Radiotherapy in supratentorial gliomas. A study of 821 cases

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Heesters, M. [Dept. of Radiotherapy, Groningen Univ. Hospital (Netherlands); Molenaar, W. [Dept. of Pathology, Groningen Univ. Hospital (Netherlands); Go, G.K. [Dept. of Neurosurgery, Groningen Univ. Hospital (Netherlands)

2003-09-01

Purpose: Analysis of the results of radiotherapy in a large group of cerebral gliomas with identification of prognostic factors and the outcome with respect to different decades of treatment. Patients and Methods: Two decades (1979-1999) of radiotherapy in supratentorial astrocytic and oligodendroglial tumors (n = 821) at the University Hospital Groningen were retrospectively evaluated. Prognostic factors for survival were analyzed. Two decades of radiotherapy treatment were compared with respect to radiotherapy dose and treatment-field design. Results: Glioblastoma multiforme, including gliosarcoma, was the most frequent supratentorial glioma (n = 442) with a poor survival, i.e., median survival time (MST) 7 months, especially in patients > 50 years of age and with poor performance. Patients with good performance were selected for radiotherapy with an optimum dose of 60 Gy local-field irradiation. However, in patients with poor prognosis, no radiotherapy was applied or a shorter treatment scheme was given. Anaplastic astrocytomas (n = 131) were treated in the same way as glioblastoma multiforme. Over time, a decrease in radiation dose (from 60 to 45 Gy) and from whole brain irradiation to local-field treatment was observed, following the literature. In low-grade gliomas, prognostic factors for survival were age, performance, and extent of resection. Gemistocytic astrocytoma (n = 15) had an inferior survival compared to astrocytoma (MST 46 vs. 54 months), but a superior survival compared to anaplastic astrocytoma (MST 10 months). The presence of an oligodendroglial component in a glioma implied a superior survival compared to the astrocytic gliomas. The inherent biology of the glioma is reflected by the study of recurrent tumors with progression to higher grades of malignancy in 32-40% and by the histology of recurrent oligodendroglial tumors. In comparing two decades of radiotherapy in gliomas, no differences in survival were observed despite the technological

Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM.

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Dai, Dong-Wei; Lu, Qiong; Wang, Lai-Xing; Zhao, Wen-Yuan; Cao, Yi-Qun; Li, Ya-Nan; Han, Guo-Sheng; Liu, Jian-Min; Yue, Zhi-Jian

2013-10-14

MiR-106a is frequently down-regulated in various types of human cancer. However the underlying mechanism of miR-106a involved in glioma remains elusive. The association of miR-106a with glioma grade and patient survival was analyzed. The biological function and target of miR-106a were determined by bioinformatic analysis and cell experiments (Western blot, luciferase reporter, cell cycle, ntracellular ATP production and glucose uptake assay). Finally, rescue expression of its target SLC2A3 was used to test the role of SLC2A3 in miR-106a-mediated cell glycolysis and proliferation. Here we showed that miR-106a was a tumor suppressor miRNA was involved in GBM cell glucose uptake and proliferation. Decreased miR-106a in GBM tissues and conferred a poor survival of GBM patients. SLC2A3 was identified as a core target of miR-106a in GBM cells. Inhibition of SLC2A3 by miR-106a attenuated cell proliferation and inhibited glucose uptake. In addition, for each biological process we identified ontology-associated transcripts that significantly correlated with SLC2A3 expression. Finally, the expression of SLC2A3 largely abrogated miR-106a-mediated cell proliferation and glucose uptake in GBM cells. Taken together, miR-106a and SLC2A3 could be potential therapeutic approaches for GBM.

Molecular Therapeutic Targets for Glioma Angiogenesis

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Shingo Takano

2010-01-01

Full Text Available 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, v3 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.

Autophagy involved in resveratrol increased radiosensitivity in glioma stem cells

International Nuclear Information System (INIS)

Long Linmei; Zhang Qingqing; Yang Neng; Ji Wenjun; Song Yunzhen; Zhao Jianghu; Liang Zhongqin

2012-01-01

Objective: To investigate the effect of Resveratrol combined with X-ray on radiosensitivity in glioma stem cells. Methods: The proliferation inhibition of glioma stem cells induced by X-rays and Resveratrol was assessed with MTT assay. The activation of proapoptotic effect was characterized by Hoechst 33258 stain. MDC stain and Western blot analysis were used to analyze the autophagy mechanism in X-rays-induced death of glioma stem cells. Results: MTT assay indicated that X-rays and Resveratrol decreased the viability of glioma stem cells (P<0.05); we found the proliferative inhibition of glioma stem cells was declined when we used 3-MA to inhibit autophagy(P<0.05). When the cells were treated by the Resveratrol and x-rays, their spherical shape were changed. Apoptosis was induced in glioma stem cells by combined X-rays and Resveratrol as detected by Hoechst 33258 staining. In addition, autophagy was induced in glioma stem cells in the combined treatment group as detected by MDC staining. Western blotting showed that Bcl-2 expression was decreased. in the combined treatment group (P<0.01), and the LC3-Ⅱ expression was increased in the combined treatment group (P<0.01). Conclusion: Resveratrol can increased the radiation sensitivity of glioma stem cells, the apoptosis and autophagy was induced in the glioma stem cells in the combined treatment X-rays and Resveratrol. Our results suggest that autophagy plays an essential role in the regulation of radiosensitization of glioma stem cells. (authors)

FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading

International Nuclear Information System (INIS)

Poepperl, Gabriele; Koch, Walter; Gildehaus, Franz J.; Tatsch, Klaus; Kreth, Friedrich W.; Mehrkens, Jan H.; Tonn, Joerg C.; Herms, Jochen; Kretzschmar, Hans A.; Seelos, Klaus

2007-01-01

Treatment and prognosis of gliomas depend on their histological tumour grade. The aim of the study was to evaluate the potential of [ 18 F]fluoroethyltyrosine (FET) PET for non-invasive tumour grading in untreated patients. Dynamic FET PET studies were performed in 54 patients who, based on MRI, were estimated to have low grade (LG; n = 20), intermediate (WHO II-III; n = 4) or high grade (HG; n = 30) tumours. For standard evaluation, tumour SUV max and the ratio to background (SUV max /BG) were calculated (sum image: 20-40 min). For dynamic evaluation, mean SUV values within a 90% isocontour ROI (SUV90) and the SUV90/BG ratios were determined for each time frame to evaluate the course of FET uptake. Results were correlated with histopathological findings from PET-guided stereotactic biopsies. Histology revealed gliomas in all patients. Using the standard method a statistically significant difference (p = 0.001) was found between LG (n = 20; SUV max /BG: 2.16 ± 0.98) and HG (n = 34; SUV max /BG: 3.29 ± 1.06) gliomas (opt. threshold 2.58: SN71%/SP85%/area under ROC curve [AUC]:0.798), however, with a marked overlap between WHO II to IV tumours. Time activity curves showed slight increase in LG, whereas HG tumours presented with an early peak (10-20 min) followed by a decrease. Dynamic evaluation successfully separated LG from HG gliomas with higher diagnostic accuracy (SN94%/SP100%/AUC:0.967). Based on the ratio-based method, a statistically significant difference was found between LG and HG gliomas. Due to the interindividual variability, however, no reliable individual grading was possible. In contrast, dynamic evaluation allowed LG and HG gliomas to be differentiated with high diagnostic power and, thus, should supplement the conventional method. (orig.)

Gene expression of manganese superoxide dismutase in human glioma cells

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Novi S. Hardiany

2010-02-01

Full Text Available Aim This study analyze the MnSOD gene expression as endogenous antioxidant in human glioma cells compared with leucocyte cells as control.Methods MnSOD gene expression of 20 glioma patients was analyzed by measuring the relative expression of mRNA and enzyme activity of MnSOD in brain and leucocyte cells. The relative expression of mRNA MnSOD was determined by using quantitative Real Time RT-PCR and the enzyme activity of MnSOD using biochemical kit assay (xantine oxidase inhibition. Statistic analysis for mRNA and enzyme activity of MnSOD was performed using Kruskal Wallis test.Results mRNA of MnSOD in glioma cells of 70% sample was 0.015–0.627 lower, 10% was 1.002-1.059 and 20% was 1.409-6.915 higher than in leucocyte cells. Also the specific activity of MnSOD enzyme in glioma cells of 80% sample showed 0,064-0,506 lower and 20% sample was 1.249-2.718 higher than in leucocyte cells.Conclusion MnSOD gene expression in human glioma cells are significantly lower than its expression in leucocytes cells. (Med J Indones 2010; 19:21-5Keywords : MnSOD, glioma, gene expression

Early static {sup 18}F-FET-PET scans have a higher accuracy for glioma grading than the standard 20-40 min scans

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Albert, Nathalie L.; Winkelmann, Isabel; Wenter, Vera; Mille, Erik; Todica, Andrei; Brendel, Matthias; Bartenstein, Peter [Ludwig-Maximilians-University Munich, Department of Nuclear Medicine, Munich (Germany); Suchorska, Bogdana; Tonn, Joerg-Christian [Ludwig-Maximilians-University Munich, Department of Neurosurgery, Munich (Germany); Schmid-Tannwald, Christine [Ludwig-Maximilians-University Munich, Institute for Clinical Radiology, Munich (Germany); La Fougere, Christian [University of Tuebingen, Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Tuebingen (Germany)

2016-06-15

Current guidelines for glioma imaging by positron emission tomography (PET) using the amino acid analogue O-(2-[{sup 18}F]fluoroethyl)-L-tyrosine ({sup 18}F-FET) recommend image acquisition from 20-40 min post injection (p.i.). The maximal tumour-to-background evaluation (TBR{sub max}) obtained in these summation images does not enable reliable differentiation between low and high grade glioma (LGG and HGG), which, however, can be achieved by dynamic {sup 18}F-FET-PET. We investigated the accuracy of tumour grading using TBR{sub max} values at different earlier time points after tracer injection. Three hundred and fourteen patients with histologically proven primary diagnosis of glioma (131 LGG, 183 HGG) who had undergone 40-min dynamic {sup 18}F-FET-PET scans were retrospectively evaluated. TBR{sub max} was assessed in the standard 20-40 min summation images, as well as in summation images from 0-10 min, 5-15 min, 5-20 min, and 15-30 min p.i., and kinetic analysis was performed. TBR{sub max} values and kinetic analysis were correlated with histological classification. ROC analyses were performed for each time frame and sensitivity, specificity, and accuracy were assessed. TBR{sub max} values in the earlier summation images were significantly better for tumour grading (P < 0.001) when compared to standard 20-40 min scans, with best results for the early 5-15 min scan. This was due to higher TBR{sub max} in the HGG (3.9 vs. 3.3; p < 0.001), while TBR{sub max} remained nearly stable in the LGG (2.2 vs. 2.1). Overall, accuracy increased from 70 % in the 20-40 min analysis to 77 % in the 5-15 min images, but did not reach the accuracy of dynamic analysis (80 %). Early TBR{sub max} assessment (5-15 min p.i.) is more accurate for the differentiation between LGG and HGG than the standard static scan (20-40 min p.i.) mainly caused by the characteristic high {sup 18}F-FET uptake of HGG in the initial phase. Therefore, when dynamic {sup 18}F-FET-PET cannot be performed

Known glioma risk loci are associated with glioma with a family history of brain tumours

DEFF Research Database (Denmark)

Melin, Beatrice; Dahlin, Anna M; Andersson, Ulrika

2013-01-01

significantly associated with glioma risk, rs6010620 (ORtrend for the minor (A) allele, 0.39; 95% CI: 0.25-0.61; Bonferroni adjusted ptrend , 1.7 × 10(-4) ). In conclusion, as previously shown for glioma regardless of family history of brain tumours, rs6010620 (RTEL1) was associated with an increased risk...... family history of brain tumours, defined as having at least one first- or second-degree relative with a history of brain tumour, are associated with known glioma risk loci. One thousand four hundred and thirty-one glioma cases and 2,868 cancer-free controls were identified from four case-control studies...... and two prospective cohorts from USA, Sweden and Denmark and genotyped for seven SNPs previously reported to be associated with glioma risk in case-control designed studies. Odds ratios were calculated by unconditional logistic regression. In analyses including glioma cases with a family history of brain...

Interactions between glioma and pregnancy: insight from a 52-case multicenter series.

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Peeters, Sophie; Pagès, Mélanie; Gauchotte, Guillaume; Miquel, Catherine; Cartalat-Carel, Stéphanie; Guillamo, Jean-Sébastien; Capelle, Laurent; Delattre, Jean-Yves; Beauchesne, Patrick; Debouverie, Marc; Fontaine, Denys; Jouanneau, Emmanuel; Stecken, Jean; Menei, Philippe; De Witte, Olivier; Colin, Philippe; Frappaz, Didier; Lesimple, Thierry; Bauchet, Luc; Lopes, Manuel; Bozec, Laurence; Moyal, Elisabeth; Deroulers, Christophe; Varlet, Pascale; Zanello, Marc; Chretien, Fabrice; Oppenheim, Catherine; Duffau, Hugues; Taillandier, Luc; Pallud, Johan

2018-01-01

OBJECTIVE The goal of this study was to provide insight into the influence of gliomas on gestational outcomes, the impact of pregnancy on gliomas, and the identification of patients at risk. METHODS In this multiinstitutional retrospective study, the authors identified 52 pregnancies in 50 women diagnosed with a glioma. RESULTS For gliomas known prior to pregnancy (n = 24), we found the following: 1) An increase in the quantified imaging growth rates occurred during pregnancy in 87% of cases. 2) Clinical deterioration occurred in 38% of cases, with seizures alone resolving after delivery in 57.2% of cases. 3) Oncological treatments were immediately performed after delivery in 25% of cases. For gliomas diagnosed during pregnancy (n = 28), we demonstrated the following: 1) The tumor was discovered during the second and third trimesters in 29% and 54% of cases, respectively, with seizures being the presenting symptom in 68% of cases. 2) The quantified imaging growth rates did not significantly decrease after delivery and before oncological treatment. 3) Clinical deterioration resolved after delivery in 21.4% of cases. 4) Oncological treatments were immediately performed after delivery in 70% of cases. Gliomas with a high grade of malignancy, negative immunoexpression of alpha-internexin, or positive immunoexpression for p53 were more likely to be associated with tumor progression during pregnancy. Deliveries were all uneventful (cesarean section in 54.5% of cases and vaginal delivery in 45.5%), and the infants were developmentally normal. CONCLUSIONS When a woman harboring a glioma envisions a pregnancy, or when a glioma is discovered in a pregnant patient, the authors suggest informing her and her partner that pregnancy may impact the evolution of the glioma clinically and radiologically. They strongly advise a multidisciplinary approach to management. ■ CLASSIFICATION OF EVIDENCE Type of question: association; study design: case series; evidence: Class IV.

The relationship between Cho/NAA and glioma metabolism: implementation for margin delineation of cerebral gliomas.

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Guo, Jun; Yao, Chengjun; Chen, Hong; Zhuang, Dongxiao; Tang, Weijun; Ren, Guang; Wang, Yin; Wu, Jinsong; Huang, Fengping; Zhou, Liangfu

2012-08-01

The marginal delineation of gliomas cannot be defined by conventional imaging due to their infiltrative growth pattern. Here we investigate the relationship between changes in glioma metabolism by proton magnetic resonance spectroscopic imaging ((1)H-MRSI) and histopathological findings in order to determine an optimal threshold value of choline/N-acetyl-aspartate (Cho/NAA) that can be used to define the extent of glioma spread. Eighteen patients with different grades of glioma were examined using (1)H-MRSI. Needle biopsies were performed under the guidance of neuronavigation prior to craniotomy. Intraoperative magnetic resonance imaging (MRI) was performed to evaluate the accuracy of sampling. Haematoxylin and eosin, and immunohistochemical staining with IDH1, MIB-1, p53, CD34 and glial fibrillary acidic protein (GFAP) antibodies were performed on all samples. Logistic regression analysis was used to determine the relationship between Cho/NAA and MIB-1, p53, CD34, and the degree of tumour infiltration. The clinical threshold ratio distinguishing tumour tissue in high-grade (grades III and IV) glioma (HGG) and low-grade (grade II) glioma (LGG) was calculated. In HGG, higher Cho/NAA ratios were associated with a greater probability of higher MIB-1 counts, stronger CD34 expression, and tumour infiltration. Ratio threshold values of 0.5, 1.0, 1.5 and 2.0 appeared to predict the specimens containing the tumour with respective probabilities of 0.38, 0.60, 0.79, 0.90 in HGG and 0.16, 0.39, 0.67, 0.87 in LGG. HGG and LGG exhibit different spectroscopic patterns. Using (1)H-MRSI to guide the extent of resection has the potential to improve the clinical outcome of glioma surgery.

Influence of the depth of sedation on regional cerebral oxygen saturation monitoring in neurosurgery of supratentorial gliomas

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ZHANG Kai⁃ying

2012-12-01

Full Text Available Objective To investigate the influence on regional cerebral oxygen saturation (rScO2 of sedation depth during anesthesia induction and maintenance in supratentorial glioma resections. Methods Thirty patients with Ⅰ - Ⅱ supratentorial glioma (graded by American Society of Anesthesiologists underwent elective supratentorial glioma resection were included in this study. Rocuronium, sufentanil and propofol were used for anesthesia induction. After trachea cannula, total intravenous anesthesia (TIVA was maintained with plasma concentration of propofol 2.80-3.20 μg/ml and remifentanil 0.10-0.20 μg/(kg·min. Thirty groups of rScO2, bispectral index (BIS, mean arterial pressure (MAP and heart rate (HR were recorded continuously till the incision. Results During anesthesia induction, BIS decreased along with the infusion of anesthetics, and there was significant negative correlation between BIS and rScO2 (r = ⁃0.803, P = 0.001. During anesthesia maintenance, rScO2 and BIS were not significantly related (r = 0.147, P = 0.396. Conclusion The rScO2 monitoring can reflect the influence of sedation depth on cerebral oxygen delivery and consumption balance during supratentorial glioma resection under TIVA．

Molecular Alterations of KIT Oncogene in Gliomas

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Ana L. Gomes

2007-01-01

Full Text Available Gliomas are the most common and devastating primary brain tumours. Despite therapeutic advances, the majority of gliomas do not respond either to chemo or radiotherapy. KIT, a class III receptor tyrosine kinase (RTK, is frequently involved in tumourigenic processes. Currently, KIT constitutes an attractive therapeutic target. In the present study we assessed the frequency of KIT overexpression in gliomas and investigated the genetic mechanisms underlying KIT overexpression. KIT (CD117 immunohistochemistry was performed in a series of 179 gliomas of various grades. KIT activating gene mutations (exons 9, 11, 13 and 17 and gene amplification analysis, as defined by chromogenic in situ hybridization (CISH and quantitative real-time PCR (qRT-PCR were performed in CD117 positive cases. Tumour cell immunopositivity was detected in 15.6% (28/179 of cases, namely in 25% (1/4 of pilocytic astrocytomas, 25% (5/20 of diffuse astrocytomas, 20% (1/5 of anaplastic astrocytomas, 19.5% (15/77 of glioblastomas and one third (3/9 of anaplastic oligoastrocytomas. Only 5.7% (2/35 of anaplastic oligodendrogliomas showed CD117 immunoreactivity. No association was found between tumour CD117 overexpression and patient survival. In addition, we also observed CD117 overexpression in endothelial cells, which varied from 0–22.2% of cases, being more frequent in high-grade lesions. No KIT activating mutations were identified. Interestingly, CISH and/or qRT-PCR analysis revealed the presence of KIT gene amplification in 6 glioblastomas and 2 anaplastic oligoastrocytomas, corresponding to 33% (8/24 of CD117 positive cases. In conclusion, our results demonstrate that KIT gene amplification rather than gene mutation is a common genetic mechanism underlying KIT expression in subset of malignant gliomas. Further studies are warranted to determine whether glioma patients exhibiting KIT overexpression and KIT gene amplification may benefit from therapy with anti-KIT RTK

Glioma-related seizures in relation to histopathological subtypes: a report from the glioma international case-control study.

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Berntsson, Shala G; Merrell, Ryan T; Amirian, E Susan; Armstrong, Georgina N; Lachance, Daniel; Smits, Anja; Zhou, Renke; Jacobs, Daniel I; Wrensch, Margaret R; Olson, Sara H; Il'yasova, Dora; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Schildkraut, Joellen; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Bernstein, Jonine L; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Bondy, Melissa L; Melin, Beatrice S

2018-04-23

The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor ***for developing glioma-related seizures or glioma.

Associations between the rs6010620 polymorphism in RTEL1 and risk of glioma: a meta-analysis of 20,711 participants.

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Wu, Yao; Tong, Xiang; Tang, Ling-Li; Zhou, Kai; Zhong, Chuan-Hong; Jiang, Shu

2014-01-01

Associations between the rs6010620 polymorphism in the regulator of telomere elongation helicase1 (RTEL1) gene and glioma have been widely reported but the results were not inconclusive. The aim of the current study was to investigate the association between the rs6010620 polymorphism in RTEL1 gene and risk of glioma by meta-analysis. We searched PubMed, Embase, Wanfang Weipu and CNKI (China National Knowledge Infrastructure) databases, which included all research published 05 May 2014. A total of 8,292 cases and 12,419 controls from 14 case-control studies involving the rs6010620 polymorphism in the RTEL1 gene were included. Statistical analysis was performed using STATA 12.0 software. The results indicated that the rs6010620 polymorphism in RTEL1 gene was indeed associated with risk of glioma (OR=1.474, 95%CI=1.282-1.694, pRTEL1 gene and risk of glioma in both Caucasians and Asians. The current meta-analysis suggested that the rs6010620 polymorphism in the RTEL1 gene might increase risk of glioma. In future, larger case-control studies are needed to confirm our results.

Light-controlled inhibition of malignant glioma by opsin gene transfer

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Yang, F; Tu, J; Pan, J-Q; Luo, H-L; Liu, Y-H; Wan, J; Zhang, J; Wei, P-F; Jiang, T; Chen, Y-H; Wang, L-P

2013-01-01

Glioblastomas are aggressive cancers with low survival rates and poor prognosis because of their highly proliferative and invasive capacity. In the current study, we describe a new optogenetic strategy that selectively inhibits glioma cells through light-controlled membrane depolarization and cell death. Transfer of the engineered opsin ChETA (engineered Channelrhodopsin-2 variant) gene into primary human glioma cells or cell lines, but not normal astrocytes, unexpectedly decreased cell proliferation and increased mitochondria-dependent apoptosis, upon light stimulation. These optogenetic effects were mediated by membrane depolarization-induced reductions in cyclin expression and mitochondrial transmembrane potential. Importantly, the ChETA gene transfer and light illumination in mice significantly inhibited subcutaneous and intracranial glioma growth and increased the survival of the animals bearing the glioma. These results uncover an unexpected effect of opsin ion channels on glioma cells and offer the opportunity for the first time to treat glioma using a light-controllable optogenetic approach. PMID:24176851

[A correlation between diffusion kurtosis imaging and the proliferative activity of brain glioma].

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Tonoyan, A S; Pronin, I N; Pitshelauri, D I; Shishkina, L V; Fadeeva, L M; Pogosbekyan, E L; Zakharova, N E; Shults, E I; Khachanova, N V; Kornienko, V N; Potapov, A A

2015-01-01

The aim of the study was to assess the capabilities of diffusion kurtosis imaging (DKI) in diagnosis of the glioma proliferative activity and to evaluate a relationship between the glioma proliferative activity index and diffusion parameters of the contralateral normal appearing white matter (CNAWM). The study included 47 patients with newly diagnosed brain gliomas (23 low grade, 13 grade III, and 11 grade IV gliomas). We determined a relationship between absolute and normalized parameters of the diffusion tensor (mean (MD), axial (AD), and radial (RD) diffusivities; fractional (FA) and relative (RA) anisotropies) and diffusion kurtosis (mean (MK), axial (AK), and radial (RK) kurtosis; kurtosis anisotropy (KA)) and the proliferative activity index in the most malignant glioma parts (pAK, and RK) and anisotropy (KA, FA, RA) values increased, and diffusivity (MD, AD, RD) values decreased as the glioma proliferative activity index increased. A strong correlation between the proliferative activity index and absolute RK (r=0,71; p=0.000001) and normalized values of MK (r=0.8; p=0.000001), AK (r=0.71; p=0.000001), RK (r=0.81; p=0.000001), and RD (r=-0.71; p=0.000001) was found. A weak, but statistically significant correlation between the glioma proliferative activity index and diffusion values RK (r=-0.36; p=0.014), KA (r=-0.39; p=0.007), RD (r=0.35; p=0.017), FA (r=-0.42; p=0.003), and RA (r=-0.41; p=0.004) of CNAWM was found. DKI has good capabilities to detect immunohistochemical changes in gliomas. DKI demonstrated a high sensitivity in detection of microstructural changes in the contralateral normal appearing white matter in patients with brain gliomas.

Approaching a Scientific Consensus on the Association between Allergies and Glioma Risk: A Report from the Glioma International Case-Control Study.

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Amirian, E Susan; Zhou, Renke; Wrensch, Margaret R; Olson, Sara H; Scheurer, Michael E; Il'yasova, Dora; Lachance, Daniel; Armstrong, Georgina N; McCoy, Lucie S; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S; Jenkins, Robert B; Bernstein, Jonine L; Merrell, Ryan T; Davis, Faith G; Lai, Rose; Shete, Sanjay; Amos, Christopher I; Melin, Beatrice S; Bondy, Melissa L

2016-02-01

Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58-0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. ©2016 American Association for Cancer Research.

Mitochondrial Dysfunction in Gliomas

Czech Academy of Sciences Publication Activity Database

Katsetos, C.D.; Anni, H.; Dráber, Pavel

2013-01-01

Roč. 20, č. 3 (2013), s. 216-227 ISSN 1071-9091 R&D Projects: GA MŠk LH12050 Institutional support: RVO:68378050 Keywords : gliomas * mitochondrial dysfunction * microtubule proteins Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.883, year: 2013

A report on radiation-induced gliomas

International Nuclear Information System (INIS)

Salvati, M.; Artico, M.; Caruso, R.; Rocchi, G.; Orlando, E.R.; Nucci, F.

1991-01-01

Radiation-induced gliomas are uncommon, with only 73 cases on record to date. The disease that most frequently occasioned radiation therapy has been acute lymphoblastic leukemia (ALL). Three more cases are added here, two after irradiation for ALL and one after irradiation for tinea capitis. In a review of the relevant literature, the authors stress the possibility that the ALL-glioma and the retinoblastoma-glioma links point to syndromes in their own right that may occur without radiation therapy.56 references

Minimally invasive neuronavigator-guided microsurgery and photodynamic therapy for gliomas.

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Wang, Yezhong; Lei, Ting; Wang, Zhi

2009-06-01

In order to evaluate the effectiveness of neuronavigator-guided microsurgery and keyhole technique for the resection of gliomas, a total of 60 patients with gliomas were exactly located by using neuronavigator during microsurgery. Forty deep-seated gliomas were resected through a keyhole operative approach. Thirty out of the 60 cases were subjected to photodynamic therapy (PDT) after tumor resection. The therapeutic effectiveness of all the cases was recorded and analyzed. The results showed that glioma was totally resected in 52 cases (86.7%), subtotally in 5 (8.3%), and most partially in 3 (5%). Neurological deficits occurred postoperatively in 4 cases. One patient died of multiple system organ failure 4 days after operation. It was concluded that the application of minimally invasive technique could dramatically decrease surgical complications following resection of glioma, and its combination with PDT could obviously improve the quality of life of patients and prolong the survival time.

Smoking and adult glioma: a population-based case-control study in China.

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Hou, Lei; Jiang, Jingmei; Liu, Boqi; Han, Wei; Wu, Yanping; Zou, Xiaonong; Nasca, Philip C; Xue, Fang; Chen, Yuanli; Zhang, Biao; Pang, Haiyu; Wang, Yuyan; Wang, Zixing; Li, Junyao

2016-01-01

Smoking increases the risk of numerous cancers; however, an association of smoking with adult gliomas has not been found in a population. This case-control study included 4556 glioma cases (ICD-9 code 191.0-191.9) aged ≥ 30 years and 9112 controls from a national survey of smoking and mortality in China in 1989-1991. Controls from 325 255 surviving spouses of all-cause deaths were randomly assigned to cases in each of 103 areas according to sex and age groups at a ratio of 2:1. Smoking information was ascertained retrospectively by interviewing surviving spouses. After adjustment for confounders, smoking increased the risk of glioma deaths by 11% (odds ratio [OR] = 1.11; 95% confidence interval [CI]: 1.03-1.21). Compared with non-smokers; the increased risk was 9% (OR = 1.09; 95% CI: 0.99-1.20) in men and 16% (OR = 1.16; 95% CI: 1.00-1.36) in women. The risk increased with age and doses. For individuals aged ≥ 50 years, smoking was associated with higher risk of glioma death by 25% (OR = 1.25; 95% CI: 1.15-1.38); this increased risk for smokers who smoked ≥ 20 cigarettes daily for ≥ 30 years was 53% (OR = 1.53; 95% CI: 1.34-1.74). There were similar findings in both men and women and with either pathology-based or non-pathology-based comparisons. This study indicates that smoking is associated with glioma deaths in the Chinese population. Long-term heavy smoking could be a factor for risk stratification in individuals attending brain tumor clinics. © The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A computational model incorporating neural stem cell dynamics reproduces glioma incidence across the lifespan in the human population.

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Roman Bauer

Full Text Available Glioma is the most common form of primary brain tumor. Demographically, the risk of occurrence increases until old age. Here we present a novel computational model to reproduce the probability of glioma incidence across the lifespan. Previous mathematical models explaining glioma incidence are framed in a rather abstract way, and do not directly relate to empirical findings. To decrease this gap between theory and experimental observations, we incorporate recent data on cellular and molecular factors underlying gliomagenesis. Since evidence implicates the adult neural stem cell as the likely cell-of-origin of glioma, we have incorporated empirically-determined estimates of neural stem cell number, cell division rate, mutation rate and oncogenic potential into our model. We demonstrate that our model yields results which match actual demographic data in the human population. In particular, this model accounts for the observed peak incidence of glioma at approximately 80 years of age, without the need to assert differential susceptibility throughout the population. Overall, our model supports the hypothesis that glioma is caused by randomly-occurring oncogenic mutations within the neural stem cell population. Based on this model, we assess the influence of the (experimentally indicated decrease in the number of neural stem cells and increase of cell division rate during aging. Our model provides multiple testable predictions, and suggests that different temporal sequences of oncogenic mutations can lead to tumorigenesis. Finally, we conclude that four or five oncogenic mutations are sufficient for the formation of glioma.

Interaction between 5 genetic variants and allergy in glioma risk

DEFF Research Database (Denmark)

Schoemaker, Minouk J; Robertson, Lindsay; Wigertz, Annette

2010-01-01

, CDKN2A-CDKN2B), 11q23.3 (rs498872, PHLDB1), and 20q13.33 (rs6010620, RTEL1) as determinants of glioma risk. The authors investigated whether there is interaction between the effects of allergy and these 5 variants on glioma risk. Data from 5 case-control studies carried out in Denmark, Finland, Sweden...

Resection of deep-seated brain glioma by microsurgery assisted with neuronavigation

International Nuclear Information System (INIS)

Feng Ming; Zhou Youxin; Sun Chunming; Zhang Shiming

2009-01-01

Objective: To investigate the clinical value of neuronavigator assisted microsurgery for deep-seated brain glioma. Methods: The electromagnetic neuronavigation system had been applied for microsurgery of deep-seated brain glioma in fifteen cases. Results: Ten from 15 patients were totally removed, 2 were subtotally removed and 3 were partial removed.All patients had no new neurological deficit. Conclusion: The neuronavigator assisted microsurgery for deep-seated brain glioma is of characters including accurate location, minimal invasiveness, and can enhance the rate of total resection and decrease the operative complications in the patients with deep-seated brain glioma. (authors)

Glutamate/glutamine metabolism coupling between astrocytes and glioma cells: neuroprotection and inhibition of glioma growth.

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Yao, Pei-Sen; Kang, De-Zhi; Lin, Ru-Ying; Ye, Bing; Wang, Wei; Ye, Zu-Cheng

2014-07-18

Glioma glutamate release has been shown to promote the growth of glioma cells and induce neuronal injuries from epilepsy to neuronal death. However, potential counteractions from normal astrocytes against glioma glutamate release have not been fully evaluated. In this study, we investigated the glutamate/glutamine cycling between glioma cells and astrocytes and their impact on neuronal function. Co-cultures of glioma cells with astrocytes (CGA) in direct contact were established under different mix ratio of astrocyte/glioma. Culture medium conditioned in these CGAs were sampled for HPLC measurement, for neuronal ratiometric calcium imaging, and for neuronal survival assay. We found: (1) High levels of glutaminase expression in glioma cells, but not in astrocytes, glutaminase enables glioma cells to release large amount of glutamate in the presence of glutamine. (2) Glutamate levels in CGAs were directly determined by the astrocyte/glioma ratios, indicating a balance between glioma glutamate release and astrocyte glutamate uptake. (3) Culture media from CGAs of higher glioma/astrocyte ratios induced stronger neuronal Ca(2+) response and more severe neuronal death. (4) Co-culturing with astrocytes significantly reduced the growth rate of glioma cells. These results indicate that normal astrocytes in the brain play pivotal roles in glioma growth inhibition and in reducing neuronal injuries from glioma glutamate release. However, as tumor growth, the protective role of astrocytes gradually succumb to glioma cells. Copyright © 2014 Elsevier Inc. All rights reserved.

