) and may become a new and useful in vitro model for glioblastoma.
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PMID:Isolation and partial characterization of a new human glioblastoma cell line. 1988 54

Recent evidence suggests that vascular permeability and the presence of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) are important mediators of brain tumor growth in addition to angiogenesis. Perfusion and permeability magnetic resonance (MR) imaging can now measure parameters such as cerebral blood volume and vascular permeability, which can be directly correlated with these histopathologic changes as well as molecular markers such as VEGF. The major techniques currently used in both the clinical and research settings are T1-weighted steady-state dynamic contrast-enhanced MR imaging (DCE MR imaging) and T2 *-weighted first-pass, dynamic susceptibility contrast MR imaging (DSC MR imaging). The advantages and disadvantages of each technique with regard to characterizing tumor biology are discussed in this article. Most clinicians and investigators are currently using the DSC MR imaging T2 *-weighted technique for brain tumor perfusion MR imaging. The existence of multiple approaches to pathologic classification of human glioma implies that there is a lack of consensus among experts as to which is the single best approach. These multiple grading systems do, however, agree on the histologic parameters that are important in the determination of glioma biology, namely hypercellularity, pleomorphism, vascular endothelial proliferation, mitotic activity, and necrosis.
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PMID:Magnetic resonance perfusion and permeability imaging in brain tumors. 1995 4

Irinotecan (CPT-11) has shown emerging promise in the treatment of malignant gliomas. It is believed the mechanism of action of irinotecan is to sensitize glioma cells to the cytotoxic action of radiation therapy and alkylating agents. However, clinical trials using weekly or three-weekly doses of CPT-11 have demonstrated imaging responses in only 10-15% of patients. In this study, we evaluated another mechanism of action, angiosuppression by CPT-11 of ACNU-resistant gliomas, using a metronomic administration schedule. Two different types of treatment, (1) conventional and (2) metronomic, were applied to the subcutaneous U87 model. We found that metronomic administration of CPT-11 significantly inhibited malignant glioma growth by inhibiting angiogenesis; this treatment procedure reduced the number of tumor vessels and the area of hypoxic lesions and reduced expression of VEGF and HIF-1alpha, the most important angiogenic factors in gliomas. Metronomic treatment was superior to conventional treatment with regard to the severe systemic side effect of body weight loss. The growth inhibitory effect was very similar for both low and high doses of CPT-11. These angiosuppressive effects of CPT-11 show promise for another use of CPT-11 in metronomic and scheduled angiosuppressive chemotherapy with low dose and long-term administration for malignant gliomas without systemic side effects.
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PMID:Metronomic treatment of malignant glioma xenografts with irinotecan (CPT-11) inhibits angiogenesis and tumor growth. 2006 73

The inhibitor of growth 1 (ING1) homologue ING4 has previously been implicated as a negative regulator of angiogenesis in a murine glioma and a multiple myeloma model. An association between ING1 and angiogenesis has not been reported yet. Our previous studies using tumor samples from patients have shown that ING1 levels are downregulated in glioblastoma multiforme (GBM), one of the most highly vascularized malignancies. Based on this background, the goal of this study was to test the effects of the major ING1 splicing isoforms, p47ING1a and p33ING1b, on pathological angiogenesis induced by human GBM cells. We used a chorioallantoic membrane (CAM) assay to examine whether LN229 human GBM cells can induce angiogenesis and whether alterations in ING1 expression, such as ING1 knockdown by siRNA or ectopic ING1 overexpression using ING1a and ING1b expression constructs, can affect this process. Increased ING1 protein expression significantly suppressed LN229 cell-induced angiogenesis in the CAM assay. While no effects on the proangiogenic factors VEGF or IL-8 were noted, the expression of angiopoietins (Ang) 1 and 4 were increased by the p47ING1a, but not by the p33ING1b isoform. Levels of Ang-2 were not sensitive to altered ING1 levels. Our data are the first to suggest that ING1 proteins suppress neoangiogenesis in GBM. Moreover, our results may support the idea that ING1 proteins regulate the expression of proteins that are critical for angiogenesis in GBM such as the angiopoietins.
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PMID:The inhibitor of growth 1 (ING1) proteins suppress angiogenesis and differentially regulate angiopoietin expression in glioblastoma cells. 2006 99

Vascularization of the vertebrate brain takes place during embryonic development from a preformed perineural vascular plexus. As a consequence of the intimate contact with neuroectodermal cells the vessels, which are entering the brain exclusively via sprouting angiogenesis, acquire and maintain unique barrier properties known as the blood-brain barrier (BBB). The endothelial BBB depends upon the close association of endothelial cells with pericytes, astrocytes, neurons and microglia, which are summarized in the term neuro-vascular unit. Although it is known since decades that the CNS tissue provides the cues for BBB induction and differentiation in endothelial cells, the molecular mechanism remained obscure.Only recently, the canonical Wnt/beta-catenin pathway and the Wnt7a/7b growth factors have been implicated in brain angiogenesis on the one hand and in BBB induction on the other. This breakthrough in understanding the differentiation of the brain vasculature prompted us to review these findings embedded in the emerging concepts of Wnt signaling in the vasculature. In particular, interactions with other pathways that are crucial for vascular development such as VEGF, Notch, angiopoietins and Sonic hedgehog are discussed. Finally, we considered the potential role of the Wnt pathway in vascular brain pathologies in which BBB function is hampered, as for example in glioma, stroke and Alzheimer's disease.
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PMID:Differentiation of the brain vasculature: the answer came blowing by the Wnt. 2015 Sep 91