Polifeprosan 20, 3.85% carmustine slow release wafer in malignant glioma: patient selection and perspectives on a low-burden therapy

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Kleinberg L

2016-11-01

Full Text Available Lawrence Kleinberg Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University, Baltimore, MD, USA Abstract: Polifeprosan 20 with carmustine (GLIADEL® polymer implant wafer is a biodegradable compound containing 3.85% carmustine (BCNU, bischloroethylnitrosourea implanted in the brain at the time of planned tumor surgery, which then slowly degrades to release the BCNU chemotherapy directly into the brain thereby bypassing the blood–brain barrier. Carmustine implant wafers were demonstrated to improve survival in randomized placebo-controlled trials in patients undergoing a near total resection of newly diagnosed or recurrent malignant glioma. Based on these trials and other supporting data, carmustine wafer therapy was approved for use for newly diagnosed and recurrent malignant glioma in the United States and the European Union. Adverse events are uncommon, and as this therapy is placed at the time of surgery, it does not add to patient treatment burden. Nevertheless, this therapy appears to be underutilized. This article reviews the evidence for a favorable therapeutic ratio for the patient and the potential barriers. Consideration of these issues is important for optimal use of this therapeutic approach and may be important as this technology and other local therapies are further developed in the future. Keywords: carmustine, wafer, gliadel, glioblastoma

Effect of microenviroment hypoxia on glioma cells radiosensitivity through cancer stem cell pathway

International Nuclear Information System (INIS)

Tong Liumei; Feng Libo; Lu Xueguan; Chen Liesong; Guo Xinwei; Tian Ye

2010-01-01

Objective: To investigate the effect of microenviroment hypoxia on glioma cells radiosensitivity through cancer stem pathway, and to explore the related mechanism. Methods: Glioma cell lines SHG44 and U251 were cultured in normoxia (20% O 2 ) or continuous hypoxia (1% O 2 ) for 12 and 24 h. The fraction of glioma cells with positive expression of CD133 was assayed by flow cytometry. The radiosensitivity of glioma cells was determined by clonogenic cell assay. Western blotting was used to investigate the expressions of HIF-1 α and its downstream gene Notch 1. Results: The fraction of glioma cells with positive expression of CD133 was higher after hypoxic culture for 12 and 24 h than that of the corresponding cells cultured in normoxia. Compared to the cells cultured in normoxia, SF 2 (survival fraction at 2 Gy) were enhanced significantly in SHG44 and U251 cells cultured in hypoxia for 12 and 24 h. The OER (oxygen-enhancement ratio) of SHG44 cells in hypoxia for 12 and 24 h was 1.54 and 1.38, respectively. The OER of U251 cells was 1.44 and 1.23, respectively. The radiosensitivity of these two cell line was decreased in hypoxia. The protein expressions of HIF-1 α and Notch 1 genes were elevated more significantly for cells cultured in hypoxia for 12 and 24 h than for those in normoxia. Conclusions: Microenviroment hypoxia could increase the radioresistance of glioma cells through enrichment of cancer stem cells, and HIF-1 α-Notch 1 signal pathway may play an important role in this process. (authors)

The expression of cytoglobin as a prognostic factor in gliomas: a retrospective analysis of 88 patients

International Nuclear Information System (INIS)

Xu, Hong-Wu; Huang, Hai-Hua; Wei, Xiao-Long; Man, Kwan; Zhang, Guo-Jun; Huang, Yue-Jun; Xie, Ze-Yu; Lin, Lan; Guo, Yan-Chun; Zhuang, Ze-Rui; Lin, Xin-Peng; Zhou, Wen; Li, Mu

2013-01-01

Evidence suggests that cytoglobin (Cygb) may function as a tumor suppressor gene. We immunohistochemically evaluated the expression of Cygb, phosphatidylinositol-3 kinase (PI-3K), phosphorylated (p)-Akt, Interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and vascular endothelial growth factor (VEGF) in 88 patients with 41 high-grade gliomas and 47 low-grade gliomas. Intratumoral microvessel density (IMD) was also determined and associated with clinicopathological factors. Low expression of Cygb was significantly associated with the higher histological grading and tumor recurrence. A significant negative correlation emerged between Cygb expression and PI3K, p-Akt, IL-6, TNFα or VEGF expression. Cygb expression was negatively correlated with IMD. There was a positive correlation between PI3K, p-Akt, IL-6, TNFα and VEGF expression with IMD.High histologic grade, tumor recurrence, decreased Cygb expression, increased PI3K expression, increased p-Akt expression and increased VEGF expression correlated with patients’ overall survival in univariate analysis. However, only histological grading and Cygb expression exhibited a relationship with survival of patients as independent prognostic factors of glioma by multivariate analysis. Cygb loss may contribute to tumor recurrence and a worse prognosis in gliomas. Cygb may serve as an independent predictive factor for prognosis of glioma patients

A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model.

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Towner, Rheal A; Ihnat, Michael; Saunders, Debra; Bastian, Anja; Smith, Nataliya; Pavana, Roheeth Kumar; Gangjee, Aleem

2015-07-17

High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule. GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively. Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.

Long-term culture of organotypic multicellular glioma spheroids: a good culture model for studying gliomas

NARCIS (Netherlands)

Kaaijk, P.; Troost, D.; Das, P. K.; Leenstra, S.; Bosch, D. A.

1995-01-01

Gliomas, as well as other solid tumours, contain tumour stroma composed of connective tissue, macrophages, capillaries and other non-cellular constituents. Therefore, a homogeneous culture of tumour cells alone, as is often used as a culture model for gliomas, is not ideal to study all aspects of

Long non-coding RNA TUG1 acts as a miR-26a sponge in human glioma cells.

Science.gov (United States)

Li, Jun; An, Gang; Zhang, Meng; Ma, Qingfang

2016-09-02

Long non-coding RNA taurine upregulated gene 1 (TUG1) acts as an important regulator in cancer pathogenesis; however, its functional mechanism in glioma development remains unclear. This study aims to explore the potential function of TUG1 in glioma by sponging miR-26a. The expression of TUG1, miR-26a, and phosphatase and tensin homolog (PTEN) in 20 paired glioma tissues was detected by quantitative real-time PCR and subjected to correlation analysis. Bioinformatics analysis was performed by using DIANA Tools. Abnormal TUG1 expression was conducted in two glioma cells to analyze its regulation on miR-26a and PTEN using real-time PCR, western blot, and luciferase reporter assay. TUG1 expression was confirmed to be upregulated in glioma tissues, and showed an inverse correlation with downregulated miR-26a. TUG1 could negatively regulate the expression of miR-26a in glioma cells. The bioinformatics prediction revealed putative miR-26a binding sites within TUG1 transcripts. Further experiments demonstrated the positive regulation of TUG1 on the miR-26a target, PTEN, wherein TUG1 could inhibit the negative regulation of miR-26a on PTEN by binding its 3'UTR. Additionally, the expression of PTEN was also upregulated in glioma tissues, showing a positive or negative correlation with TUG1 or miR-26a, respectively. TUG1 could serve as a miR-26a sponge in human glioma cells, contributing to the upregulation of PTEN. This study revealed a new TUG1/miR-26a/PTEN regulatory mechanism and provided a further understanding of the tumor-suppressive role of TUG1 in glioma development. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo detection of c-Met expression in a rat C6 glioma model.

Science.gov (United States)

Towner, R A; Smith, N; Doblas, S; Tesiram, Y; Garteiser, P; Saunders, D; Cranford, R; Silasi-Mansat, R; Herlea, O; Ivanciu, L; Wu, D; Lupu, F

2008-01-01

The tyrosine kinase receptor, c-Met, and its substrate, the hepatocyte growth factor (HGF), are implicated in the malignant progression of glioblastomas. In vivo detection of c-Met expression may be helpful in the diagnosis of malignant tumours. The C6 rat glioma model is a widely used intracranial brain tumour model used to study gliomas experimentally. We used a magnetic resonance imaging (MRI) molecular targeting agent to specifically tag the cell surface receptor, c-Met, with an anti-c-Met antibody (Ab) linked to biotinylated Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-albumin in rat gliomas to detect overexpression of this antigen in vivo. The anti-c-Met probe (anti-c-Met-Gd-DTPA-albumin) was administered intravenously, and as determined by an increase in MRI signal intensity and a corresponding decrease in regional T(1) relaxation values, this probe was found to detect increased expression of c-Met protein levels in C6 gliomas. In addition, specificity for the binding of the anti-c-Met contrast agent was determined by using fluorescence microscopic imaging of the biotinylated portion of the targeting agent within neoplastic and 'normal'brain tissues following in vivo administration of the anti-c-Met probe. Controls with no Ab or with a normal rat IgG attached to the contrast agent component indicated no non-specific binding to glioma tissue. This is the first successful visualization of in vivo overexpression of c-Met in gliomas.

A comparative study of MR imaging scores and MR perfusion imaging in pre-operative grading of intracranial gliomas

International Nuclear Information System (INIS)

Wu Honglin; Chen Junkun; Zhang Zongjun; Lu Guangming; Chen Ziqian; Wang Wei; Ji Xueman; Tang Xiaojun; Li Lin

2005-01-01

Objective: To compare the accuracy of MR imaging scores with MR perfusion imaging in pre-operative grading of intracranial gliomas. Methods: Thirty patients with intracranial gliomas (8 low-grade and 22 high-grade, according to WHO criteria) were examined with MR perfusion imaging pre-operatively. The lesions were evaluated by using an MR imaging score based on nine criteria. rCBV of the lesions were calculated by comparing the CBV of the lesion and that of contralateral normal white matter. The scores and ratios in high-grade and low-grade tumours were compared. Results: The MR imaging score of low grade (grades I and II) gliomas (0.67±0.29) were significantly lower than that of grades III (1.32 ± 0.47) (t=-3.48, P=0.003) and IV (1.56 ± 0.20) (t=-7.36, P=0.000) gliomas. There was no statistical difference when MR imaging scores of grades III and IV gliomas (t=-1.39, P=0.182) were compared. The maximum rCBV ratio of low grade (grades I and II) gliomas (2.38 ± 0.66 ) were significantly lower than that of grades III (5.81 ± 3.20) (t=-3.57, P=0.003) and IV (6.99 ± 2.47) (t=-5.09, P=0.001). There was no statistical difference when rCBV ratios of grades III and IV (t =-0.93, P=0.365) gliomas were compared. The accuracy of MR imaging scores in the noninvasive grading of untreated gliomas was all most the same as that of MR perfusion imaging (90.00% vs 89.29%). Conclusion: The MR imaging scores and MR perfusion imaging are two very useful tools in the evaluation of the histopathologic grade of cerebral gliomas. The overall accuracy in the noninvasive grading of gliomas may be imp roved if MR imaging scores and MR perfusion imaging are combined. (authors)

Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro

International Nuclear Information System (INIS)

Sun, Ting; Zhang, Zizhu; Li, Bin; Chen, Guilin; Xie, Xueshun; Wei, Yongxin; Wu, Jie; Zhou, Youxin; Du, Ziwei

2013-01-01

Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells. The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression. The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins. Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma

Dosimetric comparison of three-dimensional conformal and intensity modulated radiotherapy in brain glioma

International Nuclear Information System (INIS)

Lu Jie; Zhang Guifang; Bai Tong; Yin Yong; Fan Tingyong; Wu Chaoxia

2009-01-01

Objective: To investigate the dosimetry advantages of intensity modulated radiotherapy (IMRT)of brain glioma compared with that of three-dimensional conformal radiotherapy (SD CRT). Methods: Ten patients with brain glioma were enrolled in this study. Three-dimensional conf0rmal and intensity modulated radiotherapy plans were performed for each patient. The dose distributions of target volume and normal tissues, conformal index (CI) and heterogeneous index (HI) were analyzed using the dose-volume histogram (DVH). The prescription dose was 60 Gy in 30 fractions. Results: IMRT plans decrease the maximum dose and volume of brainstem, mean dose of affected side parotid and maximum dose of spinal-cord. The CI for PTV of IMRT was superior to that of SD CRT, the HI for PTV has no statistical significance of the two model plans. Conclusions: IMRT plans can obviously decrease the dose and volume of brainstem. IMRT is a potential method in the treatment of brain glioma, and dose escalation was possible in patients with brain glioma. (authors)

Increased Expression of microRNA-17 Predicts Poor Prognosis in Human Glioma

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Shengkui Lu

2012-01-01

Full Text Available Aim. To investigate the clinical significance of microRNA-17 (miR-17 expression in human gliomas. Methods. Quantitative real-time polymerase chain reaction (qRT-PCR analysis was used to characterize the expression patterns of miR-17 in 108 glioma and 20 normal brain tissues. The associations of miR-17 expression with clinicopathological factors and prognosis of glioma patients were also statistically analyzed. Results. Compared with normal brain tissues, miR-17 expression was significantly higher in glioma tissues (P<0.001. In addition, the increased expression of miR-17 in glioma was significantly associated with advanced pathological grade (P=0.006 and low Karnofsky performance score (KPS, P=0.01. Moreover, Kaplan-Meier survival and Cox regression analyses showed that miR-17 overexpression (P=0.008 and advanced pathological grade (P=0.02 were independent factors predicting poor prognosis for gliomas. Furthermore, subgroup analyses showed that miR-17 expression was significantly associated with poor overall survival in glioma patients with high pathological grades (for grade III~IV: P<0.001. Conclusions. Our data offer the convinced evidence that the increased expression of miR-17 may have potential value for predicting poor prognosis in glioma patients with high pathological grades, indicating that miR-17 may contribute to glioma progression and be a candidate therapeutic target for this disease.

MRI and morphological observation in C6 glioma model rats and significance

International Nuclear Information System (INIS)

Zhou Ying; Yuan Bo; Wang Hao; Lu Jin; Yuan Changji; Ma Yue; Tong Dan; Zhang Kun; Gao Feng; Wu Xiaogang

2013-01-01

Objective: To establish stable and reliable rat C6 glioma model, and to perform MRI dynamic observation and pathomorphological observation in model animal brain, and to provide experimental basis for pharmaceutical research on anti-glioma drugs. Methods: The C6 glioma cells were cultured and 20 μL cultural fluid containing 1×10 6 C6 cells was sterotactically implanted into the left caudate nuclei in 10 male Wistar rats, respectively. The changes in the behavior of the rats after implantation were observed and recorded. MRI dynamic scanning was performed in 10 rats 2, 3 and 4 weeks after implantation and the brain tissues were taken for general and pathological examination when the 10 rats were naturally dead. The survival period of tumor-bearing rats was calculated. Results: 2 weeks after implantation the rats showed decreased activities and food intake, fur lackluster, and conjunctival congestion and so on; 3 weeks later, some rats appeared nerve symptoms such as body twitch, body hemiplegy, body distortion, rotation and so on. All the 10 rats died in 8-30 d. The median survival period of the tumor-bearing rats was 18 d, the average survival period was (18.3±7.3) d. The pathological examination showed that the tumor cells were arranged irregularly closely and karyokinesis was easy to see; tumor vascular tissue proliferation and tumor invasive growth into surrounding normal tissues were found. The expression of glial fibrillary acidic protein (GFAP) was positive in the tumors. Conclusion: A stable animal model of intracranial glioma is successfully established by stereotactic implantation of C6 cells into the rat caudate nucleus. The results of MRI dynamic observation and pathohistological observation on the model animal brain tissue. Can provide experimental basis for selecting the appropriate time window to perform the pharmaceutical research on anti-glioma drugs. (authors)

Genetic Alterations in Glioma

International Nuclear Information System (INIS)

Bralten, Linda B. C.; French, Pim J.

2011-01-01

Gliomas are the most common type of primary brain tumor and have a dismal prognosis. Understanding the genetic alterations that drive glioma formation and progression may help improve patient prognosis by identification of novel treatment targets. Recently, two major studies have performed in-depth mutation analysis of glioblastomas (the most common and aggressive subtype of glioma). This systematic approach revealed three major pathways that are affected in glioblastomas: The receptor tyrosine kinase signaling pathway, the TP53 pathway and the pRB pathway. Apart from frequent mutations in the IDH1/2 gene, much less is known about the causal genetic changes of grade II and III (anaplastic) gliomas. Exceptions include TP53 mutations and fusion genes involving the BRAF gene in astrocytic and pilocytic glioma subtypes, respectively. In this review, we provide an update on all common events involved in the initiation and/or progression across the different subtypes of glioma and provide future directions for research into the genetic changes

Radiosensitive effect of hypoxia-inducible factor 1α inhibitor YC-1 on hypoxic glioma SHG44 cell line

International Nuclear Information System (INIS)

Guo Xinwei; Lu Xueguan; Tong Liumei; Zong Tianzhou; Chen Liesong

2011-01-01

Objective: To investigate the radiosensitive effect of hypoxia-inducible factor 1α (HIF-1α) inhibitor YC-1 on hypoxic glioma SHG44 cell line and its related mechanism. Methods: Glioma SHG44 cell line was cultured in normoxic (20% O 2 ), continuous hypoxia (1% O 2 ) for 12 h and 24 h, continuous hypoxia plus YC-1 was performed for 12 h and 24 h, respectively. The expression of HIF-1α was assessed by Western blot. The radiosensitivity was evaluated by the survival curve, and the sublethal damage repair (SLDR) ability was measured by dose-fraction experiment. Results: HIF-1α protein levels of glioma SHG44 cells were significantly increased after hypoxic cultures for 12 h and 24 h than those of the corresponding cells cultured in normoxic, while the radiosensitivity was lower. The OER (oxygen-enhancement ratio) of SHG44 cells in hypoxia for 12 h and 24 h were 1.22 and 1.37, respectively. By the further statistical analysis it was found that SLDR ability of glioma SHG44 was increased at hypoxia, and when irradiation was carried one at the interval of 8, 10, 12 h it was statistically significant (P<0.05). HIF-1α protein levels of glioma SHG44 cells cultured in hypoxia plus YC-1 for 12 h and 24 h were decreased significantly compared to the corresponding cells cultured in hypoxia only, while the radiosensitivity was significantly increased. the EF (enhancement factor) of YC-1 for glioma SHG44 cells at hypoxia for 12 h and 24 h was 1.27. By the further statistical analysis it was also found that SLDR ability was decreased significantly for hypoxic SHG44 cells which was co-cultured with YC-1, and at the interval of 8, 10, 12 h irradiation was statistically significant (P<0.05). Conclusion: YC-1 can increase the radiosensitivity of hypoxic glioma SHG44 cell line, and its mechanism is related to SLDR inhibited by YC-1. (authors)

TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients

International Nuclear Information System (INIS)

Wang, Chao; Cao, Shouqiang; Yan, Ying; Ying, Qiao; Jiang, Tao; Xu, Ke; Wu, Anhua

2010-01-01

Our study aims to evaluate the expression of TLR9 in glioma tissues, examine the association between TLR9 expression, clinicopathological variables, and glioma patient outcome, we further characterized the direct effects of TLR9 agonist CpG ODN upon the proliferation and invasion of glioma cells in vitro. RT-PCR and immunofluorescence were used to determine the expression of TLR9 in glioma cell lines and clinical glioma samples. Tissue microarry and immunohistochemistry were applied to evaluated TLR9 expression in 292 newly diagnosed glioma and 13 non-neoplastic brain tissues. We further investigated the effect of CpG ODN on the proliferation and invasion of glioma cells in vitro with MTT assays and matrigel transwell assay respectively. RT-PCR showed that TLR9 expressed in all the glioma samples and glioma cell lines we examined. The tissue array analysis indicated that TLR9 expression is correlated with malignancy of glioma (p < 0.01). Multivariate Cox regression analysis revealed that TLR9 expression is an independent prognostic factor for PFS of GBM patients(P = 0.026). TLR9 agonist CpG ODN has no significant effect on glioma proliferation, but matrigel transwell analysis showed that TLR9 agonist CpG ODN can significantly enhance glioma invasion in vitro. Our data indicated that TLR9 expression increases according to the histopathological grade of glioma, and the TLR9 expression level is related to the PFS of GBM patients. In addition, our findings warrant caution in the directly injection of TLR9 agonist CpG ODN into glioma tissues for the glioma immunotherapy

MicroRNA in Human Glioma

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Li, Mengfeng, E-mail: limf@mail.sysu.edu.cn [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Li, Jun [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Liu, Lei; Li, Wei [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Yang, Yi [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080 (China); Yuan, Jie [Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou 510080 (China); Key Laboratory of Functional Molecules from Oceanic Microorganisms (Sun Yat-sen University), Department of Education of Guangdong Province, Guangzhou 510080 (China)

2013-10-23

Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy.

MicroRNA in Human Glioma

International Nuclear Information System (INIS)

Li, Mengfeng; Li, Jun; Liu, Lei; Li, Wei; Yang, Yi; Yuan, Jie

2013-01-01

Glioma represents a serious health problem worldwide. Despite advances in surgery, radiotherapy, chemotherapy, and targeting therapy, the disease remains one of the most lethal malignancies in humans, and new approaches to improvement of the efficacy of anti-glioma treatments are urgently needed. Thus, new therapeutic targets and tools should be developed based on a better understanding of the molecular pathogenesis of glioma. In this context, microRNAs (miRNAs), a class of small, non-coding RNAs, play a pivotal role in the development of the malignant phenotype of glioma cells, including cell survival, proliferation, differentiation, tumor angiogenesis, and stem cell generation. This review will discuss the biological functions of miRNAs in human glioma and their implications in improving clinical diagnosis, prediction of prognosis, and anti-glioma therapy

Glia to glioma: A wrathful journey

Directory of Open Access Journals (Sweden)

Krishnendu Ghosh

2017-05-01

Full Text Available Glial cells, unlike neurons in the brain, can undergo cellular division to maintain their functional continuity. However, sometimes this divisional attribute gets uncontrolled, which breaches tissue organization and transforms tissues into neoplasm. The proliferative abnormality of neuroglia results in one of the most dreaded neoplasm amounting to 30% of all brain tumors—the glioma. The abnormal proliferation, high level of progression and invasive potential makes glioma one of the most lethal killers in its class. The pathological scenario becomes more moribund owing to poor prognosis and high mortality rate of the menace. Conventional onco-therapies yield dismal results compared to other soft tissue tumors. In time, with the advent of newer trends of prognosis and treatment modalities in the field of oncology, a hope for betterment is expected, but not yet achieved. These advancements would fetch some better results with proper and minute understanding of the biology of glioma, both at physiological as well as molecular level. In the present context, we have tried to document an insight to glioma biology that can serve as a primer to understand this lethal killer and its killing spree, with some approaches to combat its carnage.

The role of drebrin in glioma migration and invasion

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Terakawa, Yuzo [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka (Japan); Agnihotri, Sameer; Golbourn, Brian; Nadi, Mustafa; Sabha, Nesrin; Smith, Christian A. [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Croul, Sidney E. [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Division of Neuropathology, University Health Network, Department of Laboratory Medicine and Pathobiology (Canada); Rutka, James T., E-mail: james.rutka@sickkids.ca [The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario (Canada); Department of Surgery, University of Toronto, Toronto, Ontario (Canada)

2013-02-15

Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite current advances in therapy consisting of surgery followed by chemotherapy and radiation, the overall survival rate still remains poor. Therapeutic failures are partly attributable to the highly infiltrative nature of tumor adjacent to normal brain parenchyma. Recently, evidence is mounting to suggest that actin cytoskeleton dynamics are critical components of the cell invasion process. Drebrin is an actin-binding protein involved in the regulation of actin filament organization, and plays a significant role in cell motility; however, the role of drebrin in glioma cell invasiveness has not yet been fully elucidated. Therefore, this study was aimed to clarify the role of drebrin in glioma cell morphology and cell motility. Here we show that drebrin is expressed in glioma cell lines and in operative specimens of GBM. We demonstrate that stable overexpression of drebrin in U87 cells leads to alterations in cell morphology, and induces increased invasiveness in vitro while knockdown of drebrin in U87 cells by small interfering RNA (siRNA) decreases invasion and migration. In addition, we show that depletion of drebrin by siRNA alters glioma cell morphology in A172 GBM cell line. Our results suggest that drebrin contributes to the maintenance of cell shape, and may play an important role in glioma cell motility. - Highlights: ► Drebrin is an actin-binding protein aberrantly expressed in several cancers. ► Role of drebrin in glioma cell morphology and motility is previously unknown. ► We demonstrate that drebrin is expressed in 40% of glioblastoma specimens. ► Drebrin plays a significant role in modulating glioma cell migration and invasion.

The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas.

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Ma, Huihui; Wang, Zhen; Hu, Lei; Zhang, Shangrong; Zhao, Chenggang; Yang, Haoran; Wang, Hongzhi; Fang, Zhiyou; Wu, Lijun; Chen, Xueran

2018-02-19

More than 40% of glioma patients have tumors that harbor PTEN (phosphatase and tensin homologue deleted on chromosome ten) mutations; this disease is associated with poor therapeutic resistance and outcome. Such mutations are linked to increased cell survival and growth, decreased apoptosis, and drug resistance; thus, new therapeutic strategies focusing on inhibiting glioma tumorigenesis and progression are urgently needed. Melatonin, an indolamine produced and secreted predominantly by the pineal gland, mediates a variety of physiological functions and possesses antioxidant and antitumor properties. Here, we analyzed the relationship between PTEN and the inhibitory effect of melatonin in primary human glioma cells and cultured glioma cell lines. The results showed that melatonin can inhibit glioma cell growth both in culture and in vivo. This inhibition was associated with PTEN levels, which significantly correlated with the expression level of MT1 in patients. In fact, c-fos-mediated MT1 was shown to be a key modulator of the effect of melatonin on gliomas that harbor wild type PTEN. Taken together, these data suggest that melatonin-MT1 receptor complexes represent a potential target for the treatment of glioma. Copyright © 2018 Elsevier Inc. All rights reserved.

MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

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Lee, Hae Kyung; Bier, Ariel; Cazacu, Simona; Finniss, Susan; Xiang, Cunli; Twito, Hodaya; Poisson, Laila M; Mikkelsen, Tom; Slavin, Shimon; Jacoby, Elad; Yalon, Michal; Toren, Amos; Rempel, Sandra A; Brodie, Chaya

2013-01-01

Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

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Hae Kyung Lee

Full Text Available Glioblastomas (GBM, the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

A phase I dose escalation study of hypofractionated stereotactic radiotherapy as salvage therapy for persistent or recurrent malignant glioma

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Hudes, Richard S.; Corn, Benjamin W.; Werner-Wasik, Maria; Andrews, David; Rosenstock, Jeffrey; Thoron, Louisa; Downes, Beverly; Curran, Walter J.

1999-01-01

Purpose: A phase I dose escalation of hypofractionated stereotactic radiotherapy (H-SRT) in recurrent or persistent malignant gliomas as a means of increasing the biologically effective dose and decreasing the high rate of reoperation due to toxicity associated with single-fraction stereotactic radiosurgery (SRS) and brachytherapy. Materials and Methods: From November 1994 to September 1996, 25 lesions in 20 patients with clinical and/or imaging evidence of malignant glioma persistence or recurrence received salvage H-SRT. Nineteen patients at the time of initial diagnosis had glioblastoma multiforme (GBM) and one patient had an anaplastic astrocytoma. All of these patients with tumor persistence or recurrence had received initial fractionated radiation therapy (RT) with a mean and median dose of 60 Gy (44.0-72.0 Gy). The median time from completion of initial RT to H-SRT was 3.1 months (0.7-45.5 months). Salvage H-SRT was delivered using daily 3.0-3.5 Gy fractions (fxs). Three different total dose levels were sequentially evaluated: 24.0 Gy/3.0 Gy fxs (five lesions), 30.0 Gy/3.0 Gy fxs (10 lesions), and 35.0 Gy/3.5 Gy fxs (nine lesions). Median treated tumor volume measured 12.66 cc (0.89-47.5 cc). The median ratio of prescription volume to tumor volume was 2.8 (1.4-5.0). Toxicity was judged by RTOG criteria. Response was determined by clinical neurologic improvement, a decrease in steroid dose without clinical deterioration, and/or radiologic imaging. Results: No grade 3 toxicities were observed and no reoperation due to toxicity was required. At the time of analysis, 13 of 20 patients had died. The median survival time from the completion of H-SRT is 10.5 months with a 1-year survival rate of 20%. Neurological improvement was found in 45% of patients. Decreased steroid requirements occurred in 60% of patients. Minor imaging response was noted in 22% of patients. Using Fisher's exact test, response of any kind correlated strongly to total dose (p = 0.0056). None

A Novel Candidate Molecule in Pathological Grading Of Gliomas: ELABELA.

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Artas, Gokhan; Ozturk, Sait; Kuloglu, Tuncay; Dagli, Adile Ferda; Gonen, Murat; Artas, Hakan; Aydin, Suleyman; Erol, Fatih Serhat

2018-04-06

This study aimed to investigate the possible role of ELABELA (ELA) in the histopathological grading of gliomas. We retrospectively assessed pathological specimens of patients who underwent surgery for intracranial space-occupying lesions. Only primary glioma specimens were included in this study. We enrolled 11 patients histologically diagnosed with low-grade glioma and 22 patients with high-grade glioma. The ELA antibody was applied to 4-6-µm-thick sections obtained from paraffin blocks. Histoscores were calculated using the distribution and intensity of staining immunoreactivity. An independent sample t-test was used for two-point inter-group assessments, whereas one-way analysis of variance was used for the other assessments. P 0.05 was considered statistically significant. The histoscores of the control brain, low-grade glioma, and high-grade glioma tissues were found to be 0.08, 0.37, and 0.92, respectively. The difference in ELA immunoreactivity between the control brain tissue and glioma tissue was statistically significant (p 0.05). In addition, a statistically significant increase was observed in ELA immunoreactivity in high-grade glioma tissues compared with that in low-grade glioma tissues (p 0.05). ELA has an angiogenetic role in the progression of glial tumors. ELA, which is an endogenous ligand of the apelin receptor, activates the apelinergic system and causes the progression of glial tumors. Further studies with a large number of patients are necessary to investigate the angiogenetic role of ELA in glial tumors.

Eckol suppresses maintenance of stemness and malignancies in glioma stem-like cells

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Hyun, Kyung-Hwan; Yoon, Chang-Hwan; Kim, Rae-Kwon; Lim, Eun-Jung; An, Sungkwan; Park, Myung-Jin; Hyun, Jin-Won; Suh, Yongjoon; Kim, Min-Jung; Lee, Su-Jae

2011-01-01

A subpopulation of cancer cells with stem cell properties is responsible for tumor maintenance and progression, and may contribute to resistance to anticancer treatments. Thus, compounds that target cancer stem-like cells could be usefully applied to destroy cancer. In this study, we investigated the effect of Eckol, a phlorotannin compound, on stemness and malignancies in glioma stem-like cells. To determine whether Eckol targets glioma stem-like cells, we examined whether Eckol treatment could change the expression levels of glioma stem-like cell markers and self-renewal-related proteins as well as the sphere forming ability, and the sensitivity to anticancer treatments. Alterations in the malignant properties of sphere-derived cells by Eckol were also investigated by soft-agar colony forming assay, by xenograft assay in nude mice, and by cell invasion assay. Treatment of sphere-forming glioma cells with Eckol effectively decreased the sphere formation as well as the CD133 + cell population. Eckol treatment suppressed expression of the glioma stem-like cell markers and the self-renewal-related proteins without cell death. Moreover, treatment of glioma stem-like cells with Eckol significantly attenuated anchorage-independent growth on soft agar and tumor formation in xenograft mice. Importantly, Eckol treatment effectively reduced the resistance of glioma stem-like cells to ionizing radiation and temozolomide. Treatment of glioma stem-like cells with Eckol markedly blocked both phosphoinositide 3-kinase-Akt and Ras-Raf-1-Erk signaling pathways. These results indicate that the natural phlorotannin Eckol suppresses stemness and malignancies in glioma stem-like cells, and thereby makes glioma stem-like cells more sensitive to anticancer treatments, providing novel therapeutic strategies targeting specifically cancer stem-like cells.

MEG network differences between low- and high-grade glioma related to epilepsy and cognition.

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Edwin van Dellen

Full Text Available OBJECTIVE: To reveal possible differences in whole brain topology of epileptic glioma patients, being low-grade glioma (LGG and high-grade glioma (HGG patients. We studied functional networks in these patients and compared them to those in epilepsy patients with non-glial lesions (NGL and healthy controls. Finally, we related network characteristics to seizure frequency and cognitive performance within patient groups. METHODS: We constructed functional networks from pre-surgical resting-state magnetoencephalography (MEG recordings of 13 LGG patients, 12 HGG patients, 10 NGL patients, and 36 healthy controls. Normalized clustering coefficient and average shortest path length as well as modular structure and network synchronizability were computed for each group. Cognitive performance was assessed in a subset of 11 LGG and 10 HGG patients. RESULTS: LGG patients showed decreased network synchronizability and decreased global integration compared to healthy controls in the theta frequency range (4-8 Hz, similar to NGL patients. HGG patients' networks did not significantly differ from those in controls. Network characteristics correlated with clinical presentation regarding seizure frequency in LGG patients, and with poorer cognitive performance in both LGG and HGG glioma patients. CONCLUSION: Lesion histology partly determines differences in functional networks in glioma patients suffering from epilepsy. We suggest that differences between LGG and HGG patients' networks are explained by differences in plasticity, guided by the particular lesional growth pattern. Interestingly, decreased synchronizability and decreased global integration in the theta band seem to make LGG and NGL patients more prone to the occurrence of seizures and cognitive decline.

A choline derivate-modified nanoprobe for glioma diagnosis using MRI

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Li, Jianfeng; Huang, Shixian; Shao, Kun; Liu, Yang; An, Sai; Kuang, Yuyang; Guo, Yubo; Ma, Haojun; Wang, Xuxia; Jiang, Chen

2013-04-01

Gadolinium (Gd) chelate contrast-enhanced magnetic resonance imaging (MRI) is a preferred method of glioma detection and preoperative localisation because it offers high spatial resolution and non-invasive deep tissue penetration. Gd-based contrast agents, such as Gd-diethyltriaminepentaacetic acid (DTPA-Gd, Magnevist), are widely used clinically for tumor diagnosis. However, the Gd-based MRI approach is limited for patients with glioma who have an uncompromised blood-brain barrier (BBB). Moreover, the rapid renal clearance and non-specificity of such contrast agents further hinders their prevalence. We present a choline derivate (CD)-modified nanoprobe with BBB permeability, glioma specificity and a long blood half-life. Specific accumulation of the nanoprobe in gliomas and subsequent MRI contrast enhancement are demonstrated in vitro in U87 MG cells and in vivo in a xenograft nude model. BBB and glioma dual targeting by this nanoprobe may facilitate precise detection of gliomas with an uncompromised BBB and may offer better preoperative and intraoperative tumor localization.

Regrowth patterns of supratentorial gliomas: estimation from computed tomographic scans

International Nuclear Information System (INIS)

Tsuboi, K.; Yoshii, Y.; Nakagawa, K.; Maki, Y.

1986-01-01

To clarify the regrowth patterns of benign and malignant gliomas, we chose 27 intervals (between two operations or between an operation and autopsy) from 21 patients with pathologically verified recurrent supratentorial gliomas. Serial computed tomographic (CT) scans of these cases were analyzed to determine the doubling time (Td) calculated from the change in volume of enhanced and low density areas, the enhancement effect graded from 0 to 4 according to the Hounsfield number, and the presence of dissemination and contralateral extension. We studied 5 benign gliomas (including 1 case of radiation necrosis), 8 malignant astrocytomas, and 8 glioblastomas. The Td's of enhanced areas on CT scans of benign gliomas, malignant astrocytomas, and glioblastomas were 937 +/- 66.5 days, 65.1 +/- 29.4 days, and 48.1 +/- 20.9 days, respectively. The Td's of low density areas were 895 +/- 130.6 days, 70.8 +/- 22.2 days, and 50.5 +/- 14.7 days. There was a significant correlation between the Td's of the enhanced and low density areas (0.97). The enhancement effect increased at recurrence in 55% of the cases, with an average increase of 1.1 grades. The increase in enhancement effect at recurrence showed a tendency to become smaller as the tumor's degree of anaplasia increased. Radiotherapy was effective in significantly retarding the growth rate of malignant gliomas, whose Td's were doubled. Although the Td's of both enhanced and low density areas of benign gliomas were significantly longer than those of malignant gliomas, there was no significant difference in the Td's of enhanced areas between malignant astrocytomas and glioblastomas

Therapeutic Strategy for Targeting Aggressive Malignant Gliomas by Disrupting Their Energy Balance.

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Hegazy, Ahmed M; Yamada, Daisuke; Kobayashi, Masahiko; Kohno, Susumu; Ueno, Masaya; Ali, Mohamed A E; Ohta, Kumiko; Tadokoro, Yuko; Ino, Yasushi; Todo, Tomoki; Soga, Tomoyoshi; Takahashi, Chiaki; Hirao, Atsushi

2016-10-07

Although abnormal metabolic regulation is a critical determinant of cancer cell behavior, it is still unclear how an altered balance between ATP production and consumption contributes to malignancy. Here we show that disruption of this energy balance efficiently suppresses aggressive malignant gliomas driven by mammalian target of rapamycin complex 1 (mTORC1) hyperactivation. In a mouse glioma model, mTORC1 hyperactivation induced by conditional Tsc1 deletion increased numbers of glioma-initiating cells (GICs) in vitro and in vivo Metabolic analysis revealed that mTORC1 hyperactivation enhanced mitochondrial biogenesis, as evidenced by elevations in oxygen consumption rate and ATP production. Inhibition of mitochondrial ATP synthetase was more effective in repressing sphere formation by Tsc1-deficient glioma cells than that by Tsc1-competent glioma cells, indicating a crucial function for mitochondrial bioenergetic capacity in GIC expansion. To translate this observation into the development of novel therapeutics targeting malignant gliomas, we screened drug libraries for small molecule compounds showing greater efficacy in inhibiting the proliferation/survival of Tsc1-deficient cells compared with controls. We identified several compounds able to preferentially inhibit mitochondrial activity, dramatically reducing ATP levels and blocking glioma sphere formation. In human patient-derived glioma cells, nigericin, which reportedly suppresses cancer stem cell properties, induced AMPK phosphorylation that was associated with mTORC1 inactivation and induction of autophagy and led to a marked decrease in sphere formation with loss of GIC marker expression. Furthermore, malignant characteristics of human glioma cells were markedly suppressed by nigericin treatment in vivo Thus, targeting mTORC1-driven processes, particularly those involved in maintaining a cancer cell's energy balance, may be an effective therapeutic strategy for glioma patients. © 2016 by The American

RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.

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Bao, Zhao-Shi; Chen, Hui-Min; Yang, Ming-Yu; Zhang, Chuan-Bao; Yu, Kai; Ye, Wan-Lu; Hu, Bo-Qiang; Yan, Wei; Zhang, Wei; Akers, Johnny; Ramakrishnan, Valya; Li, Jie; Carter, Bob; Liu, Yan-Wei; Hu, Hui-Min; Wang, Zheng; Li, Ming-Yang; Yao, Kun; Qiu, Xiao-Guang; Kang, Chun-Sheng; You, Yong-Ping; Fan, Xiao-Long; Song, Wei Sonya; Li, Rui-Qiang; Su, Xiao-Dong; Chen, Clark C; Jiang, Tao

2014-11-01

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs. © 2014 Bao et al.; Published by Cold Spring Harbor Laboratory Press.

PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation

KAUST Repository

Hou, Xu; Liu, Yaohua; Liu, Huailei; Chen, Xin; Liu, Min; Che, Hui; Guo, Fei; Wang, Chunlei; Zhang, Daming; Wu, Jianing; Chen, Xiaofeng; Shen, Chen; Li, Chenguang; Peng, Fei; Bi, Yunke; Yang, Zhuowen; Yang, Guang; Ai, Jing; Gao, Xin; Zhao, Shiguang

2015-01-01

Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.

PERK silence inhibits glioma cell growth under low glucose stress by blockage of p-AKT and subsequent HK2's mitochondria translocation

KAUST Repository

Hou, Xu

2015-03-12

Glioma relies on glycolysis to obtain energy and sustain its survival under low glucose microenvironment in vivo. The mechanisms on glioma cell glycolysis regulation are still unclear. Signaling mediated by Double-stranded RNA-activated protein kinase (PKR) - like ER kinase (PERK) is one of the important pathways of unfolded protein response (UPR) which is comprehensively activated in cancer cells upon the hypoxic and low glucose stress. Here we show that PERK is significantly activated in human glioma tissues. PERK silencing results in decreased glioma cell viability and ATP/lactate production upon low glucose stress, which is mediated by partially blocked AKT activation and subsequent inhibition of Hexokinase II (HK2)\\'s mitochondria translocation. More importantly, PERK silenced glioma cells show decreased tumor formation capacity. Our results reveal that PERK activation is involved in glioma glycolysis regulation and may be a potential molecular target for glioma treatment.

Aberrant rhythmic expression of cryptochrome2 regulates the radiosensitivity of rat gliomas.

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Fan, Wang; Caiyan, Li; Ling, Zhu; Jiayun, Zhao

2017-09-29

In this study, we investigated the role of the clock regulatory protein cryptochrome 2 (Cry2) in determining the radiosensitivity of C6 glioma cells in a rat model. We observed that Cry2 mRNA and protein levels showed aberrant rhythmic periodicity of 8 h in glioma tissues, compared to 24 h in normal brain tissue. Cry2 mRNA and protein levels did not respond to irradiation in normal tissues, but both were increased at the ZT4 (low Cry2) and ZT8 (high Cry2) time points in gliomas. Immunohistochemical staining of PCNA and TUNEL assays demonstrated that high Cry2 expression in glioma tissues was associated with increased cell proliferation and decreased apoptosis. Western blot analysis showed that glioma cell fate was independent of p53, but was probably dependent on p73, which was more highly expressed at ZT4 (low Cry2) than at ZT8 (high Cry2). Levels of both p53 and p73 were unaffected by irradiation in normal brain tissues. These findings suggest aberrant rhythmic expression of Cry2 influence on radiosensitivity in rat gliomas.

Regulation of Glioma Cell Migration by Seri ne-Phosphorylated P3111

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Wendy S. McDonough

2005-09-01

Full Text Available P311, an 8-kDa polypeptide, was previously shown to be highly expressed in invasive glioma cells. Here, we report the functional characteristics of P311 with regard to influencing glioma cell migration. P311 is constitutively serine-phosphorylated; decreased phosphorylation is observed in migration-activated glioma cells. The primary amino acid sequence of P311 indicates a putative serine phosphorylation site (S59 near the PEST domain. Site-directed mutagenesis of S59A retarded P311 degradation, induced glioma cell motility. In contrast, S59D mutation resulted in the rapid degradation of P311, reduced glioma cell migration. Coimmunoprecipitation coupled with matrixassisted laser desorption/ionization time-of-flight mass spectrometry analysis identified Filamin A as a binding partner of P311, immunofluorescence studies showed that both proteins colocalized at the cell periphery. Moreover, P311-induced cell migration was abrogated by inhibition of β1 integrin function using TACβ1A, a dominant-negative inhibitor of β1 integrin signaling, suggesting that P311 acts downstream of β1 signaling. Finally, overexpression of P311 or P311 S59A mutant protein activates Raci GTPase; small interfering RNA-mediated depletion of Raci suppresses P311-induced motility. Collectively, these results suggest a role for levels of P311 in regulating glioma motility, invasion through the reorganization of actin cytoskeleton at the cell periphery.

Analysis of difference of association between polymorphisms in the XRCC5, RPA3 and RTEL1 genes and glioma, astrocytoma and glioblastoma.

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Jin, Tianbo; Wang, Yuan; Li, Gang; Du, Shuli; Yang, Hua; Geng, Tingting; Hou, Peng; Gong, Yongkuan

2015-01-01

Gliomas are the most common aggressive brain tumors and have many complex pathological types. Previous reports have discovered that genetic mutations are associated with the risk of glioma. However, it is unclear whether uniform genetic mutations exist difference between glioma and its two pathological types in the Han Chinese population. We evaluated 20 SNPs of 703 glioma cases (338 astrocytoma cases, 122 glioblastoma cases) and 635 controls in a Han Chinese population using χ(2) test and genetic model analysis. In three case-control studies, we found rs9288516 in XRCC5 gene showed a decreased risk of glioma (OR, 0.85; 95% CI, 0.73-0.99; P = 0.042) and glioblastoma (OR, 0.70; 95% CI, 0.52-0.92; P = 0.001) in the allele model. We identified rs414805 in RPA3 gene showed an increased risk of glioblastoma in allele model (OR, 1.38; 95% CI, 1.00-1.89; P = 0.047) and dominant model (OR, 1.57; 95% CI, 1.05-2.35; P = 0.027), analysis respectively. Meanwhile, rs2297440 in RTEL1 gene showed an increased risk of glioma (OR, 1.30; 95% CI, 1.10-1.54; P = 0.002) and astrocytoma (OR, 1.26; 95% CI, 1.02-1.54; P = 0.029) in the allele model. In addition, we also observed a haplotype of "GCT" in the RTEL1 gene with an increased risk of astrocytoma (P = 0.005). Polymorphisms in the XRCC5, RPA3 and RTEL1 genes, combinating with previous reaserches, are associated with glioma developing. However, those genes mutations may play different roles in the glioma, astrocytoma and glioblastoma, respectively.

Oxygenation and response to irradiation of organotypic multicellular spheroids of human glioma.

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Sminia, Peter; Acker, Helmut; Eikesdal, Hans Petter; Kaaijk, Patricia; Enger, Per øvind; Slotman, Ben; Bjerkvig, Rolf

2003-01-01

Investigation of the oxygenation status of organotypic multicellular spheroids (OMS) and their response to irradiation. Tumour specimens of glioblastoma multiforme patients (n = 16) were initiated as OMS. Following 20 Gy gamma-irradiation, the cell migratory capacity was evaluated. Spheroid oxygenation was determined by micro-electrode pO2 measurements and pimonidazole immunostaining. Spheroids prepared from established human glioma cell lines were used as a reference. Irradiation inhibited spheroid outgrowth by 12 to 88% relative to the non-irradiated controls. A large interpatient variation was noticed. Oxygen measurements revealed a gradual decrease in pO2 level from the periphery to the core of the spheroids, but the pO2 values remained within an oxygenated range. However, in the cell line spheroids an intermediate layer of hypoxia surrounding the central core was observed. Cell line spheroids with a hypoxic cell fraction and well-oxygenated OMS both show high resistance to irradiation, indicating that hypoxia may not be the biological factor determining the radioresistance of glioma spheroids in vitro.

Resveratrol represses YKL-40 expression in human glioma U87 cells

International Nuclear Information System (INIS)

Zhang, Wei; Tamiya, Takashi; Murao, Koji; Zhang, Xiang; Matsumoto, Kensuke; Diah, Suwarni; Okada, Masaki; Miyake, Keisuke; Kawai, Nobuyuki; Fei, Zhou

2010-01-01

Glioblastoma multiforme (GBM) is the most malignant intracranial tumour that develops in both adults and children. Microarray gene analyses have confirmed that the human YKL-40 gene is one of the most over-expressed genes in these tumours but not in normal brain tissue. Clinical studies have shown that serum YKL-40 levels are positively correlated with tumour burden in addition to being an independent prognostic factor of a short relapse-free interval as well as short overall survival in patients with various cancers. Our previous study revealed that YKL-40 was closely correlated with the pathological grades of human primary astrocytomas and played a crucial role in glioma cell proliferation. Hence, YKL-40 could be an attractive target in the design of anti-cancer therapies. Cell viability and invasion assays were performed to detect the cell proliferation and invasive ability of U87 cells induced by resveratrol (3, 5, 4'-trihydroxystilbene; Res) or YKL-40 small-interfering RNAs (siRNAs). In addition, the luciferase assay, real-time RT-PCR, western blotting, and ELISA were used to measure YKL-40 promoter activity, mRNA, and protein expression, respectively. The expressions of phosphor-ERK1/2 and ERK1/2 were determined by western blotting. Res inhibited U87 cell proliferation and invasion in vitro and repressed YKL-40 in U87 cells by decreasing the activity of its promoter and reducing mRNA transcription and protein expression in vitro. YKL-40 siRNA treatment also impaired the invasiveness of U87 cells. When U87 cells were cultured with 20 μM PD98059 (an ERK1/2 inhibitor) alone, with 20 μM PD98059 and 100 μM Res, or with 100 μM Res alone for 48 h, YKL-40 protein expression decreased most significantly in the Res-treated group. PD98059 partially reversed the decrease of YKL-40 protein expression induced by Res. Furthermore, phosphor-ERK1/2 expression was reduced by Res treatment in a time-dependent manner. We demonstrated for the first time that Res

Resveratrol induces cellular senescence with attenuated mono-ubiquitination of histone H2B in glioma cells

International Nuclear Information System (INIS)

Gao, Zhen; Xu, Michael S.; Barnett, Tamara L.; Xu, C. Wilson

2011-01-01

Research highlights: → Resveratrol induces cellular senescence in glioma cell. → Resveratrol inhibits mono-ubiquitination of histone H2B at K120. → Depletion of RNF20, phenocopies the inhibitory effects of resveratrol. → Mono-ubiquitination of histone H2B at K120 is a novel target of resveratrol. → RNF20 inhibits cellular senescence in proliferating glioma cells. -- Abstract: Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenol naturally occurring in grapes and other plants, has cancer chemo-preventive effects and therapeutic potential. Although resveratrol modulates multiple pathways in tumor cells, how resveratrol or its affected pathways converge on chromatin to mediate its effects is not known. Using glioma cells as a model, we showed here that resveratrol inhibited cell proliferation and induced cellular hypertrophy by transforming spindle-shaped cells to enlarged, irregular and flatten-shaped ones. We further showed that resveratrol-induced hypertrophic cells expressed senescence-associated-β-galactosidase, suggesting that resveratrol-induced cellular senescence in glioma cells. Consistent with these observations, we demonstrated that resveratrol inhibited clonogenic efficiencies in vitro and tumor growth in a xenograft model. Furthermore, we found that acute treatment of resveratrol inhibited mono-ubiquitination of histone H2B at K120 (uH2B) in breast, prostate, pancreatic, lung, brain tumor cells as well as primary human cells. Chronic treatment with low doses of resveratrol also inhibited uH2B in the resveratrol-induced senescent glioma cells. Moreover, we showed that depletion of RNF20, a ubiquitin ligase of histone H2B, inhibited uH2B and induced cellular senescence in glioma cells in vitro, thereby recapitulated the effects of resveratrol. Taken together, our results suggest that uH2B is a novel direct or indirect chromatin target of resveratrol and RNF20 plays an important role in inhibiting cellular senescence programs that are

Resveratrol induces cellular senescence with attenuated mono-ubiquitination of histone H2B in glioma cells

Energy Technology Data Exchange (ETDEWEB)

Gao, Zhen; Xu, Michael S.; Barnett, Tamara L. [Nevada Cancer Institute, Las Vegas, NV 89135 (United States); Xu, C. Wilson, E-mail: wxu@nvcancer.org [Nevada Cancer Institute, Las Vegas, NV 89135 (United States)

2011-04-08

Research highlights: {yields} Resveratrol induces cellular senescence in glioma cell. {yields} Resveratrol inhibits mono-ubiquitination of histone H2B at K120. {yields} Depletion of RNF20, phenocopies the inhibitory effects of resveratrol. {yields} Mono-ubiquitination of histone H2B at K120 is a novel target of resveratrol. {yields} RNF20 inhibits cellular senescence in proliferating glioma cells. -- Abstract: Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenol naturally occurring in grapes and other plants, has cancer chemo-preventive effects and therapeutic potential. Although resveratrol modulates multiple pathways in tumor cells, how resveratrol or its affected pathways converge on chromatin to mediate its effects is not known. Using glioma cells as a model, we showed here that resveratrol inhibited cell proliferation and induced cellular hypertrophy by transforming spindle-shaped cells to enlarged, irregular and flatten-shaped ones. We further showed that resveratrol-induced hypertrophic cells expressed senescence-associated-{beta}-galactosidase, suggesting that resveratrol-induced cellular senescence in glioma cells. Consistent with these observations, we demonstrated that resveratrol inhibited clonogenic efficiencies in vitro and tumor growth in a xenograft model. Furthermore, we found that acute treatment of resveratrol inhibited mono-ubiquitination of histone H2B at K120 (uH2B) in breast, prostate, pancreatic, lung, brain tumor cells as well as primary human cells. Chronic treatment with low doses of resveratrol also inhibited uH2B in the resveratrol-induced senescent glioma cells. Moreover, we showed that depletion of RNF20, a ubiquitin ligase of histone H2B, inhibited uH2B and induced cellular senescence in glioma cells in vitro, thereby recapitulated the effects of resveratrol. Taken together, our results suggest that uH2B is a novel direct or indirect chromatin target of resveratrol and RNF20 plays an important role in inhibiting cellular

Nitrosoureas inhibit the stathmin-mediated migration and invasion of malignant glioma cells.

Science.gov (United States)

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L; Park, John K

2008-07-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule-destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement-related processes. Scratch wound-healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down-regulation of cellular stathmin levels and in the absence and presence of sublethal nitrosourea ([1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]; CCNU) concentrations. We show that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 micromol/L, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain, and that nitrosoureas may have therapeutic benefits in addition to their antiproliferative effects.

Nitrosoureas Inhibit the Stathmin Mediated Migration and Invasion of Malignant Glioma Cells

Science.gov (United States)

Liang, Xing-Jie; Choi, Yong; Sackett, Dan L.; Park, John K.

2008-01-01

Malignant gliomas are the most common primary intrinsic brain tumors and are highly lethal. The widespread migration and invasion of neoplastic cells from the initial site of tumor formation into the surrounding brain render these lesions refractory to definitive surgical treatment. Stathmin, a microtubule destabilizing protein that mediates cell cycle progression, can also regulate directed cell movement. Nitrosoureas, traditionally viewed as DNA alkylating agents, can also covalently modify proteins such as stathmin. We therefore sought to establish a role for stathmin in malignant glioma cell motility, migration, and invasion and determine the effects of nitrosoureas on these cell movement related processes. Scratch-wound healing recovery, Boyden chamber migration, Matrigel invasion, and organotypic slice invasion assays were performed before and after the down regulation of cellular stathmin levels and in the absence and presence of sub-lethal nitrosourea (CCNU; [1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea]) concentrations. We demonstrate that decreases in stathmin expression lead to significant decreases in malignant glioma cell motility, migration, and invasion. CCNU, at a concentration of 10 μM, causes similar significant decreases, even in the absence of any effects on cell viability. The direct inhibition of stathmin by CCNU is likely a contributing factor. These findings suggest that the inhibition of stathmin expression and function may be useful in limiting the spread of malignant gliomas within the brain and that nitrosoureas may have therapeutic benefits in addition to their anti-proliferative effects. PMID:18593927

SNAI2/Slug promotes growth and invasion in human gliomas

International Nuclear Information System (INIS)

Yang, Hong Wei; Menon, Lata G; Black, Peter M; Carroll, Rona S; Johnson, Mark D

2010-01-01

Numerous factors that contribute to malignant glioma invasion have been identified, but the upstream genes coordinating this process are poorly known. To identify genes controlling glioma invasion, we used genome-wide mRNA expression profiles of primary human glioblastomas to develop an expression-based rank ordering of 30 transcription factors that have previously been implicated in the regulation of invasion and metastasis in cancer. Using this approach, we identified the oncogenic transcriptional repressor, SNAI2/Slug, among the upper tenth percentile of invasion-related transcription factors overexpressed in glioblastomas. SNAI2 mRNA expression correlated with histologic grade and invasive phenotype in primary human glioma specimens, and was induced by EGF receptor activation in human glioblastoma cells. Overexpression of SNAI2/Slug increased glioblastoma cell proliferation and invasion in vitro and promoted angiogenesis and glioblastoma growth in vivo. Importantly, knockdown of endogenous SNAI2/Slug in glioblastoma cells decreased invasion and increased survival in a mouse intracranial human glioblastoma transplantation model. This genome-scale approach has thus identified SNAI2/Slug as a regulator of growth and invasion in human gliomas

Sirt2 suppresses glioma cell growth through targeting NF-κB–miR-21 axis

International Nuclear Information System (INIS)

Li, Ya’nan; Dai, Dongwei; Lu, Qiong; Fei, Mingyu; Li, Mengmeng; Wu, Xi

2013-01-01

Highlights: •Sirt2 expression is down-regulated in human glioma tissues and cell lines. •Sirt2 regresses glioma cell growth and colony formation via inducing apoptosis. •miR-21 is essential for the functions of Sirt2 in glioma cells. •Sirt2 deacetylates p65 to decrease miR-21 expression. -- Abstract: Sirtuins are NAD + -dependent deacetylases that regulate numerous cellular processes including aging, DNA repair, cell cycle, metabolism, and survival under stress conditions. The roles of sirtuin family members are widely studied in carcinogenesis. However, their roles in glioma remain unclear. Here we report that Sir2 was under expressed in human glioma tissues and cell lines. We found that Sirt2 overexpression decreased cell proliferation and colony formation capacity. In addition, Sirt2 overexpression induced cellular apoptosis via up-regulating cleaved caspase 3 and Bax, and down-regulating anti-apoptotic protein Bcl-2. Sirt2 knockdown obtained opposing results. We showed that Sirt2 overexpression inhibited miR-21 expression, and Sirt2 was not sufficient to reduce cell proliferation and colony formation as well as to induce apoptosis when miR-21 was knocked down in glioma cells. Mechanically, we demonstrated that Sirt2 deacetylated p65 at K310 and blocked p65 binding to the promoter region of miR-21, thus regressing the transcription of miR-21. In summary, Sirt2 is critical in human glioma via NF-κB–miR-21 pathway and Sirt2 activator may serve as candidate drug for glioma therapy

Resveratrol Represses Pokemon Expression in Human Glioma Cells.

Science.gov (United States)

Yang, Yutao; Cui, Jiajun; Xue, Feng; Overstreet, Anne-Marie; Zhan, Yiping; Shan, Dapeng; Li, Hui; Li, Hui; Wang, Yongjun; Zhang, Mengmeng; Yu, Chunjiang; Xu, Zhi-Qing David

2016-03-01

POK erythroid myeloid ontogenic factor (Pokemon), an important proto-oncoprotein, is a transcriptional repressor that regulates the expression of many genes and plays an important role in tumorigenesis. Resveratrol (RSV), a natural polyphenolic compound, has many beneficial biological effects on health. In this study, we investigated the role of Pokemon in RSV-induced biological effects and the effect of RSV on the expression of Pokemon in glioma cells. We found that overexpression of Pokemon decreased RSV-induced cell apoptosis, senescence, and anti-proliferative effects. Moreover, we showed that RSV could efficiently decrease the activity of the Pokemon promoter and the expression of Pokemon. Meanwhile, RSV also inhibited Sp1 DNA binding activity to the Pokemon promoter; whereas, it did not influence the expression and nuclear translocation of Sp1. In addition, we found that RSV could increase the recruitment of HDAC1, but decreased p300 to the Pokemon promoter. Taken together, all these results extended our understanding on the anti-cancer mechanism of RSV in glioma cells.

Prognostic value of choline and creatine in WHO grade II gliomas

International Nuclear Information System (INIS)

Hattingen, Elke; Zanella, Friedhelm E.; Pilatus, Ulrich; Raab, Peter; Franz, Kea; Setzer, Matthias; Gerlach, Ruediger; Lanfermann, Heiner

2008-01-01

The purpose of this study was to evaluate whether proton magnetic resonance spectroscopy ( 1 H-MRS) predicts survival time, tumor progression, and malignant transformation in patients with WHO grade II gliomas. 1 H-MRS and MR imaging (MRI) were performed before surgery in 45 patients with histologically proven WHO grade II gliomas. Metabolite concentrations of choline-containing compounds (Cho) and creatine/phosphocreatine (tCr) were normalized to contralateral brain tissue. Spectroscopic data as well as the extent of tumor resection, contrast enhancement, size and histopatholocical type of the tumor, age, sex, and first neurological symptoms of the patients were analyzed for survival, tumor progression, and malignant transformation for a follow-up period of 1 to 5 years. The normalized tCr of WHO grade II gliomas was a significant predictor for tumor progression (p=0.011) and for malignant tumor transformation (p=0.016). Further, contrast enhancement of the tumor (p=0.014) at the time of diagnosis was significant for malignant tumor transformation and extent of tumor resection for the tumor progression (p=0.007). All other parameters failed to predict any of the three endpoints. Normalized values of tCr in WHO grade II gliomas may have prognostic implications for this group of gliomas. As a rule of the thumb, low-grade gliomas with decreased tCr (relative tCr values below 1.0) may show longer progression-free times and later malignant transformation than low-grade gliomas with regular or increased tCr values. (orig.)

Regrowth patterns of supratentorial gliomas: estimation from computed tomographic scans

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Tsuboi, K.; Yoshii, Y.; Nakagawa, K.; Maki, Y.

1986-12-01

To clarify the regrowth patterns of benign and malignant gliomas, we chose 27 intervals (between two operations or between an operation and autopsy) from 21 patients with pathologically verified recurrent supratentorial gliomas. Serial computed tomographic (CT) scans of these cases were analyzed to determine the doubling time (Td) calculated from the change in volume of enhanced and low density areas, the enhancement effect graded from 0 to 4 according to the Hounsfield number, and the presence of dissemination and contralateral extension. We studied 5 benign gliomas (including 1 case of radiation necrosis), 8 malignant astrocytomas, and 8 glioblastomas. The Td's of enhanced areas on CT scans of benign gliomas, malignant astrocytomas, and glioblastomas were 937 +/- 66.5 days, 65.1 +/- 29.4 days, and 48.1 +/- 20.9 days, respectively. The Td's of low density areas were 895 +/- 130.6 days, 70.8 +/- 22.2 days, and 50.5 +/- 14.7 days. There was a significant correlation between the Td's of the enhanced and low density areas (0.97). The enhancement effect increased at recurrence in 55% of the cases, with an average increase of 1.1 grades. The increase in enhancement effect at recurrence showed a tendency to become smaller as the tumor's degree of anaplasia increased. Radiotherapy was effective in significantly retarding the growth rate of malignant gliomas, whose Td's were doubled. Although the Td's of both enhanced and low density areas of benign gliomas were significantly longer than those of malignant gliomas, there was no significant difference in the Td's of enhanced areas between malignant astrocytomas and glioblastomas.

Glioma cells on the run – the migratory transcriptome of 10 human glioma cell lines

Directory of Open Access Journals (Sweden)

Holz David

2008-01-01

Full Text Available Abstract Background Glioblastoma multiforme (GBM is the most common primary intracranial tumor and despite recent advances in treatment regimens, prognosis for affected patients remains poor. Active cell migration and invasion of GBM cells ultimately lead to ubiquitous tumor recurrence and patient death. To further understand the genetic mechanisms underlying the ability of glioma cells to migrate, we compared the matched transcriptional profiles of migratory and stationary populations of human glioma cells. Using a monolayer radial migration assay, motile and stationary cell populations from seven human long term glioma cell lines and three primary GBM cultures were isolated and prepared for expression analysis. Results Gene expression signatures of stationary and migratory populations across all cell lines were identified using a pattern recognition approach that integrates a priori knowledge with expression data. Principal component analysis (PCA revealed two discriminating patterns between migrating and stationary glioma cells: i global down-regulation and ii global up-regulation profiles that were used in a proband-based rule function implemented in GABRIEL to find subsets of genes having similar expression patterns. Genes with up-regulation pattern in migrating glioma cells were found to be overexpressed in 75% of human GBM biopsy specimens compared to normal brain. A 22 gene signature capable of classifying glioma cultures based on their migration rate was developed. Fidelity of this discovery algorithm was assessed by validation of the invasion candidate gene, connective tissue growth factor (CTGF. siRNA mediated knockdown yielded reduced in vitro migration and ex vivo invasion; immunohistochemistry on glioma invasion tissue microarray confirmed up-regulation of CTGF in invasive glioma cells. Conclusion Gene expression profiling of migratory glioma cells induced to disperse in vitro affords discovery of genomic signatures; selected

The use of TMZ embedded hydrogels for the treatment of orthotopic human glioma xenografts.

Science.gov (United States)

Adhikari, Bandita; Li, Jie; Brandel, Michael G; Futalan, Diahnn; Akers, Johnny; Deming, Timothy; Chen, Clark C; Carter, Bob S

2017-11-01

The current treatment of glioblastoma multiforme (GBM) is limited by the restricted arsenal of agents which effectively cross the blood brain barrier (BBB). For example, only a fraction of temozolomide (TMZ) administered systemically is available for therapeutic effect because of the BBB and the instability of TMZ under physiologic conditions. A novel approach to overcome this obstacle is to bypass the BBB and locally deliver chemotherapeutic agents directly to the tumor mass. We have explored the loading of TMZ into a novel hydrogel matrix, which can be delivered in liquid form and then solidifies in situ and releases chemotherapy as the matrix dissolves. Here, we tested the effect of amphiphilic diblock copolypeptide hydrogels (DCHs) of 180-poly-lysine and 20-poly-leucine (K 180 L 20 ) on TMZ using Glioblastoma models. In both the in vitro model, which involved treatment of a human glioblastoma GSC line suspended as neurospheres, and in vivo using an orthotopic glioma xenograft mouse model, we found that K 180 L 20 could safely enhance the efficacy of TMZ. This technique may offer the opportunity to 'coat' the inner lining of the cavity following glioma resection with a slow-release TMZ and potentially decrease recurrence. Future studies in larger animals are needed to delineate this effect. Copyright © 2017. Published by Elsevier Ltd.

Economics of Malignant Gliomas: A Critical Review.

Science.gov (United States)

Raizer, Jeffrey J; Fitzner, Karen A; Jacobs, Daniel I; Bennett, Charles L; Liebling, Dustin B; Luu, Thanh Ha; Trifilio, Steven M; Grimm, Sean A; Fisher, Matthew J; Haleem, Meraaj S; Ray, Paul S; McKoy, Judith M; DeBoer, Rebecca; Tulas, Katrina-Marie E; Deeb, Mohammed; McKoy, June M

2015-01-01

Approximately 18,500 persons are diagnosed with malignant glioma in the United States annually. Few studies have investigated the comprehensive economic costs. We reviewed the literature to examine costs to patients with malignant glioma and their families, payers, and society. A total of 18 fully extracted studies were included. Data were collected on direct and indirect costs, and cost estimates were converted to US dollars using the conversion rate calculated from the study's publication date, and updated to 2011 values after adjustment for inflation. A standardized data abstraction form was used. Data were extracted by one reviewer and checked by another. Before approval of effective chemotherapeutic agents for malignant gliomas, estimated total direct medical costs in the United States for surgery and radiation therapy per patient ranged from $50,600 to $92,700. The addition of temozolomide (TMZ) and bevacizumab to glioblastoma treatment regimens has resulted in increased overall costs for glioma care. Although health care costs are now less front-loaded, they have increased over the course of illness. Analysis using a willingness-to-pay threshold of $50,000 per quality-adjusted life-year suggests that the benefits of TMZ fall on the edge of acceptable therapies. Furthermore, indirect medical costs, such as productivity losses, are not trivial. With increased chemotherapy use for malignant glioma, the paradigm for treatment and associated out-of-pocket and total medical costs continue to evolve. Larger out-of-pocket costs may influence the choice of chemotherapeutic agents, the economic implications of which should be evaluated prospectively. Copyright © 2015 by American Society of Clinical Oncology.

3-Bromopyruvate antagonizes effects of lactate and pyruvate, synergizes with citrate and exerts novel anti-glioma effects.