Sphingosine-1-phosphate (S1P) is an important bioactive sphingolipid involved in angiogenesis and lymphangiogenesis, 2 important processes that influence the growth, survival, and spread of tumors. S1P acts as an extracellular mediator through binding to 5 highly specific S1P receptors, S1P(1-5). Sphingosine kinase-1 (SK1), one of 2 known sphingosine kinase enzymes responsible for S1P production, appears to be overexpressed in many tumors. Although a role for S1P in angiogenesis and lymphangiogenesis has been established, it is unclear whether S1P secreted from cancer cells has a paracrine function in a tumor environment. Here we investigated whether modulation of cellular SK1 could initiate a paracrine angiogenic and lymphangiogenic switch. We found that SK1 overexpression in HEK cells or its down-regulation in glioma or breast cancer cells modulated extracellular S1P levels accordingly, which in turn increased or decreased both migration and tube formation in cocultured vascular or lymphatic endothelial cells. In contrast, down-regulation of sphingosine kinase 2 in both glioma and breast cancer cells had no appreciable effect on cellular or secreted S1P levels. In addition, vascular endothelial growth factors VEGF and VEGF-C down-regulation in cancer cells appeared insufficient to block the angiogenic and lymphangiogenic switch triggered by these cells. Moreover, S1P initiated endothelial cell sprouting in 3-dimensional collagen matrices, which is representative of a multistep angiogenic process. Our data collectively demonstrate for the first time that SK1 plays an essential role in regulating in vitro paracrine angiogenesis and lymphangiogenesis.
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PMID:Role of sphingosine kinase-1 in paracrine/transcellular angiogenesis and lymphangiogenesis in vitro. 2033 28

The general strategy developed aims to favor the vascular effect of photodynamic therapy by targeting tumor vasculature. Since angiogenic endothelial cells represent an interesting target to potentiate this vascular effect, we previously described the conjugation of a photosensitizer to a peptide targeting neuropilins (NRPs) over-expressed specially in tumor angiogenic vessels and we recently characterized the mechanism of photosensitization-induced thrombogenic events. Nevertheless, in glioma-bearing nude mice, we demonstrated that the peptide moiety was degraded to various rates according to time after intravenous administration. In this study, new peptidases-resistant pseudopeptides were tested, demonstrating a molecular affinity for NRP-1 and NRP-2 recombinant chimeric proteins and devoid of affinity for VEGF receptor type 1 (Flt-1). To argue the involvement of NRP-1, MDA-MB-231 breast cancer cells were used, strongly over-expressing NRP-1 receptor. We evidenced a statistically significant decrease of the different peptides-conjugated photosensitizers uptake after RNA interference-mediated silencing of NRP-1. Peptides-conjugated photosensitizers allowed a selective accumulation into cells. In mice, no degradation was observed in plasma in vivo 4h after intravenous injection by MALDI-TOF mass spectrometry. This study draws attention to this potential problem with peptides, especially in the case of targeting strategies, and provides useful information for the future design of more stable molecules.
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PMID:Photodynamic therapy targeting neuropilin-1: Interest of pseudopeptides with improved stability properties. 2038 Aug 12

Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, alpha(v)beta(3) integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs) likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4) results in a nonfunctioning vasculature and could be another important target distinct from VEGF.
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PMID:Molecular therapeutic targets for glioma angiogenesis. 2041 63

Despite recent advances in the understanding of its cell biology, glioma remains highly lethal. Development of effective therapies requires a cost-effective in vitro tumor model that more accurately resembles the in vivo tumor microenvironment as standard two-dimensional (2D) tissue culture conditions do so poorly. Here we report on the use of a three-dimensional (3D) chitosan-alginate (CA) scaffold to serve as an extracellular matrix that promotes the conversion of cultured cancer cells to a more malignant in vivo-like phenotype. Human U-87 MG and U-118 MG glioma cells and rat C6 glioma cells were chosen for the study. In vitro tumor cell proliferation and secretion of factors that promote tumor malignancy, including VEGF, MMP-2, fibronectin, and laminin, were assessed. The scaffolds pre-cultured with U-87 MG and C6 cells were then implanted into nude mice to evaluate tumor growth and blood vessel recruitment compared to the standard 2D cell culture and 3D Matrigel matrix xenograft controls. Our results indicate that while the behavior of C6 cells showed minimal differences due to their highly malignant and invasive nature, U-87 MG and U-118 MG cells exhibited notably higher malignancy when cultured in CA scaffolds. CA scaffolds provide a 3D microenvironment for glioma cells that is more representative of the in vivo tumor, thus can serve as a more effective platform for development and study of anticancer therapeutics. This unique CA scaffold platform may offer a valuable alternative strategy to the time-consuming and costly animal studies for a wide variety of experimental designs.
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PMID:Chitosan-alginate 3D scaffolds as a mimic of the glioma tumor microenvironment. 2041 55


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