Science.gov (United States)

El Sayed, S M; El-Magd, R M Abou; Shishido, Y; Chung, S P; Diem, T H; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

2012-02-01

Oxidative stress-energy depletion therapy using oxidative stress induced by D-amino acid oxidase (DAO) and energy depletion induced by 3-bromopyruvate (3BP) was reported recently (El Sayed et al., Cancer Gene Ther., 19, 1-18, 2012). Even in the presence of oxygen, cancer cells oxidize glucose preferentially to produce lactate (Warburg effect) which seems vital for cancer microenvironment and progression. 3BP is a closely related structure to lactate and pyruvate and may antagonize their effects as a novel mechanism of its action. Pyruvate exerted a potent H(2)O(2) scavenging effect to exogenous H(2)O(2), while lactate had no scavenging effect. 3BP induced H(2)O(2) production. Pyruvate protected against H(2)O(2)-induced C6 glioma cell death, 3BP-induced C6 glioma cell death but not against DAO/D-serine-induced cell death, while lactate had no protecting effect. Lactate and pyruvate protected against 3BP-induced C6 glioma cell death and energy depletion which were overcome with higher doses of 3BP. Lactate and pyruvate enhanced migratory power of C6 glioma which was blocked by 3BP. Pyruvate and lactate did not protect against C6 glioma cell death induced by other glycolytic inhibitors e.g. citrate (inhibitor of phosphofructokinase) and sodium fluoride (inhibitor of enolase). Serial doses of 3BP were synergistic with citrate in decreasing viability of C6 glioma cells and spheroids. Glycolysis subjected to double inhibition using 3BP with citrate depleted ATP, clonogenic power and migratory power of C6 glioma cells. 3BP induced a caspase-dependent cell death in C6 glioma. 3BP was powerful in decreasing viability of human glioblastoma multiforme cells (U373MG) and C6 glioma in a dose- and time-dependent manner.

Frequent Nek1 overexpression in human gliomas

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Zhu, Jun [School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai (China); Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Cai, Yu, E-mail: aihaozuqiu22@163.com [School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai (China); Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China); Liu, Pin [Med-X Research Institute, Shanghai Jiao Tong University, Shanghai (China); Zhao, Weiguo [Neurosurgery Department, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai (China)

2016-08-05

Never in mitosis A (NIMA)-related kinase 1 (Nek1) regulates cell cycle progression to mitosis. Its expression and potential functions in human gliomas have not been studied. Here, our immunohistochemistry (IHC) assay and Western blot assay results showed that Nek1 expression was significantly upregulated in fresh and paraffin-embedded human glioma tissues. Its level in normal brain tissues was low. Nek1 overexpression in human gliomas was correlated with the proliferation marker (Ki-67), tumor grade, Karnofsky performance scale (KPS) and more importantly, patients’ poor survival. Further studies showed that Nek1 expression level was also increased in multiple human glioma cell lines (U251-MG, U87-MG, U118, H4 and U373). Significantly, siRNA-mediated knockdown of Nek1 inhibited glioma cell (U87-MG/U251-MG) growth. Nek1 siRNA also sensitized U87-MG/U251-MG cells to temozolomide (TMZ), causing a profound apoptosis induction and growth inhibition. The current study indicates Nek1 might be a novel and valuable oncotarget of glioma, it is important for glioma cell growth and TMZ-resistance. - Highlights: • Nek1 is upregulated in multiple human glioma tissues and cell lines. • Nek1 overexpression correlates with glioma grades and patients’ KPS score. • Nek1 overexpression correlates with patients’ poor overall survival. • siRNA knockdown of Nek1 inhibits glioma cell growth. • siRNA knockdown of Nek1 sensitizes human glioma cells to temozolomide.

Frequent Nek1 overexpression in human gliomas

International Nuclear Information System (INIS)

Zhu, Jun; Cai, Yu; Liu, Pin; Zhao, Weiguo

2016-01-01

Never in mitosis A (NIMA)-related kinase 1 (Nek1) regulates cell cycle progression to mitosis. Its expression and potential functions in human gliomas have not been studied. Here, our immunohistochemistry (IHC) assay and Western blot assay results showed that Nek1 expression was significantly upregulated in fresh and paraffin-embedded human glioma tissues. Its level in normal brain tissues was low. Nek1 overexpression in human gliomas was correlated with the proliferation marker (Ki-67), tumor grade, Karnofsky performance scale (KPS) and more importantly, patients’ poor survival. Further studies showed that Nek1 expression level was also increased in multiple human glioma cell lines (U251-MG, U87-MG, U118, H4 and U373). Significantly, siRNA-mediated knockdown of Nek1 inhibited glioma cell (U87-MG/U251-MG) growth. Nek1 siRNA also sensitized U87-MG/U251-MG cells to temozolomide (TMZ), causing a profound apoptosis induction and growth inhibition. The current study indicates Nek1 might be a novel and valuable oncotarget of glioma, it is important for glioma cell growth and TMZ-resistance. - Highlights: • Nek1 is upregulated in multiple human glioma tissues and cell lines. • Nek1 overexpression correlates with glioma grades and patients’ KPS score. • Nek1 overexpression correlates with patients’ poor overall survival. • siRNA knockdown of Nek1 inhibits glioma cell growth. • siRNA knockdown of Nek1 sensitizes human glioma cells to temozolomide.

The RTEL1 rs6010620 polymorphism and glioma risk: a meta-analysis based on 12 case-control studies.

Science.gov (United States)

Du, Shu-Li; Geng, Ting-Ting; Feng, Tian; Chen, Cui-Ping; Jin, Tian-Bo; Chen, Chao

2014-01-01

The association between the RTEL1 rs6010620 single nucleotide polymorphism (SNP) and glioma risk has been extensively studied. However, the results remain inconclusive. To further examine this association, we performed a meta-analysis. A computerized search of the PubMed and Embase databases for publications regarding the RTEL1 rs6010620 polymorphism and glioma cancer risk was performed. Genotype data were analyzed in a meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Sensitivity analyses, tests of heterogeneity, cumulative meta-analyses, and assessments of bias were performed in our meta-analysis. Our meta-analysis confirmed that risk with allele A is lower than with allele G for glioma. The A allele of rs6010620 in RTEL1 decreased the risk of developing glioma in the 12 case-control studies for all genetic models: the allele model (OR=0.752, 95%CI: 0.715-0.792), the dominant model (OR=0.729, 95%CI: 0.685-0.776), the recessive model (OR=0.647, 95%CI: 0.569-0.734), the homozygote comparison (OR=0.528, 95%CI: 0.456-0.612), and the heterozygote comparison (OR=0.761, 95%CI: 0.713-0.812). In all genetic models, the association between the RTEL1 rs6010620 polymorphism and glioma risk was significant. This meta-analysis suggests that the RTEL1 rs6010620 polymorphism may be a risk factor for glioma. Further functional studies evaluating this polymorphism and glioma risk are warranted.

Forkhead box K2 inhibits the proliferation, migration, and invasion of human glioma cells and predicts a favorable prognosis.

Science.gov (United States)

Wang, Bo; Zhang, XueBin; Wang, Wei; Zhu, ZhiZhong; Tang, Fan; Wang, Dong; Liu, Xi; Zhuang, Hao; Yan, XiaoLing

2018-01-01

Forkhead box K2 (FOXK2) is a member of the forkhead box family of transcription factors. Recently, researchers discovered that overexpression of FOXK2 inhibits the proliferation and metastasis of breast cancer, non-small cell lung cancer, and colorectal cancer, and is related to the clinical prognosis. However, in hepatocellular carcinoma, FOXK2 results in the opposite phenotypes. Currently, the contribution of FOXK2 to glioma pathogenesis is not clear. We evaluated the expression of FOXK2 in 151 glioma patients using immunohistochemistry assays. The associations among the expression of FOXK2, clinicopathological parameters, and the prognosis of glioma patients were statistically analyzed. We downregulated and upregulated the level of FOXK2 in glioma cells by transfections with small interfering RNA and plasmids. Then, we investigated the effects on tumor cell behavior in vitro by Cell Counting Kit-8 assays, colony-formation assay, transwell assay, and the epithelial-to-mesenchymal transition (EMT) biomarker levels. The clinical data showed that expression of FOXK2 gradually decreased with increasing World Health Organization (WHO) grades and a low level of FOXK2 indicates a poor prognosis. FOXK2 expression is negatively correlated with Ki67 expression and the WHO degree but is not correlated with other clinicopathological parameters, including sex, age, Karnofsky Performance Status, tumor diameter, O -6-methylguanine-DNA methyltransferase, and glutathione S -transferase pi. FOXK2 knockdown enhances glioma cell proliferation, migration, invasion, and EMT process, and, in contrast, FOXK2 overexpression inhibits glioma cell proliferation, migration, invasion, and the EMT process. Expression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process.

The Glioma International Case-Control Study

DEFF Research Database (Denmark)

Amirian, E. Susan; Armstrong, Georgina N; Zhou, Renke

2016-01-01

Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly...... describe the Glioma International Case-Control (GICC) Study (recruitment, 2010-2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen...

Small gliomas; Metabolism and blood flow

Energy Technology Data Exchange (ETDEWEB)

Tamura, Masaru; Shibasaki, Takashi; Horikoshi, Satoru; Ono, Nobuo; Zama, Akira; Kakegawa, Tohru; Ishiuchi, Shogo [Gunma Univ., Maebashi (Japan). School of Medicine

1994-02-01

Eight patients with small gliomas (6 low-grade and 2 high-grade) localized in a single gyrus or less than 2 cm diameter were investigated using positron tomography and single photon emission computed tomography. All three tumors examined demonstrated hypermetabolism of amino acids. High-grade gliomas demonstrated hypermetabolism of glucose and high blood flow, but normal or low oxygen metabolism. High-grade gliomas also showed accumulation of [sup 201]Tl chloride and high or low accumulation of [sup 123]I-isopropyl iodoamphetamine. These indications allow preoperative diagnosis of the malignancy of small gliomas, which is important because small gliomas with high-grade malignancy need more extensive removal and adjuvant therapy. (author).

CD44 Interacts with HIF-2α to Modulate the Hypoxic Phenotype of Perinecrotic and Perivascular Glioma Cells

DEFF Research Database (Denmark)

Johansson, Elinn; Grassi, Elisa S.; Pantazopoulou, Vasiliki

2017-01-01

Hypoxia-inducible factors enhance glioma stemness, and glioma stem cells have an amplified hypoxic response despite residing within a perivascular niche. Still, little is known about differential HIF regulation in stem versus bulk glioma cells. We show that the intracellular domain of stem cell...... marker CD44 (CD44ICD) is released at hypoxia, binds HIF-2α (but not HIF-1α), enhances HIF target gene activation, and is required for hypoxia-induced stemness in glioma. In a glioma mouse model, CD44 was restricted to hypoxic and perivascular tumor regions, and in human glioma, a hypoxia signature...... correlated with CD44. The CD44ICD was sufficient to induce hypoxic signaling at perivascular oxygen tensions, and blocking CD44 cleavage decreased HIF-2α stabilization in CD44-expressing cells. Our data indicate that the stem cell marker CD44 modulates the hypoxic response of glioma cells and that the pseudo-hypoxic...

12 years' experience with intraoperative radiotherapy (IORT) of malignant gliomas

International Nuclear Information System (INIS)

Schueller, P.; Micke, O.; Moustakis, C.; Bruns, F.; Schuck, A.; Willich, N.; Palkovic, S.; Schroeder, J.; Wassmann, H.

2005-01-01

Background: Even after surgery and radiotherapy, malignant gliomas still have a poor prognosis. The authors report on their experience with IORT in 71 patients. Patients and methods: From May 1992 to February 2004, 71 patients with malignant gliomas were treated with IORT. 26 patients suffered from grade III gliomas, 45 patients from glioblastomas (GBM). IORT was carried out using a standard electron tube and 9- to 18-MeV electrons. 52/71 patients who were primarily treated received 20 Gy IORT + 60 Gy postoperative radiotherapy, 19/71 patients with recurrences only received IORT (20-25 Gy). Results: The complication rates were 1.4% for wound infections and 5.6% for hemorrhage. Median disease-specific survival amounted to 14.9 months (gliomass III) and 14.2 months (GBM). The 2-year survival rates amounted to 26.9% (gliomas III) and 6.8% (GBM; p=0.0296). Total versus subtotal resection had no significant influence on survival (p=0.0741), nor had age, sex, tumor site, performance status, size, primary versus recurrence, and radiation dose. A comparison to a conventionally treated patient group did not show a significant survival improvement. 3 months after treatment, initial symptoms had improved in 59% (hemiparesis), 50% (aphasia), 50% (hemianopsia), and 60% (convulsions). Conclusion: IORT has been shown to be feasible; perioperative complication rates were not increased. Survival was generally not improved compared to a historical control group. Recurrences achieved the same survival as primary tumors, and GBM also had a slightly increased survival, thus being possible indications for IORT. (orig.)

Molecular markers in glioma.

Science.gov (United States)

Ludwig, Kirsten; Kornblum, Harley I

2017-09-01

Gliomas are the most malignant and aggressive form of brain tumors, and account for the majority of brain cancer related deaths. Malignant gliomas, including glioblastoma are treated with radiation and temozolomide, with only a minor benefit in survival time. A number of advances have been made in understanding glioma biology, including the discovery of cancer stem cells, termed glioma stem cells (GSC). Some of these advances include the delineation of molecular heterogeneity both between tumors from different patients as well as within tumors from the same patient. Such research highlights the importance of identifying and validating molecular markers in glioma. This review, intended as a practical resource for both clinical and basic investigators, summarizes some of the more well-known molecular markers (MGMT, 1p/19q, IDH, EGFR, p53, PI3K, Rb, and RAF), discusses how they are identified, and what, if any, clinical relevance they may have, in addition to discussing some of the specific biology for these markers. Additionally, we discuss identification methods for studying putative GSC's (CD133, CD15, A2B5, nestin, ALDH1, proteasome activity, ABC transporters, and label-retention). While much research has been done on these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature. Furthermore, it is unlikely that the investigator will be able to utilize one single marker to prospectively identify and isolate GSC from all, or possibly, any gliomas.

Perspectives in Intraoperative Diagnostics of Human Gliomas

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O. Tyurikova

2015-01-01

Full Text Available Amongst large a variety of oncological diseases, malignant gliomas represent one of the most severe types of tumors. They are also the most common type of the brain tumors and account for over half of the astrocytic tumors. According to different sources, the average life expectancy of patients with various glioblastomas varies between 10 and 12 months and that of patients with anaplastic astrocytic tumors between 20 and 24 months. Therefore, studies of the physiology of transformed glial cells are critical for the development of treatment methods. Modern medical approaches offer complex procedures, including the microsurgical tumor removal, radiotherapy, and chemotherapy, supplemented with photodynamic therapy and immunotherapy. The most radical of them is surgical resection, which allows removing the largest part of the tumor, reduces the intracranial hypertension, and minimizes the degree of neurological deficit. However, complete removal of the tumor remains impossible. The main limitations are insufficient visualization of glioma boundaries, due to its infiltrative growth, and the necessity to preserve healthy tissue. This review is devoted to the description of advantages and disadvantages of modern intraoperative diagnostics of human gliomas and highlights potential perspectives for development of their treatment.

Spinal metastases of malignant gliomas

International Nuclear Information System (INIS)

Materlik, B.; Steidle-Katic, U.; Feyerabend, T.; Richter, E.; Wauschkuhn, B.

1998-01-01

Purpose: Extracranial metastases of malignant gliomas are rare. We report 2 cases with spinal metastases in patients suffering from glioma. Patients and Method: Two patients (33 and 57 years old) developed spinal canal metastases of a glioblastoma multiforme and anaplastic astrocytoma Grade III respectively 25 and 9 months after surgical resection and radiotherapy. Both metastases were confirmed pathohistologically. Results: Intraspinal metastases were irradiated with a total dose of 12.6 Gy and 50 Gy. Treatment withdrawal was necessary in one patient due to reduced clinical condition. Regression of neurological symptoms was observed in the second patient. Conclusions: Spinal spread of malignant glioma should be considered during care and follow-up in glioma patients with spinal symptoms. (orig.) [de

Cigarette smoking, alcohol intake, and risk of glioma in the NIH-AARP Diet and Health Study.

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Braganza, M Z; Rajaraman, P; Park, Y; Inskip, P D; Freedman, N D; Hollenbeck, A R; de González, A Berrington; Kitahara, C M

2014-01-07

Although cigarette smoking and alcohol drinking increase the risk of several cancers and certain components of cigarette smoke and alcohol can penetrate the blood-brain barrier, it remains unclear whether these exposures influence the risk of glioma. We examined the associations between cigarette smoking, alcohol intake, and risk of glioma in the National Institutes of Health-AARP Diet and Health Study, a prospective study of 477,095 US men and women ages 50-71 years at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using models with age as the time metric and adjusted for sex, race/ethnicity, education, and marital status. During a median 10.5 person-years of follow-up, 492 men and 212 women were diagnosed with first primary glioma. Among men, current, heavier smoking was associated with a reduced risk of glioma compared with never smoking, but this was based on only nine cases. No associations were observed between smoking behaviours and glioma risk in women. Greater alcohol consumption was associated with a decreased risk of glioma, particularly among men (>2 drinks per day vs Smoking and alcohol drinking do not appear to increase the risk of glioma.

TCGA_LowerGradeGliomas

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TCGA researchers analyzed nearly 300 cases of diffuse low- and intermediate-grade gliomas, which together comprise lower-grade gliomas. LGGs occur mainly in adults and include astrocytomas, oligodendrogliomas and oligoastrocytomas.

Overexpressed KDM5B is associated with the progression of glioma and promotes glioma cell growth via downregulating p21

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Dai, Bin [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Hu, Zhiqiang, E-mail: zhiqhutg@126.com [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Huang, Hui; Zhu, Guangtong; Xiao, Zhiyong [Department of Neurosurgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038 (China); Wan, Weiqing; Zhang, Peng; Jia, Wang; Zhang, Liwei [Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050 (China)

2014-11-07

Highlights: • KDM5B is overexpressed in glioma samples. • KDM5B stimulated proliferation of glioma cells. • Inhibition of p21contributes to KDM5B-induced proliferation. - Abstract: Epigenetic alterations such as aberrant expression of histone-modifying enzymes have been implicated in tumorigenesis. Upregulation of lysine (K)-specific demethylase 5B (KDM5B) has been reported in a variety of malignant tumors. However, the impact of KDM5B in glioma remains unclear. The objective of this study was to investigate the expression and prognostic value of KDM5B in glioma. In clinical glioma samples, we found that KDM5B expression was significantly upregulated in cancer lesions compared with normal brain tissues. Kaplan–Meier analysis showed that patients with glioma and higher KDM5B expression tend to have shorter overall survival time. By silencing or overexpressing KDM5B in glioma cells, we found that KDM5B could promote cell growth both in vitro and in vivo. Moreover, we demonstrated that KDM5B promoted glioma proliferation partly via regulation of the expression of p21. Our study provided evidence that KDM5B functions as a novel tumor oncogene in glioma and may be a potential therapeutic target for glioma management.

RTVP-1 promotes mesenchymal transformation of glioma via a STAT-3/IL-6-dependent positive feedback loop

Science.gov (United States)

Giladi, Nis David; Ziv-Av, Amotz; Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Ben-Asher, Hiba Waldman; deCarvalho, Ana; Mikkelsen, Tom; Poisson, Laila; Brodie, Chaya

2015-01-01

Glioblastomas (GBMs), the most aggressive primary brain tumors, exhibit increased invasiveness and resistance to anti-tumor treatments. We explored the role of RTVP-1, a glioma-associated protein that promotes glioma cell migration, in the mesenchymal transformation of GBM. Analysis of The Cancer Genome Atlas (TCGA) demonstrated that RTVP-1 expression was higher in mesenchymal GBM and predicted tumor recurrence and poor clinical outcome. ChiP analysis revealed that the RTVP-1 promoter binds STAT3 and C/EBPβ, two master transcription factors that regulate mesenchymal transformation of GBM. In addition, IL-6 induced RTVP-1 expression in a STAT3-dependent manner. RTVP-1 increased the migration and mesenchymal transformation of glioma cells. Similarly, overexpression of RTVP-1 in human neural stem cells induced mesenchymal differentiation, whereas silencing of RTVP-1 in glioma stem cells (GSCs) decreased the mesenchymal transformation and stemness of these cells. Silencing of RTVP-1 also increased the survival of mice bearing GSC-derived xenografts. Using gene array analysis of RTVP-1 silenced glioma cells we identified IL-6 as a mediator of RTVP-1 effects on the mesenchymal transformation and migration of GSCs, therefore acting in a positive feedback loop by upregulating RTVP-1 expression via the STAT3 pathway. Collectively, these results implicate RTVP-1 as a novel prognostic marker and therapeutic target in GBM. PMID:26267319

Joint associations between genetic variants and reproductive factors in glioma risk among women.

Science.gov (United States)

Wang, Sophia S; Hartge, Patricia; Yeager, Meredith; Carreón, Tania; Ruder, Avima M; Linet, Martha; Inskip, Peter D; Black, Amanda; Hsing, Ann W; Alavanja, Michael; Beane-Freeman, Laura; Safaiean, Mahboobeh; Chanock, Stephen J; Rajaraman, Preetha

2011-10-15

In a pooled analysis of 4 US epidemiologic studies (1993-2001), the authors evaluated the role of 5 female reproductive factors in 357 women with glioma and 822 controls. The authors further evaluated the independent association between 5 implicated gene variants and glioma risk among the study population, as well as the joint associations of female reproductive factors (ages at menarche and menopause, menopausal status, use of oral contraceptives, and menopausal hormone therapy) and these gene variants on glioma risk. Risk estimates were calculated as odds ratios and 95% confidence intervals that were adjusted for age, race, and study. Three of the gene variants (rs4295627, a variant of CCDC26; rs4977756, a variant of CDKN2A and CDKN2B; and rs6010620, a variant of RTEL1) were statistically significantly associated with glioma risk in the present population. Compared with women who had an early age at menarche (<12 years of age), those who reported menarche at 12-13 years of age or at 14 years of age or older had a 1.7-fold higher risk and a 1.9-fold higher risk of glioma, respectively (P for trend = 0.009). Postmenopausal women and women who reported ever having used oral contraceptives had a decreased risk of glioma. The authors did not observe joint associations between these reproductive characteristics and the implicated glioma gene variants. These results require replication, but if confirmed, they would suggest that the gene variants that have previously been implicated in the development of glioma are unlikely to act through the same hormonal mechanisms in women.

ER stress inducer tunicamycin suppresses the self-renewal of glioma-initiating cell partly through inhibiting Sox2 translation.

Science.gov (United States)

Xing, Yang; Ge, Yuqing; Liu, Chanjuan; Zhang, Xiaobiao; Jiang, Jianhai; Wei, Yuanyan

2016-06-14

Glioma-initiating cells possess tumor-initiating potential and are relatively resistant to conventional chemotherapy and irradiation. Therefore, their elimination is an essential factor for the development of efficient therapy. Here, we report that endoplasmic reticulum (ER) stress inducer tunicamycin inhibits glioma-initiating cell self-renewal as determined by neurosphere formation assay. Moreover, tunicamycin decreases the efficiency of glioma-initiating cell to initiate tumor formation. Although tunicamycin induces glioma-initiating cell apoptosis, apoptosis inhibitor z-VAD-fmk only partly abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Indeed, tunicamycin reduces the expression of self-renewal regulator Sox2 at translation level. Overexpression of Sox2 obviously abrogates the reduction in glioma-initiating cell self-renewal induced by tunicamycin. Taken together, tunicamycin suppresses the self-renewal and tumorigenic potential of glioma-initiating cell partly through reducing Sox2 translation. This finding provides a cue to potential effective treatment of glioblastoma through controlling stem cells.

Cognitive impairments in patients with low grade gliomas and high grade gliomas

Directory of Open Access Journals (Sweden)

Eliane C. Miotto

2011-08-01

Full Text Available OBJECTIVE: The relationship between brain tumors and cognitive deficits is well established in the literature. However, studies investigating the cognitive status in low and high-grade gliomas patients are scarce, particularly in patients with average or lower educational level. This study aimed at investigating the cognitive functioning in a sample of patients with low and high-grade gliomas before surgical intervention. METHOD: The low-grade (G1, n=19 and high-grade glioma (G2, n=8 patients underwent a detailed neuropsychological assessment of memory, executive functions, visuo-perceptive and visuo-spatial abilities, intellectual level and language. RESULTS: There was a significant impairment on verbal and visual episodic memory, executive functions including mental flexibility, nominal and categorical verbal fluency and speed of information processing in G2. G1 showed only specific deficits on verbal and visual memory recall, mental flexibility and processing speed. CONCLUSION: These findings demonstrated different levels of impairments in the executive and memory domains in patients with low and high grade gliomas.

Improving Seroreactivity-Based Detection of Glioma

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Nicole Ludwig

2009-12-01

Full Text Available Seroreactivity profiling emerges as valuable technique for minimal invasive cancer detection. Recently, we provided first evidence for the applicability of serum profiling of glioma using a limited number of immunogenic antigens. Here, we screened 57 glioma and 60 healthy sera for autoantibodies against 1827 Escherichia coli expressed clones, including 509 in-frame peptide sequences. By a linear support vector machine approach, we calculated mean specificity, sensitivity, and accuracy of 100 repetitive classifications. We were able to differentiate glioma sera from sera of the healthy controls with a specificity of 90.28%, a sensitivity of 87.31% and an accuracy of 88.84%. We were also able to differentiate World Health Organization grade IV glioma sera from healthy sera with a specificity of 98.45%, a sensitivity of 80.93%, and an accuracy of 92.88%. To rank the antigens according to their information content, we computed the area under the receiver operator characteristic curve value for each clone. Altogether, we found 46 immunogenic clones including 16 in-frame clones that were informative for the classification of glioma sera versus healthy sera. For the separation of glioblastoma versus healthy sera, we found 91 informative clones including 26 in-frame clones. The best-suited in-frame clone for the classification glioma sera versus healthy sera corresponded to the vimentin gene (VIM that was previously associated with glioma. In the future, autoantibody signatures in glioma not only may prove useful for diagnosis but also offer the prospect for a personalized immune-based therapy.

The association between birth order, sibship size and glioma development in adulthood.

Science.gov (United States)

Amirian, E; Scheurer, Michael E; Bondy, Melissa L

2010-06-01

The etiology of brain tumors is still largely unknown. Previous research indicates that infectious agents and immunological characteristics may influence adult glioma risk. The purpose of our study was to evaluate the effects of birth order and sibship size (total number of siblings), as indicators of the timing and frequency of early life infections, on adult glioma risk using a population of 489 cases and 540 cancer-free controls from the Harris County Brain Tumor Study. Odds ratios for birth order and sibship size were calculated separately from multivariable logistic regression models, adjusting for sex, family history of cancer, education, and age. Each one-unit increase in birth order confers a 13% decreased risk of glioma development in adulthood (OR = 0.87, 95% CI = 0.79-0.97). However, sibship size was not significantly associated with adult glioma status (OR = 0.97, 95% CI = 0.91-1.04). Our study indicates that individuals who were more likely to develop common childhood infections at an earlier age (those with a higher birth order) may be more protected against developing glioma in adulthood. More biological and epidemiological research is warranted to clarify the exact mechanisms through which the timing of common childhood infections and the course of early life immune development affect gliomagenesis.

Critical role of the FERM domain in Pyk2 stimulated glioma cell migration

International Nuclear Information System (INIS)

Lipinski, Christopher A.; Tran, Nhan L.; Dooley, Andrea; Pang, Yuan-Ping; Rohl, Carole; Kloss, Jean; Yang, Zhongbo; McDonough, Wendy; Craig, David; Berens, Michael E.; Loftus, Joseph C.

2006-01-01

The strong tendency of malignant glioma cells to invade locally into surrounding normal brain precludes effective surgical resection, reduces the efficacy of radiotherapy, and is associated with increased resistance to chemotherapy regimens. We report that the N-terminal FERM domain of Pyk2 regulates its promigratory function. A 3-dimensional model of the Pyk2 FERM domain was generated and mutagenesis studies identified residues essential for Pyk2 promigratory function. Model-based targeted mutations within the FERM domain decreased Pyk2 phosphorylation and reduced the capacity of Pyk2 to stimulate glioma cell migration but did not significantly alter the intracellular distribution of Pyk2. Expression of autonomous Pyk2 FERM domain fragments containing analogous mutations exhibited reduced capacity to inhibit glioma cell migration and Pyk2 phosphorylation relative to expression of an autonomous wild type FERM domain fragment. These results indicate that the FERM domain plays an important role in regulating the functional competency of Pyk2 as a promigratory factor in glioma

Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

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Ge, Yuqing; Zhou, Fengbiao; Chen, Hong; Cui, Chunhong; Liu, Dan [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Li, Qiuping [Zhongshan Hospital of Fudan University, Shanghai 200032 (China); Yang, Zhiyuan; Wu, Guoqiang [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Sun, Shuhui [Key Laboratory of Medical Molecular Virology, Ministry of Education and Health, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Gu, Jianxin [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Institutes of Biomedical Sciences of Fudan University, Shanghai 200032 (China); Wei, Yuanyan, E-mail: yywei@fudan.edu.cn [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China); Jiang, Jianhai, E-mail: jianhaijiang@fudan.edu.cn [Key Laboratory of Glycoconjuates Research, Ministry of Public Health and Gene Research Center, Shanghai Medical College of Fudan University, Shanghai 200032 (China)

2010-07-09

Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.

Sox2 is translationally activated by eukaryotic initiation factor 4E in human glioma-initiating cells

International Nuclear Information System (INIS)

Ge, Yuqing; Zhou, Fengbiao; Chen, Hong; Cui, Chunhong; Liu, Dan; Li, Qiuping; Yang, Zhiyuan; Wu, Guoqiang; Sun, Shuhui; Gu, Jianxin; Wei, Yuanyan; Jiang, Jianhai

2010-01-01

Sox2, a master transcription factor, contributes to the generation of induced pluripotent stem cells and plays significant roles in sustaining the self-renewal of neural stem cells and glioma-initiating cells. Understanding the functional differences of Sox2 between glioma-initiating cells and normal neural stem cells would contribute to therapeutic approach for treatment of brain tumors. Here, we first demonstrated that Sox2 could contribute to the self-renewal and proliferation of glioma-initiating cells. The following experiments showed that Sox2 was activated at translational level in a subset of human glioma-initiating cells compared with the normal neural stem cells. Further investigation revealed there was a positive correlation between Sox2 and eukaryotic initiation factor 4E (eIF4E) in glioma tissues. Down-regulation of eIF4E decreased Sox2 protein level without altering its mRNA level in glioma-initiating cells, indicating that Sox2 was activated by eIF4E at translational level. Furthermore, eIF4E was presumed to regulate the expression of Sox2 by its 5' untranslated region (5' UTR) sequence. Our results suggest that the eIF4E-Sox2 axis is a novel mechanism of unregulated self-renewal of glioma-initiating cells, providing a potential therapeutic target for glioma.

Assessment of type of allergy and antihistamine use in the development of glioma

Science.gov (United States)

McCarthy, Bridget J.; Rankin, Kristin; Il'yasova, Dora; Erdal, Serap; Vick, Nicholas; Ali-Osman, Francis; Bigner, Darell D.; Davis, Faith

2010-01-01

Background Allergies have been associated with decreased risk of glioma, but associations between duration and timing of allergies, and antihistamine use and glioma risk have been less consistent. The objective was to investigate this association by analyzing types, number, years since diagnosis, and age at diagnosis of allergies, and information on antihistamine usage, including type, duration, and frequency of exposure. Methods Self-report data on medically-diagnosed allergies and antihistamine use were obtained for 419 glioma cases and 612 hospital-based controls from Duke University and NorthShore University HealthSystem. Results High- and low-grade glioma cases were statistically significantly less likely to report any allergy than controls (OR= 0.66, 95% CI: 0.49–0.87 and 0.44, 95% CI: 0.25–0.76, respectively). The number of types of allergies (seasonal, medication, pet, food, and other) was inversely associated with glioma risk in a dose-response manner (p-value for trend Impact A comprehensive study of allergies and antihistamine use using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development. PMID:21300619

Use of statins and risk of glioma

DEFF Research Database (Denmark)

Gaist, David; Andersen, L; Hallas, Jesper

2013-01-01

Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting.......Laboratory studies and a single case-control study have suggested a protective effect of statins on the risk of glioma. We wished to investigate the influence of statin use on the risk of glioma in a population-based setting....

Hypothalamic glioma masquerading as craniopharyngioma

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Sameer Vyas

2013-01-01

Full Text Available Hypothalamic glioma account for 10-15% of supratentorial tumors in children. They usually present earlier (first 5 years of age than craniopharyngioma. Hypothalamic glioma poses a diagnostic dilemma with craniopharyngioma and other hypothalamic region tumors, when they present with atypical clinical or imaging patterns. Neuroimaging modalities especially MRI plays a very important role in scrutinizing the lesions in the hypothalamic region. We report a case of a hypothalamic glioma masquerading as a craniopharyngioma on imaging along with brief review of both the tumors.

Ultrasonography-guided cobalt-60 brachytherapy for malignant glioma

International Nuclear Information System (INIS)

Sakai, Noboru; Takenaka, Katsunobu; Ueda, Tatsuya

1989-01-01

Brachytherapy with cobalt-60 source is reported. In this method it is characterized that the source is inserted interstitially with remote control system by after-loading method via outer catheter (using tandem tube), which was established in the center of residual tumor, using ultrasonography guide with trepanation, or intraoperatively put within the dead space after tumor resection. Six cases of deep-seated and recurrent malignant glioma, were treated with this method. A total dose of 20 to 45 Gy (10 to 15 Gy/day for 2 to 3 days) was delivered to the target. Additionally conventional external irradiation was followed. The effect of cobalt-60 brachytherapy on such tumors were favorable especially for well-circumscribed glioma less than 3 cm on CT scan. (author)

12 years' experience with intraoperative radiotherapy (IORT) of malignant gliomas

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Schueller, P.; Micke, O.; Moustakis, C.; Bruns, F.; Schuck, A.; Willich, N. [University Hospital Muenster (Germany). Dept. of Radiotherapy and Radiation Oncology; Palkovic, S.; Schroeder, J.; Wassmann, H. [University Hospital Muenster (Germany). Dept. of Neurosurgery

2005-08-01

Background: Even after surgery and radiotherapy, malignant gliomas still have a poor prognosis. The authors report on their experience with IORT in 71 patients. Patients and methods: From May 1992 to February 2004, 71 patients with malignant gliomas were treated with IORT. 26 patients suffered from grade III gliomas, 45 patients from glioblastomas (GBM). IORT was carried out using a standard electron tube and 9- to 18-MeV electrons. 52/71 patients who were primarily treated received 20 Gy IORT + 60 Gy postoperative radiotherapy, 19/71 patients with recurrences only received IORT (20-25 Gy). Results: The complication rates were 1.4% for wound infections and 5.6% for hemorrhage. Median disease-specific survival amounted to 14.9 months (gliomass III) and 14.2 months (GBM). The 2-year survival rates amounted to 26.9% (gliomas III) and 6.8% (GBM; p=0.0296). Total versus subtotal resection had no significant influence on survival (p=0.0741), nor had age, sex, tumor site, performance status, size, primary versus recurrence, and radiation dose. A comparison to a conventionally treated patient group did not show a significant survival improvement. 3 months after treatment, initial symptoms had improved in 59% (hemiparesis), 50% (aphasia), 50% (hemianopsia), and 60% (convulsions). Conclusion: IORT has been shown to be feasible; perioperative complication rates were not increased. Survival was generally not improved compared to a historical control group. Recurrences achieved the same survival as primary tumors, and GBM also had a slightly increased survival, thus being possible indications for IORT. (orig.)

Radiation effects on human glia and glioma cells in vitro

International Nuclear Information System (INIS)

Nilsson, S.

1983-01-01

The radiosensitivity of human glia and glioma cells has been studied in vitro, and a new cloning method has been developed to overcome the difficulties due to the very low cloning efficiency of these cells. The cells were confined to small palladium areas surrounded by agarose, which increased the cell density, but kept the clones separated. Using this method, the glia cells were found to be very sensitive to gamma irradiation (D 0 =1.0-1.5 Gy and n=1) in comparision with the glioma cells (D 0 =1.5-2.5 Gy and n=3.5). The induction and repair of DNA strand breaks were studied with two DNA unwinding techniques. No differences between the two cell-lines were detected when induction and fast repair were studied with the single-labelling method, while the glioma cells showed less unrepaired DNA strand breaks than the glia cells after 1, 2 and 3 hours, when the double-labelling method was used. Detachment, attachment and growth kinetics were studied using the palladium-agarose cloning method. All of the glioma cell-lines studied, detached and attached themselves at rates higher than the normal diploid glia cell-lines. All of the cell-lines contained clones with different properties. Some clones were rapidly growing, others maintained a nearly constant number of cells or even decreased. The effects of chronic hypoxia were tested in a few experiments. Low oxygen tension in the culture medium reduced the rate of growth and the DNA synthesis of the glioma cells. The present study indicates that cultured human glioma cells are less radiosensitive than cultured glia cells. The palladium-agarose technique, enable studying growth kinetics detachment, attachment and radiosensitivity in a quantitative manner for cells with low cloning efficiency. (author)

Epileptic seizures in patients with glioma: A single centrebased ...

African Journals Online (AJOL)

Purpose: To elucidate the outcomes of treatment and epidemiology of epilepsy related to glioma in a single center in Chinese patients. Methods: Prescription medicines usage and clinical data were collected from medical records of 119 patients with gliomas between August 2009 and September 2015. Fisher's exact and ...

Radiotherapeutic management of optic nerve gliomas in children

International Nuclear Information System (INIS)

Danoff, B.F.; Kramer, S.; Thompson, N.

1980-01-01

Optic nerve gliomas represent one to five percent of all intracranial tumors in children. The management of these tumors remains controversial. From 1956 to 1977, 18 children with optic nerve gliomas were treated at Thomas Jefferson University Hospital using external beam radiotherapy. All children presented with decreased visual acuity and five of eighteen were blind in one eye. No patient was found to have involvement of a single optic nerve. in eight patients, the chiasm was involved, in ten patients, tumor had extended to the frontal lobes and/or hypothalamus. Initial surgical management included biopsy only in seven patients, inspection of tumor in two patients and partial excision in seven patients. Two patients were treated with radiotherapy based on radiological findings. A tumor dose of 5000 to 6000 rad was given in 5.5 to 6.5 weeks. Stabilization of visual impairment or improvement in vision was noted in 78 percent of patients who were evaluable. The ten year survival was 73 percent. Radiological evidence of tumor regression will be presented. It is our impression that radiotherapy is indicated in the treatment of children with optic nerve gliomas who have poor prognostic signs

Investigation of established genetic risk variants for glioma in prediagnostic samples from a population-based nested case-control study.

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Wibom, Carl; Späth, Florentin; Dahlin, Anna M; Langseth, Hilde; Hovig, Eivind; Rajaraman, Preetha; Johannesen, Tom Børge; Andersson, Ulrika; Melin, Beatrice

2015-05-01

Although glioma etiology is poorly understood in general, growing evidence indicates a genetic component. Four large genome-wide association studies (GWAS) have linked common genetic variants with an increased glioma risk. However, to date, these studies are based largely on a case-control design, where cases have been recruited at the time of or after diagnosis. They may therefore suffer from a degree of survival bias, introduced when rapidly fatal cases are not included. To confirm glioma risk variants in a prospective setting, we have analyzed 11 previously identified risk variants in a set of prediagnostic serum samples with 598 cases and 595 matched controls. Serum samples were acquired from The Janus Serum Bank, a Norwegian population-based biobank reserved for cancer research. We confirmed the association with glioma risk for variants within five genomic regions: 8q24.21 (CCDC26), 9p21.3 (CDKN2B-AS1), 11q23.3 (PHLDB1), 17p13.1 (TP53), and 20q13.33 (RTEL1). However, previously identified risk variants within the 7p11.2 (EGFR) region were not confirmed by this study. Our results indicate that the risk variants that were confirmed by this study are truly associated with glioma risk and may, consequently, affect gliomagenesis. Though the lack of positive confirmation of EGFR risk variants may be attributable to relatively limited statistical power, it nevertheless raises the question whether they truly are risk variants or markers for glioma prognosis. Our findings indicate the need for further studies to clarify the role of glioma risk loci with respect to prolonged survival versus etiology. ©2015 American Association for Cancer Research.

Glioma cell fate decisions mediated by Dll1-Jag1-Fringe in Notch1 signaling pathway.

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Shi, Xiaofei; Wang, Ruiqi

2017-09-21

The Notch family of proteins plays a vital role in determining cell fates, such as proliferation, differentiation, and apoptosis. It has been shown that Notch1 and its ligands, Dll1 and Jag1, are overexpressed in many glioma cell lines and primary human gliomas. The roles of Notch1 in some cancers have been firmly established, and recent data implicate that it plays important roles in glioma cell fate decisions. This paper focuses on devising a specific theoretical framework that incorporates Dll1, Jag1, and Fringe in Notch1 signaling pathway to explore their functional roles of these proteins in glioma cells in the tumorigenesis and progression of human gliomas, and to study how glioma cell fate decisions are modulated by both trans-activation and cis-inhibition. This paper presents a computational model for Notch1 signaling pathway in glioma cells. Based on the bifurcation analysis of the model, we show that how the glioma cell fate decisions are modulated by both trans-activation and cis-inhibition mediated by the Fringe protein, providing insight into the design and control principles of the Notch signaling system and the gliomas. This paper presents a computational model for Notch1 signaling pathway in glioma cells based on intertwined dynamics with cis-inhibition and trans-activation involving the proteins Notch1, Dll1, Jag1, and Fringe. The results show that how the glioma cell fate transitions are performed by the Notch1 signaling. Transition from grade III ∼ IV with significantly high Notch1 to grade I ∼ II with high Notch1, and then to normal cells by repressing the Fringe levels or decreasing the strength of enhancement induced by Fringe.

Long noncoding RNA CASC2 predicts the prognosis of glioma patients and functions as a suppressor for gliomas by suppressing Wnt/β-catenin signaling pathway

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Wang R

2017-07-01

Full Text Available Ronglin Wang,1,* Yuqian Li,1,* Gang Zhu,1,* Bo Tian,1 Wen Zeng,1 Yang Yang,2 Zhihong Li1 1Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University, 2Department of Neurosurgery, The 451th hospital of PLA, Xi’an, Shaanxi, People’s Republic of China *These authors contributed equally to this work Background: Previous studies have demonstrated that long noncoding RNA cancer susceptibility candidate 2 (lncRNA CASC2 is frequently downregulated in several types of tumors and functions as a tumor-suppressive factor. However, the clinical significance and function of CASC2 in human glioma remain largely unknown. The purpose of this study was to identify the clinical values of CASC2, as well as investigate the potential molecular mechanisms in glioma. Methods: This retrospective study first analyzed the expression levels of CASC2 using quantitative real-time polymerase chain reaction. Then, CASC2 expression levels were associated with various clinicopathologic characteristics and the survival rate of patients with glioma. Finally, the function and underlying molecular mechanisms of CASC2 in human glioma were investigated in U251 cell line. Results: By quantitative real-time polymerase chain reaction analysis, our data showed that CASC2 expression was significantly downregulated in glioma tissues and cell lines (U87 and U251 compared to adjacent normal brain tissues or normal human astrocytes. Moreover, its expression negatively correlated with tumor grade in glioma patients. Furthermore, Kaplan–Meier curves with log-rank analysis revealed a close correlation between downregulated CASC2 and shorter survival time in glioma patients. In addition, Cox regression analysis indicated that CASC2 could be considered as an independent risk factor for poor prognosis. Finally, in vitro experiment demonstrated that CASC2 overexpression remarkably suppressed glioma cell proliferation, migration, and invasion through suppressing Wnt

Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy.

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Maurer, Gabriele D; Brucker, Daniel P; Bähr, Oliver; Harter, Patrick N; Hattingen, Elke; Walenta, Stefan; Mueller-Klieser, Wolfgang; Steinbach, Joachim P; Rieger, Johannes

2011-07-26

Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways.

Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

International Nuclear Information System (INIS)

Maurer, Gabriele D; Brucker, Daniel P; Bähr, Oliver; Harter, Patrick N; Hattingen, Elke; Walenta, Stefan; Mueller-Klieser, Wolfgang; Steinbach, Joachim P; Rieger, Johannes

2011-01-01

Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic) diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2), 3-oxoacid-CoA transferase 1 (OXCT1) and acetyl-CoA acetyltransferase 1 (ACAT1) were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α) pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic agents that efficiently target non-oxidative pathways

Silencing Nrf2 impairs glioma cell proliferation via AMPK-activated mTOR inhibition

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Jia, Yue [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China); Wang, Handong, E-mail: njhdwang@hotmail.com [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China); Wang, Qiang [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China); Ding, Hui [Department of Neurosurgery, Jinling Hospital, School of Medicine, Southern Medical University (Guangzhou), 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China); Wu, Heming [Department of Neurosurgery, Nanjing Jingdu Hospital, No. 34, Biao 34, Yanggongjing Road, Nanjing 210002, Jiangsu Province (China); Pan, Hao [Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210002, Jiangsu Province (China)

2016-01-15

Gliomas are the leading cause of death among adults with primary brain malignancies. Treatment for malignant gliomas remains limited, and targeted therapies have been incompletely explored. Nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription regulator for antioxidant and detoxification enzymes, is abundantly expressed in cancer cells. In this study, the role and mechanism of Nrf2 in cancer cell proliferation was investigated in multiple glioma cell lines. We first evaluated the expression patterns of Nrf2 in four glioma cell lines and found all four cell lines expressed Nrf2, but the highest level was observed in U251 cells. We further evaluated the biological functions of Nrf2 in U251 glioma cell proliferation by specific inhibition of Nrf2 using short hairpin RNA (shRNA). We found that Nrf2 depletion inhibited glioma cell proliferation. Nrf2 depletion also decreased colony formation in U251 cells stably expressing Nrf2 shRNA compared to scrambled control shRNA. Moreover, suppression of Nrf2 expression could lead to ATP depletion (with concomitant rise in AMP/ATP ratio) and consequently to AMPK-activated mTOR inhibition. Finally, activation of adenosine monophosphate–activated protein kinase (AMPK) by treated with phenformin, an AMPK agonist, can mimic the inhibitory effect of Nrf2 knockdown in U251 cells. In conclusion, our findings will shed light to the role and mechanism of Nrf2 in regulating glioma proliferation via ATP-depletion-induced AMPK activation and consequent mTOR inhibition, a novel insight into our understanding the role and mechanism of Nrf2 in glioma pathoetiology. To our knowledge, this is also the first report to provide a rationale for the implication of cross-linking between Nrf2 and mTOR signaling.

RANK (TNFRSF11A Is Epigenetically Inactivated and Induces Apoptosis in Gliomas

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Anna von dem Knesebeck

2012-06-01

Full Text Available Alterations of DNA methylation play an important role in gliomas. In a genome-wide screen, we identified a CpG-rich fragment within the 5′ region of the tumor necrosis factor receptor superfamily, member 11A gene (TNFRSF11A that showed de novo methylation in gliomas. TNFRSF11A, also known as receptor activator of NF-κB (RANK, activates several signaling pathways, such as NF-κB, JNK, ERK, p38α, and Akt/PKB. Using pyrosequencing, we detected RANK/TNFRSF11A promoter methylation in 8 (57.1% of 14 diffuse astrocytomas, 17 (77.3% of 22 anaplastic astrocytomas, 101 (84.2% of 120 glioblastomas, 6 (100% of 6 glioma cell lines, and 7 (100% of 7 glioma stem cell-enriched glioblastoma primary cultures but not in four normal white matter tissue samples. Treatment of glioma cell lines with the demethylating agent 5-aza-2′-deoxycytidine significantly reduced the methylation level and resulted in increased RANK/TNFRSF11A mRNA expression. Overexpression of RANK/TNFRSF11A in glioblastoma cell lines leads to a significant reduction in focus formation and elevated apoptotic activity after flow cytometric analysis. Reporter assay studies of transfected glioma cells supported these results by showing the activation of signaling pathways associated with regulation of apoptosis. We conclude that RANK/TNFRSF11A is a novel and frequent target for de novo methylation in gliomas, which affects apoptotic activity and focus formation thereby contributing to the molecular pathogenesis of gliomas.

Arctigenin, a natural lignan compound, induces G0/G1 cell cycle arrest and apoptosis in human glioma cells.

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Maimaitili, Aisha; Shu, Zunhua; Cheng, Xiaojiang; Kaheerman, Kadeer; Sikandeer, Alifu; Li, Weimin

2017-02-01

The aim of the current study was to investigate the anticancer potential of arctigenin, a natural lignan compound, in malignant gliomas. The U87MG and T98G human glioma cell lines were treated with various concentrations of arctigenin for 48 h and the effects of arctigenin on the aggressive phenotypes of glioma cells were assessed. The results demonstrated that arctigenin dose-dependently inhibited the growth of U87MG and T98G cells, as determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and bromodeoxyuridine incorporation assays. Arctigenin exposure also induced a 60-75% reduction in colony formation compared with vehicle-treated control cells. However, arctigenin was not observed to affect the invasiveness of glioma cells. Arctigenin significantly increased the proportion of cells in the G 0 /G 1 phase and reduced the number of cells in the S phase, as compared with the control group (Parctigenin increased the expression levels of p21, retinoblastoma and p53 proteins, and significantly decreased the expression levels of cyclin D1 and cyclin-dependent kinase 4 proteins. Additionally, arctigenin was able to induce apoptosis in glioma cells, coupled with increased expression levels of cleaved caspase-3 and the pro-apoptotic BCL2-associated X protein. Furthermore, arctigenin-induced apoptosis was significantly suppressed by the pretreatment of cells with Z-DEVD-FMK, a caspase-3 inhibitor. In conclusion, the results suggest that arctigenin is able to inhibit cell proliferation and may induce apoptosis and cell cycle arrest at the G 0 /G 1 phase in glioma cells. These results warrant further investigation of the anticancer effects of arctigenin in animal models of gliomas.

Imaging of adult brainstem gliomas

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Purohit, Bela, E-mail: purohitbela@yahoo.co.in; Kamli, Ali A.; Kollias, Spyros S.

2015-04-15

Highlights: •BSG are classified on MRI into diffuse low-grade, malignant, focal tectal and exophytic subtypes. •Their prognosis and treatment is variable and is almost similar to adult supratentorial gliomas. •This article illustrates the imaging of adult BSGs on MRI and FET-PET. •We also describe prognostic factors and the treatment options of these tumours. -- Abstract: Brainstem gliomas (BSGs) are uncommon in adults accounting for about 2% of all intracranial neoplasms. They are often phenotypically low-grade as compared to their more common paediatric counterparts. Since brainstem biopsies are rarely performed, these tumours are commonly classified according to their MR imaging characteristics into 4 subgroups: (a) diffuse intrinsic low-grade gliomas, (b) enhancing malignant gliomas, (c) focal tectal gliomas and (d) exophytic gliomas/other subtypes. The prognosis and treatment is variable for the different types and is almost similar to adult supratentorial gliomas. Radiotherapy (RT) with adjuvant chemotherapy is the standard treatment of diffuse low-grade and malignant BSGs, whereas, surgical resection is limited to the exophytic subtypes. Review of previous literature shows that the detailed imaging of adult BSGs has not received significant attention. This review illustrates in detail the imaging features of adult BSGs using conventional and advanced MR techniques like diffusion weighted imaging (DWI), diffusion tensor imaging (DTI), MR perfusion weighted imaging (PWI), MR spectroscopy (MRS), as well as {sup 18}F-fluoro-ethyl-tyrosine positron emission tomography ({sup 18}F-FET/PET). We have discussed the pertinent differences between childhood and adult BSGs, imaging mimics, prognostic factors and briefly reviewed the treatment options of these tumours.

SCCRO Promotes Glioma Formation and Malignant Progression in Mice

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Stephen R. Broderick

2010-06-01

Full Text Available Originally identified as an oncogene activated by amplification in squamous cell carcinomas, several lines of evidence now suggest that squamous cell carcinoma-related oncogene (SCCRO; aka DCUN1D1 may play a role in the pathogenesis of a wide range of human cancers including gliomas. SCCRO's oncogenic function is substantiated by its ectopic expression, resulting in transformation of cells in culture and xenograft formation in nude mice. The aim of this study was to assess the in vivo oncogenicity of SCCRO in a murine model. Ubiquitous expression of SCCRO resulted in early embryonic lethality. Because SCCRO overexpression was detected in human gliomas, its in vivo oncogenic activity was assessed in an established murine glioma model. Conditional expression of SCCRO using a replication-competent ASLV long terminal repeat with splice acceptor/nestin-(tumor virus-A tv-a model system was not sufficient to induce tumor formation in a wild-type genetic background, but tumors formed with increasing frequency and decreasing latency in facilitated background containing Ink4a deletion alone or in combination with PTEN loss. Ectopic expression of SCCRO in glial progenitor cells resulted in lower-grade gliomas in Ink4a-/- mice, whereas its expression in Ink4a-/-/PTEN-/- background produced high-grade glioblastoma-like lesions that were indistinguishable from human tumors. Expression of SCCRO with platelet-derived growth factor-beta (PDGF-β resulted in an increased proportion of mice forming glioblastoma-like tumors compared with those induced by PDGF-β alone. This work substantiates SCCRO's function as an oncogene by showing its ability to facilitate malignant transformation and carcinogenic progression in vivo and supports a role for SCCRO in the pathogenesis of gliomas and other human cancers.

Evaluation glioma for C-11-methyl-L-methionine PET

International Nuclear Information System (INIS)

Kenji Torii; Joji Kawabe; Takehiro hayashi; Jin Kotani; Ai Oe; Etsushi Kawamura; Hirotaka Ishizu; Hiroyuki Tsushima; Mitsuhiro Hara; Susumu Shiomi; Naohiro Tsuyuguchi

2004-01-01

invasion) and to explore a relationship between the degree of Met accumulation and Ki-67 (a known indicator of tumor malignancy level). I investigated 67 patients (man 36, woman 31) with gliomas, from 3 to 69 years old. All gliomas according to WHO classification. (Diffusedly Astrocytoma 10 cases, Anaplastic astrocytoma 12 cases, Glioblastoma 21 cases, Ependymoma 5 cases, Oligodendroglioma 4 cases, Medulloblastoma 3 cases, DNT 2 cases, Choroid plexus papilloma 2 cases, Central neurocytoma 2 cases, Optic glioma 2 cases, Gliomatosis cerebri 2 cases, PXA 1 cases, Ganglioglioma 1 cases). The DAKO EPS(enhanced polymer one-step staining) method was applied to detect Ki67. After deparaffinization, hydrated autoclave pretreatment(121 degree C 10 min) was done. Then the section were included with anti-Ki-67 polyclonal antibody (DAKO; A047) for over night at 4 degree C. The slides were examined by light microscopy. At least 1000 cells on each specimen were counted to determin Ki-67 labeling index (abbreviated as Ki-67 LI hereinafter), the percentage of Ki-67 positive cells, in five to eight viable areas. Gliomas were respectively classified into a high Ki-67 LI group (high prolififeration group), which has high recurrence potential, showing Ki-67 LI values of not less than 2% and a low Ki-67 LI group(low prolififeration group) showing Ki-67 LI values of less than 2%. A HEADTOME IV (Shimazu Co.,Japan), a four-ring fourteen-slice positron emission tomography, was employed with the transaxial resoluton of 4.5 mm in full width at half maximum (FWHM) and clice thickness of 6.5 mm in FWHM. Patients were injected intravenously with 0.2 mCi/kg C-11 Methionin (Met) in a fastig state. Following injection, the PET scanning was started after 20 min later. The viable tumor tissue was determined using MRI accurately equivalent in scanning level with PET. A tumor of the region of' interest(ROI) was set in the circular region that was drown with the borders of the tumor region on one slice of the

A high 18F-FDOPA uptake is associated with a slow growth rate in diffuse Grade II-III gliomas.

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Isal, Sibel; Gauchotte, Guillaume; Rech, Fabien; Blonski, Marie; Planel, Sophie; Chawki, Mohammad B; Karcher, Gilles; Marie, Pierre-Yves; Taillandier, Luc; Verger, Antoine

2018-04-01

In diffuse Grade II-III gliomas, a high 3,4-dihydroxy-6-( 18 F)-fluoro-L-phenylalanine ( 18 F-FDOPA) positron emission tomography (PET) uptake, with a standardized uptake value (SUV max )/contralateral brain tissue ratio greater than 1.8, was previously found to be consistently associated with the presence of an isocitrate dehydrogenase (IDH) mutation, whereas this mutation is typically associated with a better prognosis. This pilot study was aimed to ascertain the prognostic value of this high 18 F-FDOPA uptake in diffuse Grade II-III gliomas with regard to the velocity of diameter expansion (VDE), which represents an established landmark of better prognosis when below 4 mm per year. 20 patients (42 ± 10 years, 10 female) with newly-diagnosed diffuse Grade II-III gliomas (17 with IDH mutation) were retrospectively included. All had a 18 F-FDOPA PET, quantified with SUV max ratio, along with a serial MRI enabling VDE determination. SUV max ratio was above 1.8 in 5 patients (25%) all of whom had a VDE VDE <4 mm/year in the overall population (45 vs 0%, p = 0.04) and also in the subgroup of patients with IDH mutation (45 vs 0%, p = 0.10). This pilot study shows that in diffuse Grade II-III gliomas, a high 18 F-FDOPA uptake would be predictive of low tumour growth, with a different prognostic significance than IDH mutation. Advances in knowledge: 18 F-FDOPA PET in a single session imaging could have prognostic value in initial diagnosis of diffuse Grade II-III gliomas.

Approaching a scientific consensus on the association between allergies and glioma risk

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Amirian, E. Susan; Zhou, Renke; Wrensch, Margaret R.

2016-01-01

Background: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma...... International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk.  Methods: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using...... two-stage randomeffects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema.  Results: Having a history of respiratory allergies was associated with an approximately 30...

Immunohistochemical detection and correlation between MHC antigen and cell-mediated immune system in recurrent glioma by APAAP method.

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Miyagi, K; Ingram, M; Techy, G B; Jacques, D B; Freshwater, D B; Sheldon, H

1990-09-01

As part of an on-going clinical trial of immunotherapy for recurrent malignant gliomas, using alkaline phosphatase-anti-alkaline phosphatase method with monoclonal antibodies, we investigated the correlation between expression of the major histocompatibility complex (MHC) and the subpopulation of tumor-infiltrating lymphocytes (TILs) in 38 glioma specimens (20 grade IV, 11 grade III, and 7 grade II) from 33 patients. Thirty specimens (78.9%) were positive to class I MHC antigen and 20 (52.6%) were positive to class II MHC antigen. The correlations between class I MHC antigen expression and the number of infiltrating T8 (p less than 0.01), and also between class II MHC antigen expression and the number of infiltrating T4 (p less than 0.05) were significant. We conclude that TILs are the result of immunoreaction (host-defense mechanism). 31.6% of specimens had perivascular infiltration of T cells. The main infiltrating lymphocyte subset in moderate to marked perivascular cuffing was T4. Our results may indicate that lack of MHC antigen on the glioma cell surface has a share in the poor immunogenicity in glioma-bearing patients. In addition, considering the effector/target ratio, the number of infiltrating lymphocytes against glioma cells was too small, so the immunological intervention seems to be essential in glioma therapy. Previous radiation therapy and chemotherapy, including steroid therapy, did not influence lymphocyte and macrophage infiltration.

Genetic polymorphisms of DNA double-strand break repair pathway genes and glioma susceptibility

International Nuclear Information System (INIS)

Zhao, Peng; Zou, Peng; Zhao, Lin; Yan, Wei; Kang, Chunsheng; Jiang, Tao; You, Yongping

2013-01-01

Genetic variations in DNA double-strand break repair genes can influence the ability of a cell to repair damaged DNA and alter an individual’s susceptibility to cancer. We studied whether polymorphisms in DNA double-strand break repair genes are associated with an increased risk of glioma development. We genotyped 10 potentially functional single nucleotide polymorphisms (SNPs) in 7 DNA double-strand break repair pathway genes (XRCC3, BRCA2, RAG1, XRCC5, LIG4, XRCC4 and ATM) in a case–control study including 384 glioma patients and 384 cancer-free controls in a Chinese Han population. Genotypes were determined using the OpenArray platform. In the single-locus analysis there was a significant association between gliomas and the LIG4 rs1805388 (Ex2 +54C>T, Thr9Ile) TT genotype (adjusted OR, 3.27; 95% CI, 1.87-5.71), as well as the TC genotype (adjusted OR, 1.62; 95% CI, 1.20-2.18). We also found that the homozygous variant genotype (GG) of XRCC4 rs1805377 (IVS7-1A>G, splice-site) was associated with a significantly increased risk of gliomas (OR, 1.77; 95% CI, 1.12-2.80). Interestingly, we detected a significant additive and multiplicative interaction effect between the LIG4 rs1805388 and XRCC4 rs1805377 polymorphisms with an increasing risk of gliomas. When we stratified our analysis by smoking status, LIG4 rs1805388 was associated with an increased glioma risk among smokers. These results indicate for the first time that LIG4 rs1805388 and XRCC4 rs1805377, alone or in combination, are associated with a risk of gliomas

Epileptic seizures in patients with glioma: A single centre- based ...

African Journals Online (AJOL)

were used for analysis of seizure incidence differences as per WHO Grades, histology, location ... Keywords: Brain tumour, Epilepsy, Glioma, Seizures, Levetiracetam, .... glioma patients. Characteristics. N (%). Gender. Male. Female. Histology.

Glioma Indian scenario: Is there a human leucocyte antigen association?

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Shankarkumar, U; Sridharan, B

2011-07-01

The central nervous system tumors are a rare neoplasm with little knowledge with Human Leukocyte Antigen (HLA) involvement. Primary brain tumors are cancers that originate in brain classified according to their appearance under a microscope as low grade (grade I and II) with diffuse astrocytomas, pliocytic astrocytomas, oligodendrogliomas, gangliogliomas, and mixed gliomas as common subtypes and high grade (grade III and IV). HLA associations in common glioma are reported from other parts of the world. The normal cancer treatment is surgery, followed by radiotherapy, and chemotherapy; nowadays immunotherapy is advised. HLA distribution in a Glioma patient was done based on serology and molecular techniques. The immune response gene studies have implicated the HLA allele association in most of the common diseases from India. Considerable variations are noted in HLA association with cancers; hence, we have summarized the HLA involvement in Glioma with respect to the literature. HLA A*030101, A*310102, B*350101, B*4406, Cw*040101, Cw*070101, DRB1*070101, and DRB1*1001. Ethnic diversity and HLA polymorphism precipitate differential immune response genes involved in variable disease manifestations. Therefore, caste-specific HLA allelic specificity needs to be identified, which may help in early identification of the associated HLA allele and establishing clinical practices among glioma patients.

Nasal Glioma: Case report

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Ozgur Surmelioglu

2011-02-01

Full Text Available Nasal gliomas are rare, benign, congenital tumors that are thought to be result of abnormality in embryonic development. Three types of clinical presentations have been recognized; extranasal, intranasal and combined. Clinically, these masses are non-pulsatile, gray or purple lesions that obstruct the nasal cavity and cause deformity extranasaly. Histologically, they are made up of astrocytic cells, fibrous and vascular connective tissue that is covered with nasal respiratory mucosa. Treatment of the nasal glioma requires a multidisciplinary approach including an radiologist, neurosurgeon and otorhinolaryngologist. Radiological investigation should be performed to describe intracranial extension. In this case, a 2 years old boy with nasal mass that was diagnosed as nasal glioma is reported. . [Cukurova Med J 2011; 36(1.000: 34-36

Nasal Glioma: Case report

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Ozgur Surmelioglu

2011-03-01

Full Text Available Nasal gliomas are rare, benign, congenital tumors that are thought to be result of abnormality in embryonic development. Three types of clinical presentations have been recognized; extranasal, intranasal and combined. Clinically, these masses are non-pulsatile, gray or purple lesions that obstruct the nasal cavity and cause deformity extranasaly. Histologically, they are made up of astrocytic cells, fibrous and vascular connective tissue that is covered with nasal respiratory mucosa. Treatment of the nasal glioma requires a multidisciplinary approach including an radiologist, neurosurgeon and otorhinolaryngologist. Radiological investigation should be performed to describe intracranial extension. In this case, a 2 years old boy with nasal mass that was diagnosed as nasal glioma is reported. . [Cukurova Med J 2011; 36(1: 34-36

Estradiol Receptors Regulate Differential Connexin 43 Expression in F98 and C6 Glioma Cell Lines.

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Zahra Moinfar

Full Text Available Glioma is the most common malignant primary brain tumour with male preponderance and poor prognosis. Glioma cells express variable amounts of connexin 43 (Cx43 and estrogen receptors (ERs. Both, Cx43 and ERs, play important roles in cell proliferation and migration. Therefore, we investigated the effects of 17-ß estradiol (E2 on Cx43 expression in two glioma cell lines with variable native expression of Cx43.F98 and C6 rat glioma cells were cultured for 24 h in the presence of 10 nM or 100 nM E2, and the E2-antagonist, Fulvestrant. An MTT assay was performed to evaluate cell viability. ERα, ERβ and Cx43 protein expressions were analysed by western blotting and Cx43 mRNA expression was analysed by real-time polymerase chain reaction. To quantify cell migration, an exclusive zone migration assay was used. Functional coupling of cells via gap junctions was examined using whole-cell patch-clamp technique.E2 reduced Cx43 expression in C6 cells, but increased Cx43 expression in F98 cultures. These effects were mediated via ERs. Moreover, E2 promoted C6 cell migration, but it did not affect F98 cell migration. The expression level of ERα was found to be high in C6, but low in F98 cells. ERβ was exclusively expressed in C6 cells. In addition, E2 treatment induced a significant decrease of ERβ in C6 cultures, while it decreased ERα expression in F98 glioma cells.These findings show that E2 differentially modulates Cx43 expression in F98 and C6 glioma cells, likely due to the differential expression of ERs in each of these cell lines. Our findings point to the molecular mechanisms that might contribute to the gender-specific differences in the malignancy of glioma and could have implications for therapeutic strategies against glioma.

Effects of irradiation on cytokine production in glioma cell lines

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Yamanaka, Ryuya; Tanaka, Ryuichi; Yoshida, Seiichi [Niigata Univ. (Japan). Brain Research Inst.

1993-11-01

The effects of irradiation on cytokine production in glioma cell lines, NP1, NP2 and NP3, were studied. Culture supernatants were collected after 6, 24, 48 or 72 hours and the concentrations of interleukin (IL)-6 and IL-8 measured by enzyme-linked immunosorbent assay. Spontaneous and IL-1[beta]-stimulated productions were analyzed. Some cells were given a single dose of Lineac irradiation (10 or 20 Gy). Production of IL-6 (with or without IL-1[beta] stimulation) increased gradually to a maximum after 72 hours, more in the 20 Gy-irradiated cells than 10 Gy cells (p<0.01). Production of IL-8 increased gradually to a maximum after 48 or 72 hours. Spontaneous production of IL-8 increased more in 20 Gy-irradiated cells than 10 Gy cells after 6 and 24 hours (p<0.01), but increased more in 10 Gy cells than 20 Gy cells after 48 and 72 hours (p<0.01). The production of IL-8 stimulated by IL-1[beta] increased more in 10 Gy cells than 20 Gy cells 24 hours later (p<0.01). IL-6 and IL-8 production differed in the response to irradiation. Our data suggest that bidirectional communication between the immune system and glioma cells changes after radiotherapy. (author).

Angiogenesis in gliomas.

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Elzbieta Czykier

2008-02-01

Full Text Available Brain gliomas are characterized by invasive growth and neovascularisation potential. Angiogenesis plays a major role in the progression of gliomas and its determination has a great prognostic value. The aim of the study was to assess the vascularisation of chosen brain gliomas and to estimate how it is correlated with tumour histological type, malignancy grade, location and size, and with age and sex of patients. Tumour vascularisation analysis was based on the determination of microvascular proliferation (MVP and microvessel density (MVD. Microvascular proliferation was measured with immunohistochemical methods using mouse monoclonal antibodies to detect cell proliferation antigens. The following antibodies were used Ki-67 and PCNA (DAKO. Identification of vessels was performed by CD31 antibody and anti-human von Willebrand factor (DAKO. The highest microvascular proliferation and microvascular density were observed in multiform glioblastomas and the lowest in oligodendrogliomas. Significant correlation was observed between the vascularisation and malignancy grade.

The value of diffusion tensor imaging in differentiating high-grade gliomas from brain metastases: a systematic review and meta-analysis.

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Rui Jiang

Full Text Available Differentiation of high-grade gliomas and solitary brain metastases is an important clinical issue because the treatment strategies differ greatly. Our study aimed to investigate the potential value of diffusion tensor imaging (DTI in differentiating high-grade gliomas from brain metastases using a meta-analytic approach.We searched Pubmed, Embase and the Cochrane Library for relevant articles published in English. Studies that both investigated high-grade gliomas and brain metastases using DTI were included. Random effect model was used to compare fractional anisotropy (FA and mean diffusivity (MD values in the two tumor entities.Nine studies were included into the meta-analysis. In the peritumoral region, compared with brain metastases, high-grade gliomas had a significant increase of FA (SMD  = 0.47; 95% CI, 0.22-0.71; P<0.01 and a significant decrease of MD (SMD  = -1.49; 95% CI, -1.91 to -1.06; P<0.01. However, in the intratumoral area, no significant change in FA (SMD  = 0.16; 95% CI, -0.49 to 0.82; P = 0.73 or MD (SMD  = 0.34; 95% CI, -0.91 to 1.60; P = 0.59 was detected between gliomas and metastases.High-grade gliomas may be distinguished from brain metastases by comparing the peritumoral FA and MD values. DTI appears to be a promising tool in diagnosing solitary intracranial lesions.

Human gliomas contain morphine

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Olsen, Peter; Rasmussen, Mads; Zhu, Wei

2005-01-01

BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogeno...... of the solutions used in the study nor was it present as a residual material in blank HPLC runs. CONCLUSIONS: Morphine is present in human gliomas, suggesting that it may exert an action that effects tumour physiology/pathology.......BACKGROUND: Morphine has been found in cancer cell lines originating from human and animal cells. Thus, it became important to demonstrate whether or not actual tumours contain this opiate alkaloid. MATERIAL/METHODS: Human glioma tissues were biochemically treated to isolate and separate endogenous...

Cortical and Subcortical Structural Plasticity Associated with the Glioma Volumes in Patients with Cerebral Gliomas Revealed by Surface-Based Morphometry

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Jinping Xu

2017-06-01

Full Text Available Postlesional plasticity has been identified in patients with cerebral gliomas by inducing a large functional reshaping of brain networks. Although numerous non-invasive functional neuroimaging methods have extensively investigated the mechanisms of this functional redistribution in patients with cerebral gliomas, little effort has been made to investigate the structural plasticity of cortical and subcortical structures associated with the glioma volume. In this study, we aimed to investigate whether the contralateral cortical and subcortical structures are able to actively reorganize by themselves in these patients. The compensation mechanism following contralateral cortical and subcortical structural plasticity is considered. We adopted the surface-based morphometry to investigate the difference of cortical and subcortical gray matter (GM volumes in a cohort of 14 healthy controls and 13 patients with left-hemisphere cerebral gliomas [including 1 patients with World Health Organization (WHO I, 8 WHO II, and 4 WHO III]. The glioma volume ranges from 5.1633 to 208.165 cm2. Compared to healthy controls, we found significantly increased GM volume of the right cuneus and the left thalamus, as well as a trend toward enlargement in the right globus pallidus in patients with cerebral gliomas. Moreover, the GM volumes of these regions were positively correlated with the glioma volumes of the patients. These results provide evidence of cortical and subcortical enlargement, suggesting the usefulness of surface-based morphometry to investigate the structural plasticity. Moreover, the structural plasticity might be acted as the compensation mechanism to better fulfill its functions in patients with cerebral gliomas as the gliomas get larger.

Facing Contrast-Enhancing Gliomas: Perfusion MRI in Grade III and Grade IV Gliomas according to Tumor Area

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Anna Luisa Di Stefano

2014-01-01

Full Text Available Tumoral neoangiogenesis characterizes high grade gliomas. Relative Cerebral Blood Volume (rCBV, calculated with Dynamic Susceptibility Contrast (DSC Perfusion-Weighted Imaging (PWI, allows for the estimation of vascular density over the tumor bed. The aim of the study was to characterize putative tumoral neoangiogenesis via the study of maximal rCBV with a Region of Interest (ROI approach in three tumor areas—the contrast-enhancing area, the nonenhancing tumor, and the high perfusion area on CBV map—in patients affected by contrast-enhancing glioma (grades III and IV. Twenty-one patients were included: 15 were affected by grade IV and 6 by grade III glioma. Maximal rCBV values for each patient were averaged according to glioma grade. Although rCBV from contrast-enhancement and from nonenhancing tumor areas was higher in grade IV glioma than in grade III (5.58 and 2.68; 3.01 and 2.2, resp., the differences were not significant. Instead, rCBV recorded in the high perfusion area on CBV map, independently of tumor compartment, was significantly higher in grade IV glioma than in grade III (7.51 versus 3.78, P=0.036. In conclusion, neoangiogenesis encompasses different tumor compartments and CBV maps appear capable of best characterizing the degree of neovascularization. Facing contrast-enhancing brain tumors, areas of high perfusion on CBV maps should be considered as the reference areas to be targeted for glioma grading.

The Art of Intraoperative Glioma Identification

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Zoe Z Zhang

2015-07-01

Full Text Available A major dilemma in brain tumor surgery is the identification of tumor boundaries to maximize tumor excision and minimize postoperative neurological damage. Gliomas, especially low-grade tumors, and normal brain have a similar color and texture which poses a challenge to the neurosurgeon. Advances in glioma resection techniques combine the experience of the neurosurgeon and various advanced technologies. Intraoperative methods to delineate gliomas from normal tissue consist of 1 image-based navigation, 2 intraoperative sampling, 3 electrophysiological monitoring, and 4 enhanced visual tumor demarcation. The advantages and disadvantages of each technique are discussed. A combination of these methods is becoming widely accepted in routine glioma surgery. Gross total resection in conjunction with radiation, chemotherapy, or immune/gene therapy may increase the rates of cure in this devastating disease.

Differential utilization of ketone bodies by neurons and glioma cell lines: a rationale for ketogenic diet as experimental glioma therapy

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Mueller-Klieser Wolfgang

2011-07-01

Full Text Available Abstract Background Even in the presence of oxygen, malignant cells often highly depend on glycolysis for energy generation, a phenomenon known as the Warburg effect. One strategy targeting this metabolic phenotype is glucose restriction by administration of a high-fat, low-carbohydrate (ketogenic diet. Under these conditions, ketone bodies are generated serving as an important energy source at least for non-transformed cells. Methods To investigate whether a ketogenic diet might selectively impair energy metabolism in tumor cells, we characterized in vitro effects of the principle ketone body 3-hydroxybutyrate in rat hippocampal neurons and five glioma cell lines. In vivo, a non-calorie-restricted ketogenic diet was examined in an orthotopic xenograft glioma mouse model. Results The ketone body metabolizing enzymes 3-hydroxybutyrate dehydrogenase 1 and 2 (BDH1 and 2, 3-oxoacid-CoA transferase 1 (OXCT1 and acetyl-CoA acetyltransferase 1 (ACAT1 were expressed at the mRNA and protein level in all glioma cell lines. However, no activation of the hypoxia-inducible factor-1α (HIF-1α pathway was observed in glioma cells, consistent with the absence of substantial 3-hydroxybutyrate metabolism and subsequent accumulation of succinate. Further, 3-hydroxybutyrate rescued hippocampal neurons from glucose withdrawal-induced cell death but did not protect glioma cell lines. In hypoxia, mRNA expression of OXCT1, ACAT1, BDH1 and 2 was downregulated. In vivo, the ketogenic diet led to a robust increase of blood 3-hydroxybutyrate, but did not alter blood glucose levels or improve survival. Conclusion In summary, glioma cells are incapable of compensating for glucose restriction by metabolizing ketone bodies in vitro, suggesting a potential disadvantage of tumor cells compared to normal cells under a carbohydrate-restricted ketogenic diet. Further investigations are necessary to identify co-treatment modalities, e.g. glycolysis inhibitors or antiangiogenic

Current status of cerebral glioma surgery in China.

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Wu, Jin-song; Zhang, Jie; Zhuang, Dong-xiao; Yao, Cheng-jun; Qiu, Tian-ming; Lu, Jun-feng; Zhu, Feng-ping; Mao, Ying; Zhou, Liang-fu

2011-09-01

The treatment of gliomas is highly individualized. Surgery for gliomas is essentially for histological diagnosis, to alleviate mass effect, and most importantly, to favor longer survival expectancy. During the past two decades, many surgical techniques and adjuvants have been applied to glioma surgery in China, which lead to a rapid development in the field of cerebral glioma surgery. This article broadly and critically reviewed the existing studies on cerebral glioma surgery and to portrait the current status of glioma surgery in China. A literature search was conducted covering major innovative surgical techniques and adjuvants for glioma surgery in China. The following databases were searched: the Pubmed (January 1995 to date); China Knowledge Resource Integrated Database (January 1995 to date) and VIP Database for Chinese Technical Periodicals (January 1995 to date). A selection criterion was established to exclude duplicates and irrelevant studies. The outcome measures were extracted from included studies. A total of 3307 articles were initially searched. After excluded by abstracts and full texts, 69 studies conducted in the mainland of China were included and went through further analysis. The philosophy of surgical strategies for cerebral gliomas in China is undergoing tremendous change. Nowadays Chinese neurosurgeons pay more attention to the postoperative neurofunctional status of the patients. The aim of the glioma surgery is not only the more extensive tumor resection but also the maximal safety of intervention. The well balance of longer overall survival and higher quality of life should be judged with respect to each individual patient.

Reirradiation and lomustine in patients with relapsed high-grade gliomas

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Arcicasa, Mauro; Roncadin, Mario; Bidoli, Ettore; Dedkov, Anatolyi; Gigante, Marco; Trovo, Mauro G.

1999-01-01

Purpose: The aim of this study was to evaluate the toxicity, response, and survival of patients with relapsed high-grade gliomas after radiation therapy (RT) combined with lomustine (CCNU). Methods and Materials: Thirty-one patients with relapsed gliomas at least 6 months after completion of RT were reirradiated. Twenty-four patients had a pathological diagnosis of high-grade gliomas, whereas 7 had a radiological diagnosis of relapsed malignant gliomas. The study focused on patients with high-grade relapsed gliomas. A total dose of 34.5 Gy was delivered in 23 fractions over 4.5 weeks. Oral administration of CCNU (130 mg/m 2 ) was begun at the same time as RT, and was repeated every 6 weeks until disease progression, or up to 12 courses. Results: Twelve of 24 patients had surgery before RT plus CCNU treatment. Median interval between RT courses was 14 months (range 6-73). All patients received a complete course of RT, and 22 of 24 patients received at least one course of CCNU. Objective responses were seen in 14 evaluable patients: 3 with partial response, 5 with stable disease, and 6 with progressive disease. Duration of partial response was 20, 9, and 8 months. Median time to progression and overall survival from the onset of retreatment were 8.4 months (range 1-22) and 13.7 months (range 1-63+), respectively. One case of G4 thrombocytopenia was observed. Five patients had G1 or G2 leucopenia and 3 patients had G3 leucopenia. Moderate nausea and vomiting were reported in 4 patients. One patient, after one course of CCNU, refused further chemotherapy. No significant difference in survival from relapse was found between patients who underwent surgery before RT plus CCNU and those who received only RT plus CCNU (p = 0.74). Conclusion: Overall, the acute toxicity was moderate, and patient compliance was good. Reirradiation of high-grade glioma was associated with modest subjective and objective response rates. It is remarkable that median overall survival from relapse

The effects of gene polymorphisms on glioma prognosis.

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Cui, Ying; Li, Guolin; Yan, Mengdan; Li, Jing; Jin, Tianbo; Li, Shanqu; Mu, Shijie

2017-11-01

Malignant gliomas are the most common primary brain tumors. Various genetic factors play important roles in the development and prognosis of glioma. The present study focuses on the impact of MPHOSPH6, TNIP1 and several other genes (ACYP2, NAF1, TERC, TERT, OBFC1, ZNF208 and RTEL1) on telomere length and how this affects the prognosis of glioma. Forty-three polymorphisms in nine genes from 605 glioma patients were selected. The association between genotype and survival outcome was analyzed using the Kaplan-Meier method, Cox regression analysis and the log-rank test. The 1-year overall survival (OS) rates of patients younger than 40 years of age was higher compared to those in patients older than 40 years of age. The 1-year OS rate of patients who underwent total resection was higher than that of patients whose gliomas were not completely resected. The 1-year OS rates of patients undergoing chemotherapy and of patients who did not undergo chemotherapy were 39.90% and 26.80%, respectively. Univariate analyses showed that ACYP2 rs12615793 and TERT rs2853676 loci affected progression-free survival in glioma patients; both ZNF208 rs8105767 and ACYP2 rs843720 affected the OS of patients with low-grade gliomas. Multivariate analyses suggested that MPHOSPH6 rs1056629 and rs1056654, and TERT rs2853676 loci were associated with good prognoses of patients with glioma or high-grade gliomas, whereas ZNF208 rs8105767 was associated with good prognosis of patients with low-grade glioma. Age, surgical resection and chemotherapy influenced the survival rates of glioma patients. TERT, MPHOSPH6, ACYP2 and ZNF208 genes were found to affect glioma prognosis. Copyright © 2017 John Wiley & Sons, Ltd.

Hydroxyapatite nanoparticles inhibit the growth of human glioma cells in vitro and in vivo

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Chu SH

2012-07-01

Full Text Available Sheng-Hua Chu,1 Dong-Fu Feng,1 Yan-Bin Ma,1 Zhi-Qiang Li21Department of Neurosurgery, No 3 People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; 2Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, ChinaAbstract: Hydroxyapatite nanoparticles (nano-HAPs have been reported to exhibit antitumor effects on various human cancers, but the effects of nano-HAPs on human glioma cells remain unclear. The aim of this study was to explore the inhibitory effect of nano-HAPs on the growth of human glioma U251 and SHG44 cells in vitro and in vivo. Nano-HAPs could inhibit the growth of U251 and SHG44 cells in a dose- and time-dependent manner, according to methyl thiazoletetrazolium assay and flow cytometry. Treated with 120 mg/L and 240 mg/L nano-HAPs for 48 hours, typical apoptotic morphological changes were noted under Hoechst staining and transmission electron microscopy. The tumor growth of cells was inhibited after the injection in vivo, and the related side effects significantly decreased in the nano-HAP-and-drug combination group. Because of the function of nano-HAPs, the expression of c-Met, SATB1, Ki-67, and bcl-2 protein decreased, and the expression of SLC22A18 and caspase-3 protein decreased noticeably. The findings indicate that nano-HAPs have an evident inhibitory action and induce apoptosis of human glioma cells in vitro and in vivo. In a drug combination, they can significantly reduce the adverse reaction related to the chemotherapeutic drug 1,3-bis(2-chloroethyl-1-nitrosourea (BCNU.Keywords: glioma, hydroxyapatite nanoparticles, growth mechanism

Glioma Association and Balancing Selection of ZFPM2.

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Shui-Ying Tsang

Full Text Available ZFPM2, encoding a zinc finger protein and abundantly expressed in the brain, uterus and smooth muscles, plays important roles in cardiac and gonadal development. Abnormal expression of ZFPM2 in ovarian tumors and neuroblastoma has been reported but hitherto its genetic association with cancer and effects on gliomas have not been studied. In the present study, the hexamer insertion-deletion polymorphism rs71305152, located within a large haplotype block spanning intron 1 to intron 3 of ZFPM2, was genotyped in Chinese cohorts of glioma (n = 350, non-glioma cancer (n = 354 and healthy control (n = 463 by direct sequencing and length polymorphism in gel electrophoresis, and ZFPM2 expression in glioma tissues (n = 69 of different grades was quantified by real-time RT-PCR. Moreover, potential natural selection pressure acting on the gene was investigated. Disease-association analysis showed that the overall genotype of rs71305152 was significantly associated with gliomas (P = 0.016, and the heterozygous genotype compared to the combined homozygous genotypes was less frequent in gliomas than in controls (P = 0.005 or non-glioma cancers (P = 0.020. ZFPM2 mRNA expression was negatively correlated with the grades of gliomas (P = 0.002, with higher expression levels in the low-grade gliomas. In the astrocytoma subtype, higher ZFPM2 expression was also correlated with the rs71305152 heterozygous genotype (P = 0.028. In addition, summary statistics tests gave highly positive values, demonstrating that the gene is under the influence of balancing selection. These findings suggest that ZFPM2 is a glioma susceptibility gene, its genotype and expression showing associations with incidence and severity, respectively. Moreover, the balancing selection acting on ZFPM2 may be related to the important roles it has to play in multiple organ development or associated disease etiology.

Alteration of long-distance functional connectivity and network topology in patients with supratentorial gliomas

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Park, Ji Eun; Kim, Ho Sung; Kim, Sang Joon; Shim, Woo Hyun [University of Ulsan College of Medicine, Department of Radiology and Research Institute of Radiology, Asan Medical Center, Songpa-Gu, Seoul (Korea, Republic of); Kim, Jeong Hoon [University of Ulsan College of Medicine, Department of Neurosurgery, Asan Medical Center, Seoul (Korea, Republic of)

2016-03-15

The need for information regarding functional alterations in patients with brain gliomas is increasing, but little is known about the functional consequences of focal brain tumors throughout the entire brain. Using resting-state functional MR imaging (rs-fMRI), this study assessed functional connectivity in patients with supratentorial brain gliomas with possible alterations in long-distance connectivity and network topology. Data from 36 patients with supratentorial brain gliomas and 12 healthy subjects were acquired using rs-fMRI. The functional connectivity matrix (FCM) was created using 32 pairs of cortical seeds on Talairach coordinates in each individual subject. Local and distant connectivity were calculated using z-scores in the individual patient's FCM, and the averaged FCM of patients was compared with that of healthy subjects. Weighted network analysis was performed by calculating local efficiency, global efficiency, clustering coefficient, and small-world topology, and compared between patients and healthy controls. When comparing the averaged FCM of patients with that of healthy controls, the patients showed decreased long-distance, inter-hemispheric connectivity (0.32 ± 0.16 in patients vs. 0. 42 ± 0.15 in healthy controls, p = 0.04). In network analysis, patients showed increased local efficiency (p < 0.05), but global efficiency, clustering coefficient, and small-world topology were relatively preserved compared to healthy subjects. Patients with supratentorial brain gliomas showed decreased long-distance connectivity while increased local efficiency and preserved small-world topology. The results of this small case series may provide a better understanding of the alterations of functional connectivity in patients with brain gliomas across the whole brain scale. (orig.)

Retrospective analysis of 104 histologically proven adult brainstem gliomas: clinical symptoms, therapeutic approaches and prognostic factors

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Reithmeier, Thomas; Kuzeawu, Aanyo; Hentschel, Bettina; Loeffler, Markus; Trippel, Michael; Nikkhah, Guido

2014-01-01

Adult brainstem gliomas are rare primary brain tumors (<2% of gliomas). The goal of this study was to analyze clinical, prognostic and therapeutic factors in a large series of histologically proven brainstem gliomas. Between 1997 and 2007, 104 patients with a histologically proven brainstem glioma were retrospectively analyzed. Data about clinical course of disease, neuropathological findings and therapeutic approaches were analyzed. The median age at diagnosis was 41 years (range 18-89 years), median KPS before any operative procedure was 80 (range 20-100) and median survival for the whole cohort was 18.8 months. Histopathological examinations revealed 16 grade I, 31 grade II, 42 grade III and 14 grade IV gliomas. Grading was not possible in 1 patient. Therapeutic concepts differed according to the histopathology of the disease. Median overall survival for grade II tumors was 26.4 months, for grade III tumors 12.9 months and for grade IV tumors 9.8 months. On multivariate analysis the relative risk to die increased with a KPS ≤ 70 by factor 6.7, with grade III/IV gliomas by the factor 1.8 and for age ≥ 40 by the factor 1.7. External beam radiation reduced the risk to die by factor 0.4. Adult brainstem gliomas present with a wide variety of neurological symptoms and postoperative radiation remains the cornerstone of therapy with no proven benefit of adding chemotherapy. Low KPS, age ≥ 40 and higher tumor grade have a negative impact on overall survival

Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies

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Williams, J.A.; Wessels, B.W.; Wharam, M.D.; Order, S.E.; Wanek, P.M.; Poggenburg, J.K.; Klein, J.L.

1990-01-01

Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal and polyclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein, and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. 111In-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCuries (microCi) of tumor activity per gram per 100 microCi injected activity compared to 4.5 microCi following administration of radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The proportion of tumor dose found in normal organs is less than 10%, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, and polyclonal rabbit antiferritin, which defines a tumor-associated antigen, demonstrate positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. When compared to the 111In-radiolabeled antibody, 90Y-radiolabeled P96.5 demonstrates comparable tumor targeting and percentages of tumor dose found in normal organs. To test the therapeutic potential of 90Y-radiolabeled P96.5, tumors and normal sites were implanted with miniature thermoluminescent dosimeters (TLD). Seven days following administration of 100 microCi 90Y-radiolabeled P96.5, average absorbed doses of 3770, 980, 353, and 274 cGy were observed in tumor, liver, contralateral control site, and total body, respectively

Characterization of PD-1 upregulation on tumor-infiltrating lymphocytes in human and murine gliomas and preclinical therapeutic blockade.

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Dejaegher, Joost; Verschuere, Tina; Vercalsteren, Ellen; Boon, Louis; Cremer, Jonathan; Sciot, Raf; Van Gool, Stefaan W; De Vleeschouwer, Steven

2017-11-01

Blockade of the immune checkpoint molecule programmed-cell-death-protein-1 (PD-1) yielded promising results in several cancers. To understand the therapeutic potential in human gliomas, quantitative data describing the expression of PD-1 are essential. Moreover, due the immune-specialized region of the brain in which gliomas arise, differences between tumor-infiltrating and circulating lymphocytes should be acknowledged. In this study we have used flow cytometry to quantify PD-1 expression on tumor-infiltrating T cells of 25 freshly resected glioma cell suspensions (10 newly and 5 relapsed glioblastoma, 10 lower grade gliomas) and simultaneously isolated circulating T cells. A strong upregulation of PD-1 expression in the tumor microenvironment compared to the blood circulation was seen in all glioma patients. Additionally, circulating T cells were isolated from 15 age-matched healthy volunteers, but no differences in PD-1 expression were found compared to glioma patients. In the murine GL261 malignant glioma model, there was a similar upregulation of PD-1 on brain-infiltrating lymphocytes. Using a monoclonal PD-1 blocking antibody, we found a marked prolonged survival with 55% of mice reaching long-term survival. Analysis of brain-infiltrating cells 21 days after GL261 tumor implantation showed a shift in infiltrating lymphocyte subgroups with increased CD8+ T cells and decreased regulatory T cells. Together, our results suggest an important role of PD-1 in glioma-induced immune escape, and provide translational evidence for the use of PD-1 blocking antibodies in human malignant gliomas. © 2017 UICC.

Retinoids in the treatment of glioma: a new perspective

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Mawson AR

2012-08-01

Full Text Available Anthony R MawsonDepartment of Health Policy and Management, School of Health Sciences, College of Public Service, Jackson State University, Jackson, MS, USAAbstract: Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α(RARα and reduced expression of retinoic acid receptor-β (RARβ. This suggests a potential new treatment strategy for gliomas, possibly even at a

D-amino acid oxidase gene therapy sensitizes glioma cells to the antiglycolytic effect of 3-bromopyruvate.

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El Sayed, S M; Abou El-Magd, R M; Shishido, Y; Chung, S P; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

2012-01-01

Glioma tumors are refractory to conventional treatment. Glioblastoma multiforme is the most aggressive type of primary brain tumors in humans. In this study, we introduce oxidative stress-energy depletion (OSED) therapy as a new suggested treatment for glioblastoma. OSED utilizes D-amino acid oxidase (DAO), which is a promising therapeutic protein that induces oxidative stress and apoptosis through generating hydrogen peroxide (H2O2). OSED combines DAO with 3-bromopyruvate (3BP), a hexokinase II (HK II) inhibitor that interferes with Warburg effect, a metabolic alteration of most tumor cells that is characterized by enhanced aerobic glycolysis. Our data revealed that 3BP induced depletion of energetic capabilities of glioma cells. 3BP induced H2O2 production as a novel mechanism of its action. C6 glioma transfected with DAO and treated with D-serine together with 3BP-sensitized glioma cells to 3BP and decreased markedly proliferation, clonogenic power and viability in a three-dimensional tumor model with lesser effect on normal astrocytes. DAO gene therapy using atelocollagen as an in vivo transfection agent proved effective in a glioma tumor model in Sprague-Dawley (SD) rats, especially after combination with 3BP. OSED treatment was safe and tolerable in SD rats. OSED therapy may be a promising therapeutic modality for glioma.

Study of apoptosis and Caspase-3, Fas expression in rat glioma after treatment with gamma knife

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Zhao Qingqiu; Zhao Wenqing; Yue Xiangyong; Du Yali; Dong Liying; Zhou Lixia

2003-01-01

Objective: To investigate the apoptosis and Caspase-3, Fas expression in rat glioma after treatment with gamma knife. Methods: Setting up C6 glioma model with 60 rats, which were divided into a treatment group ( n= 30) and a control group (n=30). On the 14 th day after planting glioma cells, rats of the treatment group were subjected to gamma knife irradiation. At the 12 th hr, 24 th hr, 48 th hr, 7 th day, 14 th day, 21 st day, flow cytometry was performed to estimate the glioma cells' apoptosis and the expression of Caspase-3 and Fas. The relation between apoptosis and the two kinds of proteins was analysed. Results: Compared with the control group, the apoptosis rate of the glioma cells in the treatment group increased obviously (P th hr reached its peak, then decreased gradually. The expression of Caspase-3 and Fas was positively correlated with apoptosis (r 1 =0.928, r 2 =0.916). Conclusion: The apoptosis of the tumor cells is a kind of effect of gamma knife treatment. Caspase-3 and Fas gene may take part in the regulation of apoptosis

Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity

International Nuclear Information System (INIS)

Roy, Kanaklata; Wang, Lilin; Makrigiorgos, G. Mike; Price, Brendan D.

2006-01-01

Glioblastomas are among the malignancies most resistant to radiation therapy. In contrast, cells lacking the ATM protein are highly sensitive to ionizing radiation. The relationship between ATM protein expression and radiosensitivity in 3 glioma cell lines was examined. T98G cells exhibited normal levels of ATM protein, whereas U118 and U87 cells had significantly lower levels of ATM and increased (>2-fold) sensitivity to ionizing radiation compared to T98G cells. The ATM promoter was methylated in U87 cells. Demethylation by azacytidine treatment increased ATM protein levels in the U87 cells and decreased their radiosensitivity. In contrast, the ATM promoter in U118 cells was not methylated. Further, expression of exogenous ATM did not significantly alter the radiosensitivity of U118 cells. ATM expression is therefore heterogeneous in the glioma cells examined. In conclusion, methylation of the ATM promoter may account for the variable radiosensitivity and heterogeneous ATM expression in a fraction of glioma cells

Detection of radiation brain injury of malignant glioma by 1H-MRS

International Nuclear Information System (INIS)

Zhang Mao; Jin Haiguo; Sun Shuquan; Bu Mingwei; Su Qingxiu; Liu Guigang; Sun Baosheng

2011-01-01

Objective: Using proton magnetic resonance spectroscopy ( 1 H-MRS) method, to evaluate the difference of radiation brain injury between volumetric modulated arc therapy (VMAT) and three-dimensional conformal radiation therapy (3DCRT) in patients with postoperative glioma after radiation therapy. Methods: 24 patients with malignant glioma (WHOII-IV grade glioma) confirmed with clinical surgery were selected, among them 12 patients were treated with VMAT technique, and another 12 patients with 3DCRT technique, all received DT60-66GY/30-33F dose prescriptions. 1 H-MRS examination was performed to analyze the change of metabolites in the brain tissues of region of interest (ROI) before and after radiotherapy,and the ratios of NAA/ Cr, Cho / Cr, NAA / Cho were computed. Results: The dose distribution of VMAT group was superior to 3DCRT group, the NAA/Cr in two groups after radiation were decreased compared with before radiation, there was a statistically difference in NAA/Cr after radiation between two groups (P<0.01). The Cho / Cr and NAA / Cho in two groups were increased compared with before radiation;after radiation, only NAA/Cho had a statistical difference between two groups (P<0.01). Conclusion: VMAT technique is superior to 3DCTR to reduce radiation brain injury in patients with postoperative glioma. (authors)

Malignant gliomas of the brain managed by radiotherapy after surgery

Energy Technology Data Exchange (ETDEWEB)

Fichardt, T.; Sandison, A.G. (Pretoria Univ. (South Africa). Dept. of Radiotherapy)

The article reviews the literature and gives an account of the authors' experience during a 20-year period (1960-1980) of the value of radiotherapy after surgery in the management of 76 patients suffering from brain gliomas classified into 3 grades according to the degree of anaplasia present in the histological sections, viz. grades II, III and IV. Radiotherapy was not given to grade I malignant gliomas as they are treated by surgery only. The period is divided into 2 subperiods. The first is from 1960-1972 when part-brain, high-dose irradiation following surgery was used on 33 patients in various age groups. The second period covers whole-brain, low-dose irradiation following surgery and was used on 43 patients in various age groups.

Triacetin-based acetate supplementation as a chemotherapeutic adjuvant therapy in glioma.

Science.gov (United States)

Tsen, Andrew R; Long, Patrick M; Driscoll, Heather E; Davies, Matthew T; Teasdale, Benjamin A; Penar, Paul L; Pendlebury, William W; Spees, Jeffrey L; Lawler, Sean E; Viapiano, Mariano S; Jaworski, Diane M

2014-03-15

Cancer is associated with epigenetic (i.e., histone hypoacetylation) and metabolic (i.e., aerobic glycolysis) alterations. Levels of N-acetyl-L-aspartate (NAA), the primary storage form of acetate in the brain, and aspartoacylase (ASPA), the enzyme responsible for NAA catalysis to generate acetate, are reduced in glioma; yet, few studies have investigated acetate as a potential therapeutic agent. This preclinical study sought to test the efficacy of the food additive Triacetin (glyceryl triacetate, GTA) as a novel therapy to increase acetate bioavailability in glioma cells. The growth-inhibitory effects of GTA, compared to the histone deacetylase inhibitor Vorinostat (SAHA), were assessed in established human glioma cell lines (HOG and Hs683 oligodendroglioma, U87 and U251 glioblastoma) and primary tumor-derived glioma stem-like cells (GSCs), relative to an oligodendrocyte progenitor line (Oli-Neu), normal astrocytes, and neural stem cells (NSCs) in vitro. GTA was also tested as a chemotherapeutic adjuvant with temozolomide (TMZ) in orthotopically grafted GSCs. GTA-induced cytostatic growth arrest in vitro comparable to Vorinostat, but, unlike Vorinostat, GTA did not alter astrocyte growth and promoted NSC expansion. GTA alone increased survival of mice engrafted with glioblastoma GSCs and potentiated TMZ to extend survival longer than TMZ alone. GTA was most effective on GSCs with a mesenchymal cell phenotype. Given that GTA has been chronically administered safely to infants with Canavan disease, a leukodystrophy due to ASPA mutation, GTA-mediated acetate supplementation may provide a novel, safe chemotherapeutic adjuvant to reduce the growth of glioma tumors, most notably the more rapidly proliferating, glycolytic and hypoacetylated mesenchymal glioma tumors. © 2013 UICC.

MicroRNA-mediated down-regulation of NKG2D ligands contributes to glioma immune escape.

Science.gov (United States)

Codo, Paula; Weller, Michael; Meister, Gunter; Szabo, Emese; Steinle, Alexander; Wolter, Marietta; Reifenberger, Guido; Roth, Patrick

2014-09-15

Malignant gliomas are intrinsic brain tumors with a dismal prognosis. They are well-adapted to hypoxic conditions and poorly immunogenic. NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DL). Here we evaluated the impact of miRNA on the expression of NKG2DL in glioma cells including stem-like glioma cells. Three of the candidate miRNA predicted to target NKG2DL were expressed in various glioma cell lines as well as in glioblastomas in vivo: miR-20a, miR-93 and miR-106b. LNA inhibitor-mediated miRNA silencing up-regulated cell surface NKG2DL expression, which translated into increased susceptibility to NK cell-mediated lysis. This effect was reversed by neutralizing NKG2D antibodies, confirming that enhanced lysis upon miRNA silencing was mediated through the NKG2D system. Hypoxia, a hallmark of glioblastomas in vivo, down-regulated the expression of NKG2DL on glioma cells, associated with reduced susceptibility to NK cell-mediated lysis. This process, however, was not mediated through any of the examined miRNA. Accordingly, both hypoxia and the expression of miRNA targeting NKG2DL may contribute to the immune evasion of glioma cells at the level of the NKG2D recognition pathway. Targeting miRNA may therefore represent a novel approach to increase the immunogenicity of glioblastoma.

Microglia immunophenotyping in gliomas

Science.gov (United States)

Annovazzi, Laura; Mellai, Marta; Bovio, Enrica; Mazzetti, Samanta; Pollo, Bianca; Schiffer, Davide

2018-01-01

Microglia, once assimilated to peripheral macrophages, in gliomas has long been discussed and currently it is hypothesized to play a pro-tumor role in tumor progression. Uncertain between M1 and M2 polarization, it exchanges signals with glioma cells to create an immunosuppressive microenvironment and stimulates cell proliferation and migration. Four antibodies are currently used for microglia/macrophage identification in tissues that exhibit different cell forms and cell localization. The aim of the present work was to describe the distribution of the different cell forms and to deduce their significance on the basis of what is known on their function from the literature. Normal resting microglia, reactive microglia, intermediate and bumpy forms and macrophage-like cells can be distinguished by Iba1, CD68, CD16 and CD163 and further categorized by CD11b, CD45, c-MAF and CD98. The number of microglia/macrophages strongly increased from normal cortex and white matter to infiltrating and solid tumors. The ramified microglia accumulated in infiltration areas of both high- and low-grade gliomas, when hypertrophy and hyperplasia occur. In solid tumors, intermediate and bumpy forms prevailed and there is a large increase of macrophage-like cells in glioblastoma. The total number of microglia cells did not vary among the three grades of malignancy, but macrophage-like cells definitely prevailed in high-grade gliomas and frequently expressed CD45 and c-MAF. CD98+ cells were present. Microglia favors tumor progression, but many aspects suggest that the phagocytosing function is maintained. CD98+ cells can be the product of fusion, but also of phagocytosis. Microglia correlated with poorer survival in glioblastoma, when considering CD163+ cells, whereas it did not change prognosis in isocitrate dehydrogenase-mutant low grade gliomas. PMID:29399160

Histone deacetylase inhibitor, 2-propylpentanoic acid, increases the chemosensitivity and radiosensitivity of human glioma cell lines in vitro

Institute of Scientific and Technical Information of China (English)

SHAO Cui-jie; WU Ming-wei; CHEN Fu-rong; LI Cong; XIA Yun-fei; CHEN Zhong-ping

2012-01-01

Background Treatment for malignant glioma generally consists of cytoreductive surgery followed by radiotherapy and chemotherapy.In this study,we intended to investigate the effects of 2-propylpentanoic acid (VPA),a histone deacetylase inhibitor,on chemosensitivity and radiosensitivity in human glioma cell lines.Methods Human glioma cell lines,T98-G,and SF295,were treated with temozolomide (TMZ) or irradiation (IR),with or without VPA (1.0 mmol/L).Then,cytotoxicity and clonogenic survival assay was performed.Cell cycle stage,apoptosis,and autophagy were also detected using flow cytometry and dansyl monocadaverin (MDC) incorporation assay.One-way analysis of variance (ANOVA) and t-test were used to analyze the differences among variant groups.Results Mild cytotoxicity of VPA was revealed in both cell lines,T98-G and SF295,with the 50％ inhibiting concentration (IC50) value of (3.85±0.58) mmol/L and (2.15±0.38) mmol/L,respectively; while the IC50 value of TMZ was (0.20±0.09) mmol/L for T98-G and (0.08±0.02) mmol/L for SF295.Moreover,if combined with VPA (1.0 mmol/L) for 96hours,the sensitivity of glioma cells to TMZ was significant increased (P ＜0.05).The surviving fractions at 2 Gy (SF2) of T98-G and SF295 cells exposed to IR alone were 0.52 and 0.58.However,when VPA was combined with IR,the SF2 of T98-G and SF295 dropped to 0.39 (P=0.047) and 0.49 (P=-0.049),respectively.Treatment with VPA plus TMZ or IR also resulted in a significant decrease in the proportion of cells in the G2 phase and increased apoptotic rates as well as autophagy in T98-G and SF295 cell lines (P ＜0.01).Conclusion VPA may enhance the activities of TMZ and IR on glioma cells possibly through cell cycle block and promote autophagy,and thus could be a potential sensitizer of glioma treatment.

Childhood Brain Stem Glioma Treatment (PDQ®)—Health Professional Version

Science.gov (United States)

Childhood brain stem glioma presents as a diffuse intrinsic pontine glioma (DIPG; a fast-growing tumor that is difficult to treat and has a poor prognosis) or a focal glioma (grows more slowly, is easier to treat, and has a better prognosis). Learn about the diagnosis, cellular classification, staging, treatment, and clinical trials for pediatric brain stem glioma in this expert-reviewed summary.

Activation of glioma cells generates immune tolerant NKT cells.

Science.gov (United States)

Tang, Bo; Wu, Wei; Wei, Xiaowei; Li, Yang; Ren, Gang; Fan, Wenhai

2014-12-12

Therapeutic outcomes of glioma are currently not encouraging. Tumor tolerance plays an important role in the pathogenesis of glioma. It is reported that micro RNAs (miR) are associated with tumor development. This study aims to investigate the role of miR-92a in the development of tolerant natural killer T (NKT) cells. In this study, U87 cells (a human glioma cell line) and primary glioma cells were prepared. The assessment of miR-92a was performed by real time RT-PCR. The expression of interleukin (IL)-10 and IL-6 in NKT cells was evaluated by flow cytometry. Results showed that abundant IL-6(+) IL-10(+) NKT cells were detected in glioma tissue. Cultures of glioma cells and NKT cells induced the expression of IL-6 and IL-10 in NKT cells. Glioma cells expressed miR-92a; the latter played a critical role in the induction of IL-6 and IL-10 expression in NKT cells. The expression of the antitumor molecules, including perforin, Fas ligand, and interferon-γ, was significantly attenuated compared with control NKT cells. The IL-6(+) IL-10(+) NKT cells showed less capability in the induction of apoptosis in glioma cells, but showed the immune suppressor functions on CD8(+) T cell activities. We conclude that glioma-derived miR-92a induces IL-6(+) IL-10(+) NKT cells; this fraction of NKT cells can suppress cytotoxic CD8(+) T cells. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Paediatric and adult malignant glioma

DEFF Research Database (Denmark)

Jones, Chris; Perryman, Lara; Hargrave, Darren

2012-01-01

Gliomas in children differ from their adult counterparts by their distribution of histological grade, site of presentation and rate of malignant transformation. Although rare in the paediatric population, patients with high-grade gliomas have, for the most part, a comparably dismal clinical outcome...... to older patients with morphologically similar lesions. Molecular profiling data have begun to reveal the major genetic alterations underpinning these malignant tumours in children. Indeed, the accumulation of large datasets on adult high-grade glioma has revealed key biological differences between...... the adult and paediatric disease. Furthermore, subclassifications within the childhood age group can be made depending on age at diagnosis and tumour site. However, challenges remain on how to reconcile clinical data from adult patients to tailor novel treatment strategies specifically for paediatric...

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Science.gov (United States)

Brat, Daniel J; Verhaak, Roel G W; Aldape, Kenneth D; Yung, W K Alfred; Salama, Sofie R; Cooper, Lee A D; Rheinbay, Esther; Miller, C Ryan; Vitucci, Mark; Morozova, Olena; Robertson, A Gordon; Noushmehr, Houtan; Laird, Peter W; Cherniack, Andrew D; Akbani, Rehan; Huse, Jason T; Ciriello, Giovanni; Poisson, Laila M; Barnholtz-Sloan, Jill S; Berger, Mitchel S; Brennan, Cameron; Colen, Rivka R; Colman, Howard; Flanders, Adam E; Giannini, Caterina; Grifford, Mia; Iavarone, Antonio; Jain, Rajan; Joseph, Isaac; Kim, Jaegil; Kasaian, Katayoon; Mikkelsen, Tom; Murray, Bradley A; O'Neill, Brian Patrick; Pachter, Lior; Parsons, Donald W; Sougnez, Carrie; Sulman, Erik P; Vandenberg, Scott R; Van Meir, Erwin G; von Deimling, Andreas; Zhang, Hailei; Crain, Daniel; Lau, Kevin; Mallery, David; Morris, Scott; Paulauskis, Joseph; Penny, Robert; Shelton, Troy; Sherman, Mark; Yena, Peggy; Black, Aaron; Bowen, Jay; Dicostanzo, Katie; Gastier-Foster, Julie; Leraas, Kristen M; Lichtenberg, Tara M; Pierson, Christopher R; Ramirez, Nilsa C; Taylor, Cynthia; Weaver, Stephanie; Wise, Lisa; Zmuda, Erik; Davidsen, Tanja; Demchok, John A; Eley, Greg; Ferguson, Martin L; Hutter, Carolyn M; Mills Shaw, Kenna R; Ozenberger, Bradley A; Sheth, Margi; Sofia, Heidi J; Tarnuzzer, Roy; Wang, Zhining; Yang, Liming; Zenklusen, Jean Claude; Ayala, Brenda; Baboud, Julien; Chudamani, Sudha; Jensen, Mark A; Liu, Jia; Pihl, Todd; Raman, Rohini; Wan, Yunhu; Wu, Ye; Ally, Adrian; Auman, J Todd; Balasundaram, Miruna; Balu, Saianand; Baylin, Stephen B; Beroukhim, Rameen; Bootwalla, Moiz S; Bowlby, Reanne; Bristow, Christopher A; Brooks, Denise; Butterfield, Yaron; Carlsen, Rebecca; Carter, Scott; Chin, Lynda; Chu, Andy; Chuah, Eric; Cibulskis, Kristian; Clarke, Amanda; Coetzee, Simon G; Dhalla, Noreen; Fennell, Tim; Fisher, Sheila; Gabriel, Stacey; Getz, Gad; Gibbs, Richard; Guin, Ranabir; Hadjipanayis, Angela; Hayes, D Neil; Hinoue, Toshinori; Hoadley, Katherine; Holt, Robert A; Hoyle, Alan P; Jefferys, Stuart R; Jones, Steven; Jones, Corbin D; Kucherlapati, Raju; Lai, Phillip H; Lander, Eric; Lee, Semin; Lichtenstein, Lee; Ma, Yussanne; Maglinte, Dennis T; Mahadeshwar, Harshad S; Marra, Marco A; Mayo, Michael; Meng, Shaowu; Meyerson, Matthew L; Mieczkowski, Piotr A; Moore, Richard A; Mose, Lisle E; Mungall, Andrew J; Pantazi, Angeliki; Parfenov, Michael; Park, Peter J; Parker, Joel S; Perou, Charles M; Protopopov, Alexei; Ren, Xiaojia; Roach, Jeffrey; Sabedot, Thaís S; Schein, Jacqueline; Schumacher, Steven E; Seidman, Jonathan G; Seth, Sahil; Shen, Hui; Simons, Janae V; Sipahimalani, Payal; Soloway, Matthew G; Song, Xingzhi; Sun, Huandong; Tabak, Barbara; Tam, Angela; Tan, Donghui; Tang, Jiabin; Thiessen, Nina; Triche, Timothy; Van Den Berg, David J; Veluvolu, Umadevi; Waring, Scot; Weisenberger, Daniel J; Wilkerson, Matthew D; Wong, Tina; Wu, Junyuan; Xi, Liu; Xu, Andrew W; Yang, Lixing; Zack, Travis I; Zhang, Jianhua; Aksoy, B Arman; Arachchi, Harindra; Benz, Chris; Bernard, Brady; Carlin, Daniel; Cho, Juok; DiCara, Daniel; Frazer, Scott; Fuller, Gregory N; Gao, JianJiong; Gehlenborg, Nils; Haussler, David; Heiman, David I; Iype, Lisa; Jacobsen, Anders; Ju, Zhenlin; Katzman, Sol; Kim, Hoon; Knijnenburg, Theo; Kreisberg, Richard Bailey; Lawrence, Michael S; Lee, William; Leinonen, Kalle; Lin, Pei; Ling, Shiyun; Liu, Wenbin; Liu, Yingchun; Liu, Yuexin; Lu, Yiling; Mills, Gordon; Ng, Sam; Noble, Michael S; Paull, Evan; Rao, Arvind; Reynolds, Sheila; Saksena, Gordon; Sanborn, Zack; Sander, Chris; Schultz, Nikolaus; Senbabaoglu, Yasin; Shen, Ronglai; Shmulevich, Ilya; Sinha, Rileen; Stuart, Josh; Sumer, S Onur; Sun, Yichao; Tasman, Natalie; Taylor, Barry S; Voet, Doug; Weinhold, Nils; Weinstein, John N; Yang, Da; Yoshihara, Kosuke; Zheng, Siyuan; Zhang, Wei; Zou, Lihua; Abel, Ty; Sadeghi, Sara; Cohen, Mark L; Eschbacher, Jenny; Hattab, Eyas M; Raghunathan, Aditya; Schniederjan, Matthew J; Aziz, Dina; Barnett, Gene; Barrett, Wendi; Bigner, Darell D; Boice, Lori; Brewer, Cathy; Calatozzolo, Chiara; Campos, Benito; Carlotti, Carlos Gilberto; Chan, Timothy A; Cuppini, Lucia; Curley, Erin; Cuzzubbo, Stefania; Devine, Karen; DiMeco, Francesco; Duell, Rebecca; Elder, J Bradley; Fehrenbach, Ashley; Finocchiaro, Gaetano; Friedman, William; Fulop, Jordonna; Gardner, Johanna; Hermes, Beth; Herold-Mende, Christel; Jungk, Christine; Kendler, Ady; Lehman, Norman L; Lipp, Eric; Liu, Ouida; Mandt, Randy; McGraw, Mary; Mclendon, Roger; McPherson, Christopher; Neder, Luciano; Nguyen, Phuong; Noss, Ardene; Nunziata, Raffaele; Ostrom, Quinn T; Palmer, Cheryl; Perin, Alessandro; Pollo, Bianca; Potapov, Alexander; Potapova, Olga; Rathmell, W Kimryn; Rotin, Daniil; Scarpace, Lisa; Schilero, Cathy; Senecal, Kelly; Shimmel, Kristen; Shurkhay, Vsevolod; Sifri, Suzanne; Singh, Rosy; Sloan, Andrew E; Smolenski, Kathy; Staugaitis, Susan M; Steele, Ruth; Thorne, Leigh; Tirapelli, Daniela P C; Unterberg, Andreas; Vallurupalli, Mahitha; Wang, Yun; Warnick, Ronald; Williams, Felicia; Wolinsky, Yingli; Bell, Sue; Rosenberg, Mara; Stewart, Chip; Huang, Franklin; Grimsby, Jonna L; Radenbaugh, Amie J; Zhang, Jianan

2015-06-25

Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most

Epstein–Barr Virus in Gliomas: Cause, Association, or Artifact?

Directory of Open Access Journals (Sweden)

Saghir Akhtar

2018-04-01

Full Text Available Gliomas are the most common malignant brain tumors and account for around 60% of all primary central nervous system cancers. Glioblastoma multiforme (GBM is a grade IV glioma associated with a poor outcome despite recent advances in chemotherapy. The etiology of gliomas is unknown, but neurotropic viruses including the Epstein–Barr virus (EBV that is transmitted via salivary and genital fluids have been implicated recently. EBV is a member of the gamma herpes simplex family of DNA viruses that is known to cause infectious mononucleosis (glandular fever and is strongly linked with the oncogenesis of several cancers, including B-cell lymphomas, nasopharyngeal, and gastric carcinomas. The fact that EBV is thought to be the causative agent for primary central nervous system (CNS lymphomas in immune-deficient patients has led to its investigations in other brain tumors including gliomas. Here, we provide a review of the clinical literature pertaining to EBV in gliomas and discuss the possibilities of this virus being simply associative, causative, or even an experimental artifact. We searched the PubMed/MEDLINE databases using the following key words such as: glioma(s, glioblastoma multiforme, brain tumors/cancers, EBV, and neurotropic viruses. Our literature analysis indicates conflicting results on the presence and role of EBV in gliomas. Further comprehensive studies are needed to fully implicate EBV in gliomagenesis and oncomodulation. Understanding the role of EBV and other oncoviruses in the etiology of gliomas, would likely open up new avenues for the treatment and management of these, often fatal, CNS tumors.

The 1p-encoded protein stathmin and resistance of malignant gliomas to nitrosoureas.

Science.gov (United States)

Ngo, Teri-T B; Peng, Tien; Liang, Xing-Jie; Akeju, Oluwaseun; Pastorino, Sandra; Zhang, Wei; Kotliarov, Yuri; Zenklusen, Jean C; Fine, Howard A; Maric, Dragan; Wen, Patrick Y; De Girolami, Umberto; Black, Peter McL; Wu, Wells W; Shen, Rong-Fong; Jeffries, Neal O; Kang, Dong-Won; Park, John K

2007-04-18

Malignant gliomas are generally resistant to all conventional therapies. Notable exceptions are anaplastic oligodendrogliomas with loss of heterozygosity on chromosome 1p (1p+/-). Patients with 1p+/- anaplastic oligodendroglioma frequently respond to procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine. Because the underlying biologic basis for this clinical finding is unclear, we evaluated differentially expressed 1p-encoded proteins in 1p+/- and 1p+/+ malignant glioma cell lines and then examined whether their expression was associated with outcome of patients with anaplastic oligodendroglioma. We used a comparative proteomic screen of A172 (1p+/-) and U251 (1p+/+) malignant glioma cell lines to identify differentially expressed 1p-encoded proteins, including stathmin, a microtubule-associated protein. 1p+/- and 1p+/+ anaplastic oligodendroglioma specimens from 24 patients were assessed for stathmin expression by immunohistochemistry. The relationship between stathmin expression and clinical outcome was assessed with Kaplan-Meier analyses. RNA inhibition and cDNA transfection experiments tested effects of stathmin under- and overexpression, respectively, on the in vitro and in vivo resistance of malignant glioma cells to treatment with nitrosourea. For in vivo resistance studies, 36 mice with intracranial and 16 mice with subcutaneous xenograft tumor implants were used (one tumor per mouse). Flow cytometry was used for cell cycle analysis. Immunoblotting was used to assess protein expression. All statistical tests were two-sided. Decreased stathmin expression in tumors was statistically significantly associated with loss of heterozygosity in 1p (Pnitrosourea-treated mice carrying xenograft tumors. Median survival of mice with stathmin+/- tumors was 95 days (95% CI = 68.7 to 121.3 days) and that of mice with stathmin+/+ tumors was 64 days (95% CI = 58.2 to 69.8 days) (difference = 31 days, 95% CI = 4.1 to 57.9 days; PNitrosoureas induced

Dynamic 18F-FET PET in newly diagnosed astrocytic low-grade glioma identifies high-risk patients.

Science.gov (United States)

Jansen, Nathalie L; Suchorska, Bogdana; Wenter, Vera; Eigenbrod, Sabina; Schmid-Tannwald, Christine; Zwergal, Andreas; Niyazi, Maximilian; Drexler, Mark; Bartenstein, Peter; Schnell, Oliver; Tonn, Jörg-Christian; Thon, Niklas; Kreth, Friedrich-Wilhelm; la Fougère, Christian

2014-02-01

Because the clinical course of low-grade gliomas in the individual adult patient varies considerably and is unpredictable, we investigated the prognostic value of dynamic (18)F-fluorethyltyrosine ((18)F-FET) PET in the early diagnosis of astrocytic low-grade glioma (World Health Organization grade II). Fifty-nine patients with newly diagnosed low-grade glioma and dynamic (18)F-FET PET before histopathologic assessment were retrospectively investigated. (18)F-FET PET analysis comprised a qualitative visual classification of lesions; assessment of the semiquantitative parameters maximal, mean, and total standardized uptake value as ratio to background and biologic tumor volume; and dynamic analysis of intratumoral (18)F-FET uptake over time (increasing vs. decreasing time-activity curves). The correlation between PET parameters and progression-free survival, overall survival, and time to malignant transformation was investigated. (18)F-FET uptake greater than the background level was found in 34 of 59 tumors. Dynamic (18)F-FET uptake analysis was available for 30 of these 34 patients. Increasing and decreasing time-activity curves were found in 18 and 12 patients, respectively. Neither the qualitative factor presence or absence of (18)F-FET uptake nor any of the semiquantitative uptake parameters significantly influenced clinical outcome. In contrast, decreasing time-activity curves in the kinetic analysis were highly prognostic for shorter progression-free survival and time to malignant transformation (P dynamic (18)F-FET PET constitute an unfavorable prognostic factor in astrocytic low-grade glioma and, by identifying high-risk patients, may ease treatment decisions.

Antiangiogenic Therapy and Mechanisms of Tumor Resistance in Malignant Glioma

Directory of Open Access Journals (Sweden)

Ruman Rahman

2010-01-01

Full Text Available Despite advances in surgery, radiation therapy, and chemotherapeutics, patients with malignant glioma have a dismal prognosis. The formations of aberrant tumour vasculature and glioma cell invasion are major obstacles for effective treatment. Angiogenesis is a key event in the progression of malignant gliomas, a process involving endothelial cell proliferation, migration, reorganization of extracellular matrix and tube formation. Such processes are regulated by the homeostatic balance between proangiogenic and antiangiogenic factors, most notably vascular endothelial growth factors (VEGFs produced by glioma cells. Current strategies targeting VEGF-VEGF receptor signal transduction pathways, though effective in normalizing abnormal tumor vasculature, eventually result in tumor resistance whereby a highly infiltrative and invasive phenotype may be adopted. Here we review recent anti-angiogenic therapy for malignant glioma and highlight implantable devices and nano/microparticles as next-generation methods for chemotherapeutic delivery. Intrinsic and adaptive modes of glioma resistance to anti-angiogenic therapy will be discussed with particular focus on the glioma stem cell paradigm.

Hypofractionated stereotactic radiotherapy combined with topotecan in recurrent malignant glioma

International Nuclear Information System (INIS)

Wurm, Reinhard E.; Kuczer, David A.; Schlenger, Lorenz; Matnjani, Gesa; Scheffler, Dirk; Cosgrove, Vivian P.; Ahlswede, Julia; Woiciechowsky, Christian; Budach, Volker

2006-01-01

Purpose: To assess hypofractionated stereotactic radiotherapy (H-SRT) with concurrent topotecan in patients with recurrent malignant glioma. Methods and Materials: Between February 1998 and December 2001, 25 patients with recurrent malignant glioma were treated in a phase I-II study (8 females and 17 males; median age, 45 years; range, 11-66 years; median Karnofsky performance status, 80%, range, 50-100%; median Mini Mental Standard Examination score, 25 points; range, 10-30 points). Of the 25 patients, 20% had World Health Organization Grade III and 80% World Health Organization Grade IV glioma. All patients had been treated previously by external beam radiotherapy with 54.4 Gy in 34 fractions twice daily, at least 6 h apart, within 3.5 weeks or 60 Gy in 30 fractions within 6 weeks. In addition, 84% had already received at least one chemotherapy regimen for recurrence. The median H-SRT dose at the 80% isodose was 25 Gy, and the maximal dose was 30 Gy delivered in five to six fractions on consecutive days. Topotecan (1.1 mg/m 2 /d) was given as a continuous i.v. infusion during H-SRT. Depending on the toxicity and compliance, patients received an additional 48 topotecan courses. Results: For all patients, the actuarial median progression-free survival was 10.5 months (range, 1.4-47.8 months), the median functional survival was 12.6 months (range, 1.6-49.5 months), and the median overall survival was 14.5 months (range, 3-56.4 months). Twelve percent of patients developed presumed adverse radiation effects (Radiation Therapy Oncology Group Grade 2). According to the Common Toxicity Criteria, version 2.0, no topotecan-related Grade 4 toxicity was noted. Grade 3 neutropenia was documented after 14 and Grade 3 thrombopenia after 12 courses. Conclusion: H-SRT with topotecan is feasible and well-tolerated in patients with recurrent high-grade glioma and results in similar survival compared with other repeat treatment modalities

The progress of radiosensitive genes of human brain glioma

International Nuclear Information System (INIS)

Wang Xi; Liu Qiang

2008-01-01

Human gliomas are one of the most aggressive tumors in brain which grow infiltrativly. Surgery is the mainstay of treatment. But as the tumor could not be entirely cut off, it is easy to relapse. Radiotherapy plays an important role for patients with gliomas after surgery. The efficacy of radiotherapy is associated with radio sensitivity of human gliomas. This paper makes a summary of current situation and progress for radiosensitive genes of human brain gliomas. (authors)

Single agent vinorelbine in pediatric patients with progressive optic pathway glioma.

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Cappellano, Andrea Maria; Petrilli, Antonio Sergio; da Silva, Nasjla Saba; Silva, Frederico Adolfo; Paiva, Priscila Mendes; Cavalheiro, Sergio; Bouffet, Eric

2015-01-01

The management of progressive unresectable low-grade glioma remains controversial. Treatment options have included radiotherapy, and more recently chemotherapy, usually following an initial period of observation. Within this context, we evaluated vinorelbine, a semi-synthetic vinca alkaloid that has shown evidence of activity against glioma. From July 2007 an institutional protocol with vinorelbine (30 mg/m(2) days 0, 8, 22) for a total of 18 cycles, has been conducted at IOP/GRAACC/UNIFESP for children with optic pathway glioma (OPG). The main objectives were clinical and radiological response, as well as toxicity profile. Twenty-three patients with progressive OPG with a mean age of 69 months (4-179) were enrolled. Three patients had a diagnosis of neurofibromatosis type 1. Twenty-two patients were assessable for response with an overall objective response rate of 63 %, with eight patients showing stable disease. The most important toxicity was hematologic (grade III/IV neutropenia) observed in four patients. Gastrointestinal toxicity (grade I/II vomiting) was observed in seven patients and only 1 patient showed grade I peripheral neuropathy. The median progression-free survival (PFS) was 33 months (6.9-69) with a 3 and 5 year PFS of 64 ± 19 and 37 ± 20 %, respectively, for an overall 3 and 5 year-survival of 95 ± 10 %. This study suggests that vinorelbine may be an interesting option for pediatric low-grade gliomas, showing low toxicity profile and providing a good quality of life for patients with such chronic disease.

Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma

International Nuclear Information System (INIS)

Combs, Stephanie E.; Welzel, Thomas; Debus, Juergen; Edler, Lutz; Rausch, Renate; Wick, Wolfgang

2013-01-01

Re-irradiation using high-precision radiation techniques has been established within the clinical routine for patients with recurrent gliomas. In the present work, we developed a practical prognostic score to predict survival outcome after re-irradiation. Patients and methods. Fractionated stereotactic radiotherapy (FSRT) was applied in 233 patients. Primary histology included glioblastoma (n = 89; 38%), WHO Grade III gliomas (n = 52; 22%) and low-grade glioma (n = 92; 40%). FSRT was applied with a median dose of 36 Gy in 2 Gy single fractions. We evaluated survival after re-irradiation as well as progression-free survival after re-irradiation; prognostic factors analyzed included age, tumor volume at re-irradiation, histology, time between initial radiotherapy and re-irradiation, age and Karnofsky Performance Score. Results. Median survival after FSRT was 8 months for glioblastoma, 20 months for anaplastic gliomas, and 24 months for recurrent low-grade patients. The strongest prognostic factors significantly impacting survival after re-irradiation were histology (p 12 months (p < 0.0001). We generated a four-class prognostic score to distinguish patients with excellent (0 points), good (1 point), moderate (2 points) and poor (3-4 points) survival after re-irradiation. The difference in outcome was highly significant (p < 0.0001). Conclusion. We generated a practical prognostic score index based on three clinically relevant factors to predict the benefit of patients from re-irradiation. This score index can be helpful in patient counseling, and for the design of further clinical trials. However, individual treatment decisions may include other patient-related factors not directly influencing outcome.

Metabolic remodeling precedes mitochondrial outer membrane permeabilization in human glioma xenograft cells.

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Ponnala, Shivani; Chetty, Chandramu; Veeravalli, Krishna Kumar; Dinh, Dzung H; Klopfenstein, Jeffrey D; Rao, Jasti S

2012-02-01

Glioma cancer cells adapt to changing microenvironment and shift from mitochondrial oxidative phosphorylation to aerobic glycolysis for their metabolic needs irrespective of oxygen availability. In the present study, we show that silencing MMP-9 in combination with uPAR/cathepsin B switch the glycolytic metabolism of glioma cells to oxidative phosphorylation (OXPHOS) and generate reactive oxygen species (ROS) to predispose glioma cells to mitochondrial outer membrane permeabilization. shRNA for MMP-9 and uPAR (pMU) as well as shRNA for MMP-9 and cathepsin B (pMC) activated complexes of mitochondria involved in OXPHOS and inhibited glycolytic hexokinase expression. The decreased interaction of hexokinase 2 with mitochondria in the treated cells indicated the inhibition of glycolysis activation. Overexpression of Akt reversed the pMU- and pMC-mediated OXPHOS to glycolysis switch. The OXPHOS un-coupler oligomycin A altered the expression levels of the Bcl-2 family of proteins; treatment with pMU or pMC reversed this effect and induced mitochondrial outer membrane permeabilization. In addition, our results show changes in mitochondrial pore transition to release cytochrome c due to changes in the VDAC-Bcl-XL and BAX-BAK interaction with pMU and pMC treatments. Taken together, our results suggest that pMU and pMC treatments switch glioma cells from the glycolytic to the OXPHOS pathway through an inhibitory effect on Akt, ROS induction and an increase of cytosolic cytochrome c accumulation. These results demonstrate the potential of pMU and pMC as therapeutic candidates for the treatment of glioma.

Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.

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Zhou, Nan; Yao, Yu; Ye, Hongxing; Zhu, Wei; Chen, Liang; Mao, Ying

2016-04-15

Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. © 2015 UICC.

Molecular and Genetic Determinants of Glioma Cell Invasion

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Kenta Masui

2017-12-01

Full Text Available A diffusely invasive nature is a major obstacle in treating a malignant brain tumor, “diffuse glioma”, which prevents neurooncologists from surgically removing the tumor cells even in combination with chemotherapy and radiation. Recently updated classification of diffuse gliomas based on distinct genetic and epigenetic features has culminated in a multilayered diagnostic approach to combine histologic phenotypes and molecular genotypes in an integrated diagnosis. However, it is still a work in progress to decipher how the genetic aberrations contribute to the aggressive nature of gliomas including their highly invasive capacity. Here we depict a set of recent discoveries involving molecular genetic determinants of the infiltrating nature of glioma cells, especially focusing on genetic mutations in receptor tyrosine kinase pathways and metabolic reprogramming downstream of common cancer mutations. The specific biology of glioma cell invasion provides an opportunity to explore the genotype-phenotype correlation in cancer and develop novel glioma-specific therapeutic strategies for this devastating disease.

Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas

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Peyre, Matthieu; Cartalat-Carel, Stéphanie; Meyronet, David; Ricard, Damien; Jouvet, Anne; Pallud, Johan; Mokhtari, Karima; Guyotat, Jacques; Jouanneau, Emmanuel; Sunyach, Marie-Pierre; Frappaz, Didier; Honnorat, Jérôme; Ducray, François

2010-01-01

Previous studies with temozolomide suggest that a prolonged duration of chemotherapy is important for treating low-grade gliomas (LGGs). PCV (procarbazine, CCNU, vincristine) chemotherapy has demonstrated efficacy in treating LGGs, but this therapy cannot be used for a prolonged period because of the cumulative toxicity. The aim of the present study was to evaluate the impact of first-line PCV chemotherapy on LGGs growth kinetics. The mean tumor diameter (MTD) of 21 LGGs was measured on serial magnetic resonance images before (n=13), during, and after PCV onset (n=21). During PCV treatment, a decrease in the MTD was observed in all patients. After PCV discontinuation, an ongoing decrease in MTD was observed in 20 of the 21 patients. Median duration of the MTD decrease was 3.4 years (range, 0.8–7.7) after PCV onset and 2.7 years (range, 0–7) after the end of PCV treatment with 60% of LGGs, demonstrating an ongoing and prolonged (>2 years) response despite chemotherapy no longer being administered. According to McDonald's criteria, the rates of partial and minor responses were 5% and 38% at the end of PCV but 38% and 42% at the time of maximal MTD decrease, which occurred after a median period of 3.4 years after PCV onset. These results challenge the idea that a prolonged duration of chemotherapy is necessary for treating LGGs and raise the issue of understanding the mechanisms involved in the persistent tumor volume decrease once chemotherapy is terminated. PMID:20488959

MiR-26b Mimic Inhibits Glioma Proliferation In Vitro and In Vivo Suppressing COX-2 Expression.

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Chen, Zheng-Gang; Zheng, Chuan-Yi; Cai, Wang-Qing; Li, Da-Wei; Ye, Fu-Yue; Zhou, Jian; Wu, Ran; Yang, Kun

2017-08-11

Glioma is the most common malignant tumor of the nervous system. Studies have shown the microRNA (miR)-26b/cyclooxygenase (COX)-2 axis in the development and progression in many tumor cells. Our study aims to investigate the effect and mechanism of miR-26b/COX-2 axis in glioma. Decreased expression of miR-26b with increased level of COX-2 was found in glioma tissues compared with matched normal tissues. A strong negative correlation was observed between the level of miR-26b and COX-2 in 30 glioma tissues. The miR-26b was then overexpressed by transfecting miR-26b mimic into U-373 cells. The invasive cell number and wounld closing rate were reduced in U-373 cells transfected with miR-26b mimic. Besides, COX2 siRNA enhanced the effect of miR-26b mimic in suppressing the expression of p-ERK1 and p-JNK. Finally, the in vivo experiment revealed that miR-26b mimic transfection strongly reduced the tumor growth, tumor volume and the expression of matrix metalloproteinase (MMP)-2, MMP-9). Taken together, our research indicated a miR-26b/COX-2/ERK/JNK axis in regulating the motility of glioma in vitro and in vivo, providing a new sight for treatment of glioma.

Terahertz reflectometry imaging for low and high grade gliomas

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Ji, Young Bin; Oh, Seung Jae; Kang, Seok-Gu; Heo, Jung; Kim, Sang-Hoon; Choi, Yuna; Song, Seungri; Son, Hye Young; Kim, Se Hoon; Lee, Ji Hyun; Haam, Seung Joo; Huh, Yong Min; Chang, Jong Hee; Joo, Chulmin; Suh, Jin-Suck

2016-01-01

Gross total resection (GTR) of glioma is critical for improving the survival rate of glioma patients. One of the greatest challenges for achieving GTR is the difficulty in discriminating low grade tumor or peritumor regions that have an intact blood brain barrier (BBB) from normal brain tissues and delineating glioma margins during surgery. Here we present a highly sensitive, label-free terahertz reflectometry imaging (TRI) that overcomes current key limitations for intraoperative detection of World Health Organization (WHO) grade II (low grade), and grade III and IV (high grade) gliomas. We demonstrate that TRI provides tumor discrimination and delineation of tumor margins in brain tissues with high sensitivity on the basis of Hematoxylin and eosin (H&E) stained image. TRI may help neurosurgeons to remove gliomas completely by providing visualization of tumor margins in WHO grade II, III, and IV gliomas without contrast agents, and hence, improve patient outcomes. PMID:27782153

Tricyclic Neovibsanin Scaffold Inhibits Glioma by Targeting Glioma ...

African Journals Online (AJOL)

Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, 300001 Nigeria. ... median survival time of mice bearing glioma to 34 days compared to 22 days in untreated mice. .... CX22 microscope (Olympus Corp, Inc, Tokyo,.

Retinoids in the treatment of glioma: a new perspective.

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Mawson, Anthony R

2012-01-01

Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners) in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α (RARα) and reduced expression of retinoic acid receptor-β (RARβ). This suggests a potential new treatment strategy for gliomas, possibly even at a late stage of the disease, ie, to combine the use of a RARα antagonist and a RARβ agonist. According to this hypothesis, the RARα antagonist would be expected to inhibit RAR�

Retinoids in the treatment of glioma: a new perspective

International Nuclear Information System (INIS)

Mawson, Anthony R

2012-01-01

Primary brain tumors are among the top ten causes of cancer-related deaths in the US. Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors diagnosed in adults each year and are associated with high morbidity and mortality. Despite optimal treatment, the prognosis for patients with gliomas remains poor. The use of retinoids (vitamin A and its congeners) in the treatment of certain tumors was originally based on the assumption that these conditions were associated with an underlying deficiency of vitamin A and that supplementation with pharmacological doses would correct the deficiency. Yet the results of retinoid treatment have been only modestly beneficial and usually short-lived. Studies also indicate that vitamin A excess and supplementation have pro-oxidant effects and are associated with increased risks of mortality from cancer and other diseases. The therapeutic role of vitamin A in cancer thus remains uncertain and a new perspective on the facts is needed. The modest and temporary benefits of retinoid treatment could result from a process of feedback inhibition, whereby exogenous retinoid temporarily inhibits the endogenous synthesis of these compounds. In fact, repeated and/or excessive exposure of the tissues to endogenous retinoic acid may contribute to carcinogenesis. Gliomas, in particular, may result from an imbalance in retinoid receptor expression initiated by environmental factors that increase the endogenous production of retinoic acid in glia. At the receptor level, it is proposed that this imbalance is characterized by excessive expression of retinoic acid receptor-α (RARα) and reduced expression of retinoic acid receptor-β (RARβ). This suggests a potential new treatment strategy for gliomas, possibly even at a late stage of the disease, ie, to combine the use of a RARα antagonist and a RARβ agonist. According to this hypothesis, the RARα antagonist would be expected to inhibit RAR�

Intraoperative Cerebral Glioma Characterization with Contrast Enhanced Ultrasound

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Francesco Prada

2014-01-01

Full Text Available Background. Contrast enhanced ultrasound (CEUS is a dynamic and continuous modality providing real-time view of vascularization and flow distribution patterns of different organs and tumors. Nevertheless its intraoperative use for brain tumors visualization has been performed few times, and a thorough characterization of cerebral glioma had never been performed before. Aim. To perform the first characterization of cerebral glioma using CEUS and to possibly achieve an intraoperative differentiation of different gliomas. Methods. We performed CEUS in an off-label setting in 69 patients undergoing surgery for cerebral glioma. An intraoperative qualitative analysis was performed comparing iCEUS with B-mode imaging. A postprocedural semiquantitative analysis was then performed for each case, according to EFSUMB criteria. Results were related to histopathology. Results. We observed different CE patterns: LGG show a mild, dotted CE with diffuse appearance and slower, delayed arterial and venous phase. HGG have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns. Conclusion. Our study characterizes for the first time human brain glioma with CEUS, providing further insight regarding these tumors’ biology. CEUS is a fast, safe, dynamic, real-time, and economic tool that might be helpful during surgery in differentiating malignant and benign gliomas and refining surgical strategy.

Enhanced replication of attenuated HSV-1 in irradiated human glioma xenografts

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Advani, Sunil J.; Kataoka, Yasushi; Sibley, Greg S.; Song, Paul Y.; Hallahan, Dennis E.; Roizman, Bernard; Weichselbaum, Ralph R.

1997-01-01

Purpose: Previously we had shown that combining ionizing radiation (IR) with attenuated replication competent HSV-1 (R3616) significantly increased glioma xenograft eradication compared to IR or virus alone. One hypothesis is that IR induces cell factors that contribute to augment viral replication thereby increasing the efficacy of attenuated HSV-1. The purpose of this study was to examine if IR altered viral replication of attenuated HSV-1 in glioma xenografts Material and Methods: Human U-87MG glioma cells were grown in the hindlimb of athymic mice and grown to >200 mm 3 . Tumors were infected with 2x10 7 plaque forming units (pfu) of R3616 ( γ1 34.5 - ) or R7020 (multimutated, γ1 34.5 + ) on day 0 and irradiated with 20 Gy on day 1 and 25 Gy on day 2. Tumors were harvested 3, 5, 7, and 14 days after viral injection. Tumors were homogenized and sonnicated. Serial dilutions of tumor extract were overlaid on Vero cells to determine the number of pfu. In addition, in-situ hybridization to HSV-1 DNA was performed on tumors harvested at day 7. Results: In-situ hybridization revealed larger numbers of glial cells infected with HSV along with a greater distribution in the irradiated tumors compared to non-irradiated tumors. We next quantified viral particles in infected tumors +/- IR: Conclusion: Herein we demonstrate radiation enhanced viral replication as one of the interactive effects of combining IR and attenuated HSV in treating glioma xenografts and a potential therapeutic motif in the treatment of gliomas. To reduce normal tissue toxicity of HSV in glioma therapy, viruses must be attenuated. However, attenuating the virus compromises its replication and thus its potential efficacy. Our results indicate that IR augments the amount of virus recovered from human glioma xenografts for up to 3 days post IR. The results do not appear to be related to a specific mutation in the herpes genome but rather to herpes viruses in general. Yields of R7020 were greater than R

Volumetric spiral chemical shift imaging of hyperpolarized [2-(13) c]pyruvate in a rat c6 glioma model.

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Park, Jae Mo; Josan, Sonal; Jang, Taichang; Merchant, Milton; Watkins, Ron; Hurd, Ralph E; Recht, Lawrence D; Mayer, Dirk; Spielman, Daniel M

2016-03-01

MRS of hyperpolarized [2-(13)C]pyruvate can be used to assess multiple metabolic pathways within mitochondria as the (13)C label is not lost with the conversion of pyruvate to acetyl-CoA. This study presents the first MR spectroscopic imaging of hyperpolarized [2-(13)C]pyruvate in glioma-bearing brain. Spiral chemical shift imaging with spectrally undersampling scheme (1042 Hz) and a hard-pulse excitation was exploited to simultaneously image [2-(13)C]pyruvate, [2-(13)C]lactate, and [5-(13)C]glutamate, the metabolites known to be produced in brain after an injection of hyperpolarized [2-(13)C]pyruvate, without chemical shift displacement artifacts. A separate undersampling scheme (890 Hz) was also used to image [1-(13)C]acetyl-carnitine. Healthy and C6 glioma-implanted rat brains were imaged at baseline and after dichloroacetate administration, a drug that modulates pyruvate dehydrogenase kinase activity. The baseline metabolite maps showed higher lactate and lower glutamate in tumor as compared to normal-appearing brain. Dichloroacetate led to an increase in glutamate in both tumor and normal-appearing brain. Dichloroacetate-induced %-decrease of lactate/glutamate was comparable to the lactate/bicarbonate decrease from hyperpolarized [1-(13)C]pyruvate studies. Acetyl-carnitine was observed in the muscle/fat tissue surrounding the brain. Robust volumetric imaging with hyperpolarized [2-(13)C]pyruvate and downstream products was performed in glioma-bearing rat brains, demonstrating changes in mitochondrial metabolism with dichloroacetate. © 2015 Wiley Periodicals, Inc.

EG-13GENOME-WIDE METHYLATION ANALYSIS IDENTIFIES GENOMIC DNA DEMETHYLATION DURING MALIGNANT PROGRESSION OF GLIOMAS

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Saito, Kuniaki; Mukasa, Akitake; Nagae, Genta; Aihara, Koki; Otani, Ryohei; Takayanagi, Shunsaku; Omata, Mayu; Tanaka, Shota; Shibahara, Junji; Takahashi, Miwako; Momose, Toshimitsu; Shimamura, Teppei; Miyano, Satoru; Narita, Yoshitaka; Ueki, Keisuke; Nishikawa, Ryo; Nagane, Motoo; Aburatani, Hiroyuki; Saito, Nobuhito

2014-01-01

Low-grade gliomas often undergo malignant progression, and these transformations are a leading cause of death in patients with low-grade gliomas. However, the molecular mechanisms underlying malignant tumor progression are still not well understood. Recent evidence indicates that epigenetic deregulation is an important cause of gliomagenesis; therefore, we examined the impact of epigenetic changes during malignant progression of low-grade gliomas. Specifically, we used the Illumina Infinium Human Methylation 450K BeadChip to perform genome-wide DNA methylation analysis of 120 gliomas and four normal brains. This study sample included 25 matched-pairs of initial low-grade gliomas and recurrent tumors (temporal heterogeneity) and 20 of the 25 recurring tumors recurred as malignant progressions, and one matched-pair of newly emerging malignant lesions and pre-existing lesions (spatial heterogeneity). Analyses of methylation profiles demonstrated that most low-grade gliomas in our sample (43/51; 84%) had a CpG island methylator phenotype (G-CIMP). Remarkably, approximately 50% of secondary glioblastomas that had progressed from low-grade tumors with the G-CIMP status exhibited a characteristic partial demethylation of genomic DNA during malignant progression, but other recurrent gliomas showed no apparent change in DNA methylation pattern. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands. The information of histone modifications patterns in normal human astrocytes and embryonal stem cells also showed that the ratio of active marks at the site corresponding to DNA demethylated loci in G-CIMP-demethylated tumors was significantly lower; this finding indicated that most demethylated loci in G-CIMP-demethylated tumors were likely transcriptionally inactive. A small number of the genes that were upregulated and had demethylated CpG islands were associated with cell cycle-related pathway. In

The clinical utility of multimodal MR image-guided needle biopsy in cerebral gliomas.

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Yao, Chengjun; Lv, Shunzeng; Chen, Hong; Tang, Weijun; Guo, Jun; Zhuang, Dongxiao; Chrisochoides, Nikos; Wu, Jinsong; Mao, Ying; Zhou, Liangfu

2016-01-01

Our aim was to evaluate the diagnostic value of multimodal Magnetic Resonance (MR) Image in the stereotactic biopsy of cerebral gliomas, and investigate its implications. Twenty-four patients with cerebral gliomas underwent (1)H Magnetic Resonance Spectroscopy ((1)H-MRS)- and intraoperative Magnetic Resonance Imaging (iMRI)-supported stereotactic biopsy, and 23 patients underwent only the preoperative MRI-guided biopsy. The diagnostic yield, morbidity and mortality rates were analyzed. In addition, 20 patients underwent subsequent tumor resection, thus the diagnostic accuracy of the biopsy was further evaluated. The diagnostic accuracies of biopsies evaluated by tumor resection in the trial groups were better than control groups (92.3% and 42.9%, respectively, p = 0.031). The diagnostic yield in the trial groups was better than the control groups, but the difference was not statistically significant (100% and 82.6%, respectively, p = 0.05). The morbidity and mortality rates were similar in both groups. Multimodal MR image-guided glioma biopsy is practical and valuable. This technique can increase the diagnostic accuracy in the stereotactic biopsy of cerebral gliomas. Besides, it is likely to increase the diagnostic yield but requires further validation.

Aldehyde dehydrogenase 1A1 circumscribes high invasive glioma cells and predicts poor prognosis

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Xu, Sen-Lin; Liu, Sha; Cui, Wei; Shi, Yu; Liu, Qin; Duan, Jiang-Jie; Yu, Shi-Cang; Zhang, Xia; Cui, You-Hong; Kung, Hsiang-Fu; Bian, Xiu-Wu

2015-01-01

Glioma is the most aggressive brain tumor with high invasiveness and poor prognosis. More reliable, sensitive and practical biomarkers to reveal glioma high invasiveness remain to be explored for the guidance of therapy. We herein evaluated the diagnostic and prognostic value of aldehyde dehydrogenase 1A1 (ALDH1A1) in the glioma specimens from 237 patients, and found that ADLH1A1 was frequently overexpressed in the high-grade glioma (WHO grade III-IV) as compared to the low-grade glioma (WHO grade I-II) patients. The tumor cells with ALDH1A1 expression were more abundant in the region between tumor and the borderline of adjacent tissue as compared to the central part of the tumor. ALDH1A1 overexpression was associated with poor differentiation and dismal prognosis. Notably, the overall and disease-free survivals of the patients who had ALDH1A1+ tumor cells sparsely located in the adjacent tissue were much worse. Furthermore, ALDH1A1 expression was correlated with the “classical-like” (CL) subtype as we examined GBM specimens from 72 patients. Multivariate Cox regression analysis revealed that ALDH1A1 was an independent marker for glioma patients’ outcome. Mechanistically, both in vitro and in vivo studies revealed that ALDH1A1+ cells isolated from either a glioblastoma cell line U251 or primary glioblastoma cells displayed significant invasiveness, clonogenicity, and proliferation as compared to ALDH1A1- cells, due to increased levels of mRNA and protein for matrix metalloproteinase 2, 7 and 9 (MMP2, MMP7 and MMP9). These results indicate that ALDH1A1+ cells contribute to the progression of glioma including invasion, proliferation and poor prognosis, and suggest that targeting ALDH1A1 may have important implications for the treatment of highly invasive glioma. PMID:26101711

Glioma epidemiology in the central Tunisian population: 1993-2012.

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Trabelsi, Saoussen; Brahim, Dorra H'mida-Ben; Ladib, Mohamed; Mama, Nadia; Harrabi, Imed; Tlili, Kalthoum; Yacoubi, Mohamed Tahar; Krifa, Hedi; Hmissa, Sihem; Saad, Ali; Mokni, Moncef

2014-01-01

Glioma is a heterogeneous central nervous system (CNS) tumor group that encompasses different histological subtypes with high variability in prognosis. The lesions account for almost 80% of primary malignant brain tumors. The aim of this study is to extend our understanding of the glioma epidemiology in the central Tunisian region. We analyzed 393 gliomas recorded in cancer registry of central Tunisia from 1993 to 2012. Crude incidence rates (CR) and world age-standardized rates (ASR) were estimated using annual population data size and age structure. Statistic correlations were established using Chi-square and Kaplan-Meier test. Tunisian glioma patients were identified with a mean age at diagnosis of 48 years and 1.5 sex ratio (male/female). During the 19 years period of study the highest incidence value was observed in male group between 1998 and 2002 (CR: 0.28, ASR: 0.3). Incidence results underline increasing high grade glioma occurring in the adulthood in the last period (2007-2012). Median survival was 27 months, with 1-, 2- and 5-year survival rates of 42%, 30% and 26%, respectively. Survival was greater in patients with younger age, lower tumor grade, infratentrial tumor location and undergoing a palliative treatment. This central Tunisia gliomas registry study provides important information that could improve glioma management and healthcare practice.

The rise and fall of "biopsy and radiate": a history of surgical nihilism in glioma treatment.

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Han, Seunggu J; Sughrue, Michael E

2012-04-01

Many neurosurgeons take a nihilistic approach to surgical treatment of gliomas, stating the inability to achieve a cure. Where this idea comes from is somewhat nebulous to most neurosurgeons. A review of the scientific studies supporting the commonly held beliefs about gliomas shows that these ideas regarding the surgical treatment of gliomas are based on overgeneralizations of data from older studies. One should avoid the temptation to apply them to the greater concept of what gliomas are, how they behave, and what should be done, but rather we should continue to scientifically evaluate the role of surgical resection in glioma treatment. Copyright © 2012 Elsevier Inc. All rights reserved.

Increased betulinic acid induced cytotoxicity and radiosensitivity in glioma cells under hypoxic conditions

International Nuclear Information System (INIS)

Bache, Matthias; Taubert, Helge; Vordermark, Dirk; Zschornak, Martin P; Passin, Sarina; Keßler, Jacqueline; Wichmann, Henri; Kappler, Matthias; Paschke, Reinhard; Kaluđerović, Goran N; Kommera, Harish

2011-01-01

Betulinic acid (BA) is a novel antineoplastic agent under evaluation for tumor therapy. Because of the selective cytotoxic effects of BA in tumor cells (including gliomas), the combination of this agent with conservative therapies (such as radiotherapy and chemotherapy) may be useful. Previously, the combination of BA with irradiation under hypoxic conditions had never been studied. In this study, the effects of 3 to 30 μM BA on cytotoxicity, migration, the protein expression of PARP, survivin and HIF-1α, as well as radiosensitivity under normoxic and hypoxic conditions were analyzed in the human malignant glioma cell lines U251MG and U343MG. Cytotoxicity and radiosensitivity were analyzed with clonogenic survival assays, migration was analyzed with Boyden chamber assays (or scratch assays) and protein expression was examined with Western blot analyses. Under normoxic conditions, a half maximal inhibitory concentration (IC 50 ) of 23 μM was observed in U251MG cells and 24 μM was observed in U343MG cells. Under hypoxic conditions, 10 μM or 15 μM of BA showed a significantly increased cytotoxicity in U251MG cells (p = 0.004 and p = 0.01, respectively) and U343MG cells (p < 0.05 and p = 0.01, respectively). The combination of BA with radiotherapy resulted in an additive effect in the U343MG cell line under normoxic and hypoxic conditions. Weak radiation enhancement was observed in U251MG cell line after treatment with BA under normoxic conditions. Furthermore, under hypoxic conditions, the incubation with BA resulted in increased radiation enhancement. The enhancement factor, at an irradiation dose of 15 Gy after treatment with 10 or 15 μM BA, was 2.20 (p = 0.02) and 4.50 (p = 0.03), respectively. Incubation with BA led to decreased cell migration, cleavage of PARP and decreased expression levels of survivin in both cell lines. Additionally, BA treatment resulted in a reduction of HIF-1α protein under hypoxic conditions. Our results suggest that BA is capable

C-MET overexpression and amplification in gliomas.

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Kwak, Yoonjin; Kim, Seong-Ik; Park, Chul-Kee; Paek, Sun Ha; Lee, Soon-Tae; Park, Sung-Hye

2015-01-01

We investigated c-Met overexpression and MET gene amplification in gliomas to determine their incidence and prognostic significance. c-Met immunohistochemistry and MET gene fluorescence in situ hybridization were carried out on tissue microarrays from 250 patients with gliomas (137 grade IV GBMs and 113 grade II and III diffuse gliomas). Clinicopathological features of these cases were reviewed. c-Met overexpression and MET gene amplification were detected in 13.1% and 5.1% of the GBMs, respectively. All the MET-amplified cases showed c-Met overexpression, but MET amplification was not always concordant with c-Met overexpression. None of grade II and III gliomas demonstrated c-Met overexpression or MET gene amplification. Mean survival of the GBM patients with MET amplification was not significantly different from patients without MET amplification (P=0.155). However, GBM patients with c-Met overexpression survived longer than patients without c-Met overexpression (P=0.035). Although MET amplification was not related to poor GBM prognosis, it is partially associated with the aggressiveness of gliomas, as MET amplification was found only in grade IV, not in grade II and III gliomas. We suggest that MET inhibitor therapy may be beneficial in about 5% GBMs, which was the incidence of MET gene amplification found in the patients included in this study.

Isthmin inhibits glioma growth through antiangiogenesis in vivo.

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Yuan, Bangqing; Xian, Ronghua; Ma, Jianfang; Chen, Yujian; Lin, Chuangan; Song, Yaoming

2012-09-01

Among glioma treatment strategies, antiangiogenesis emerges as a meaningful and feasible treatment approach for inducing long-term survival. Isthmin is a gene highly expressed in the isthmus of the midbrain-hindbrain organizer in Xenopus, and has recently been identified as a novel angiogenesis inhibitor. However, the potential of isthmin on the glioma angiogenesis has not been well studied. In the present study, we demonstrated that the recombinant adenovirus isthmin (Ad-isthmin) could inhibit VEGF-stimulated endothelial cell proliferation and induce apoptosis through a caspase-dependent pathway. In addition, Ad-isthmin significantly suppressed glioma growth through antiangiogenesis without apparent side effects. Taken together, our results demonstrated that isthmin could act as a novel angiogenesis inhibitor and might be utilized in the glioma antiangiogenesis therapy.

Long Non-coding RNA LINC00339 Stimulates Glioma Vasculogenic Mimicry Formation by Regulating the miR-539-5p/TWIST1/MMPs Axis

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Junqing Guo

2018-03-01

Full Text Available Glioma is recognized as a highly angiogenic malignant brain tumor. Vasculogenic mimicry (VM greatly restricts the therapeutic effect of anti-angiogenic tumor therapy for glioma patients. However, the molecular mechanisms of VM formation in glioma remain unclear. Here, we demonstrated that LINC00339 was upregulated in glioma tissue as well as in glioma cell lines. The expression of LINC00339 in glioma tissues was positively correlated with glioma VM formation. Knockdown of LINC00339 inhibited glioma cell proliferation, migration, invasion, and tube formation, meanwhile downregulating the expression of VM-related molecular MMP-2 and MMP-14. Furthermore, knockdown of LINC00339 significantly increased the expression of miR-539-5p. Both bioinformatics and luciferase reporter assay revealed that LINC00339 regulated the above effects via binding to miR-539-5p. Besides, overexpression of miR-539-5p resulted in decreased expression of TWIST1, a transcription factor known to play an oncogenic role in glioma and identified as a direct target of miR-539-5p. TWIST1 upregulated the promoter activities of MMP-2 and MMP-14. The in vivo study showed that nude mice carrying tumors with knockdown of LINC00339 and overexpression of miR-539-5p exhibited the smallest tumor volume through inhibiting VM formation. In conclusion, LINC00339 may be used as a novel therapeutic target for VM formation in glioma.

Glioma in a goat

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Marshall, C.L.; Weinstock, D.; Kramer, R.W.; Bagley, R.S.

1995-01-01

An adult goat was examined because of behavioral changes and circling. Results of neurologic examination, CSF analysis, hematologic evaluation, and computed tomography of the brain were suggestive of an intra-axial mass. The goat was euthanatized because of worsening neurologic condition and poor prognosis. Necropsy revealed a large mass in the right cerebral hemisphere and caudal brain herniation through the foramen magnum. The mass was diagnosed as a glioma, with oligodendrocyte differentiation. Results of immunohistochemical evaluation were compatible with a malignant, poorly differentiated tumor

Forkhead box K2 inhibits the proliferation, migration, and invasion of human glioma cells and predicts a favorable prognosis

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Wang B

2018-02-01

epithelial-to-mesenchymal transition (EMT biomarker levels.Results: The clinical data showed that expression of FOXK2 gradually decreased with increasing World Health Organization (WHO grades and a low level of FOXK2 indicates a poor prognosis. FOXK2 expression is negatively correlated with Ki67 expression and the WHO degree but is not correlated with other clinicopathological parameters, including sex, age, Karnofsky Performance Status, tumor diameter, O-6-methylguanine-DNA methyltransferase, and glutathione S-transferase pi. FOXK2 knockdown enhances glioma cell proliferation, migration, invasion, and EMT process, and, in contrast, FOXK2 overexpression inhibits glioma cell proliferation, migration, invasion, and the EMT process.Conclusion: Expression of FOXK2 gradually decreases with increasing WHO grades. FOXK2 inhibits tumor proliferation, migration, and invasion. FOXK2 is a critical mediator of the EMT process. Keywords: Forkhead box K2, FOXK2, glioma, oncology

In vitro drug response and efflux transporters associated with drug resistance in pediatric high grade glioma and diffuse intrinsic pontine glioma.

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Susanna J E Veringa

Full Text Available Pediatric high-grade gliomas (pHGG, including diffuse intrinsic pontine gliomas (DIPG, are the leading cause of cancer-related death in children. While it is clear that surgery (if possible, and radiotherapy are beneficial for treatment, the role of chemotherapy for these tumors is still unclear. Therefore, we performed an in vitro drug screen on primary glioma cells, including three DIPG cultures, to determine drug sensitivity of these tumours, without the possible confounding effect of insufficient drug delivery. This screen revealed a high in vitro cytotoxicity for melphalan, doxorubicine, mitoxantrone, and BCNU, and for the novel, targeted agents vandetanib and bortezomib in pHGG and DIPG cells. We subsequently determined the expression of the drug efflux transporters P-gp, BCRP1, and MRP1 in glioma cultures and their corresponding tumor tissues. Results indicate the presence of P-gp, MRP1 and BCRP1 in the tumor vasculature, and expression of MRP1 in the glioma cells themselves. Our results show that pediatric glioma and DIPG tumors per se are not resistant to chemotherapy. Treatment failure observed in clinical trials, may rather be contributed to the presence of drug efflux transporters that constitute a first line of drug resistance located at the blood-brain barrier or other resistance mechanism. As such, we suggest that alternative ways of drug delivery may offer new possibilities for the treatment of pediatric high-grade glioma patients, and DIPG in particular.

Wireless Phone Use and Risk of Adult Glioma: Evidence from a Meta-Analysis.

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Wang, Peng; Hou, Chongxian; Li, Yanwen; Zhou, Dong

2018-04-28

Wireless phone use has been increasing rapidly and is associated with the risk of glioma. Many studies have been conducted on this association without reaching agreement. The aim of this meta-analysis was to determine the possible association between wireless phone use and risk of adult glioma. Eligible studies were identified by searching PubMed and Embase up to July 2017. Random-effects or fixed-effects model was used to combine the results depending on the heterogeneity of the analysis. Publication bias was evaluated using Begg's funnel plot and Egger's regression asymmetry test. Subgroup analysis was performed to evaluate possible influence of these variables. Ten studies on the association of wireless phone use and risk of glioma were included. The combined odds ratio of adult gliomas associated with ever use of wireless phones was 1.03 (95% confidence interval [CI], 0.92-1.16) with high heterogeneity (I 2  = 54.2%, P = 0.013). In subgroup analyses, no significant association was found between tumor location in the temporal lobe and adult glioma risk, with odds ratios of 1.26 (95% CI, 0.87-1.84), 0.93 (95% CI, 0.69-1.24), and 1.61 (95% CI, 0.78-3.33). A significant association with risk of glioma was found in long-term users (≥10 years) with odds ratio of 1.33 (95% CI, 1.05-1.67). Ever use of wireless phones was not significantly associated with risk of adult glioma, but there could be increased risk in long-term users. Copyright © 2018 Elsevier Inc. All rights reserved.

Differential Signature of the Centrosomal MARK4 Isoforms in Glioma

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Ivana Magnani

2011-01-01

Full Text Available Background: MAP/microtubule affinity-regulating kinase 4 (MARK4 is a serine-threonine kinase expressed in two spliced isoforms, MARK4L and MARK4S, of which MARK4L is a candidate for a role in neoplastic transformation. Methods: We performed mutation analysis to identify sequence alterations possibly affecting MARK4 expression. We then investigated the MARK4L and MARK4S expression profile in 21 glioma cell lines and 36 tissues of different malignancy grades, glioblastoma-derived cancer stem cells (GBM CSCs and mouse neural stem cells (NSCs by real-time PCR, immunoblotting and immunohistochemistry. We also analyzed the sub-cellular localisation of MARK4 isoforms in glioma and normal cell lines by immunofluorescence. Results: Mutation analysis rules out sequence variations as the cause of the altered MARK4 expression in glioma. Expression profiling confirms that MARK4L is the predominant isoform, whereas MARK4S levels are significantly decreased in comparison and show an inverse correlation with tumour grade. A high MARK4L/MARK4S ratio also characterizes undifferentiated cells, such as GBM CSCs and NSCs. Accordingly, only MARK4L is expressed in brain neurogenic regions. Moreover, while both MARK4 isoforms are localised to the centrosome and midbody in glioma and normal cells, the L isoform exhibits an additional nucleolar localisation in tumour cells. Conclusions: The observed switch towards MARK4L suggests that the balance between the MARK4 isoforms is carefully guarded during neural differentiation but may be subverted in gliomagenesis. Moreover, the MARK4L nucleolar localisation in tumour cells features this MARK4 isoform as a nucleolus-associated tumour marker.

Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas

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Gutin, Philip H.; Iwamoto, Fabio M.; Beal, Kathryn; Mohile, Nimish A.; Karimi, Sasan; Hou, Bob L.; Lymberis, Stella; Yamada, Yoshiya; Chang, Jenghwa

2009-01-01

Purpose: Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas. Methods and Materials: After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab. Results: Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%. Discussion: Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

Differential expression of centrosomal proteins at different stages of human glioma

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Loh, Joon-Khim; Lieu, Ann-Shung; Chou, Chia-Hua; Lin, Fang-Yi; Wu, Chia-Hung; Howng, Sheng-Long; Chio, Chung-Ching; Hong, Yi-Ren

2010-01-01

High-grade gliomas have poor prognosis, requiring aggressive treatment. The aim of this study is to explore mitotic and centrosomal dysregulation in gliomas, which may provide novel targets for treatment. A case-control study was performed using 34 resected gliomas, which were separated into low- and high-grade groups. Normal human brain tissue was used as a control. Using immunohistochemical analysis, immunofluorescent microscopy, and RT-PCR, detection of centrins 1 and 2, γ-tubulin, hNinein, Aurora A, and Aurora B, expression was performed. Analysis of the GBM8401 glioma cell line was also undertaken to complement the in vivo studies. In high-grade gliomas, the cells had greater than two very brightly staining centrioles within large, atypical nuclei, and moderate-to-strong Aurora A staining. Comparing with normal human brain tissue, most of the mRNAs expression in gliomas for centrosomal structural proteins, including centrin 3, γ-tubulin, and hNinein isoforms 1, 2, 5 and 6, Aurora A and Aurora B were elevated. The significant different expression was observed between high- and low-grade glioma in both γ-tubulin and Aurora A mRNA s. In the high-grade glioma group, 78.6% of the samples had higher than normal expression of γ-tubulin mRNA, which was significantly higher than in the low-grade glioma group (18.2%, p < 0.05). Markers for mitotic dysregulation, such as supernumerary centrosomes and altered expression of centrosome-related mRNA and proteins were more frequently detected in higher grade gliomas. Therefore, these results are clinically useful for glioma staging as well as the development of novel treatments strategies

Differential expression of centrosomal proteins at different stages of human glioma

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Lin Fang-Yi

2010-06-01

Full Text Available Abstract Background High-grade gliomas have poor prognosis, requiring aggressive treatment. The aim of this study is to explore mitotic and centrosomal dysregulation in gliomas, which may provide novel targets for treatment. Methods A case-control study was performed using 34 resected gliomas, which were separated into low- and high-grade groups. Normal human brain tissue was used as a control. Using immunohistochemical analysis, immunofluorescent microscopy, and RT-PCR, detection of centrins 1 and 2, γ-tubulin, hNinein, Aurora A, and Aurora B, expression was performed. Analysis of the GBM8401 glioma cell line was also undertaken to complement the in vivo studies. Results In high-grade gliomas, the cells had greater than two very brightly staining centrioles within large, atypical nuclei, and moderate-to-strong Aurora A staining. Comparing with normal human brain tissue, most of the mRNAs expression in gliomas for centrosomal structural proteins, including centrin 3, γ-tubulin, and hNinein isoforms 1, 2, 5 and 6, Aurora A and Aurora B were elevated. The significant different expression was observed between high- and low-grade glioma in both γ-tubulin and Aurora A mRNA s. In the high-grade glioma group, 78.6% of the samples had higher than normal expression of γ-tubulin mRNA, which was significantly higher than in the low-grade glioma group (18.2%, p Conclusions Markers for mitotic dysregulation, such as supernumerary centrosomes and altered expression of centrosome-related mRNA and proteins were more frequently detected in higher grade gliomas. Therefore, these results are clinically useful for glioma staging as well as the development of novel treatments strategies.

IDH-mutant glioma specific association of rs55705857 located at 8q24.21 involves MYC deregulation

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Oktay, Yavuz; Ülgen, Ege; Can, Özge; Akyerli, Cemaliye B.; Yüksel, Şirin; Erdemgil, Yiğit; Durası, İ. Melis; Henegariu, Octavian Ioan; Nanni, E. Paolo; Selevsek, Nathalie; Grossmann, Jonas; Erson-Omay, E. Zeynep; Bai, Hanwen; Gupta, Manu; Lee, William; Turcan, Şevin; Özpınar, Aysel; Huse, Jason T.; Sav, M. Aydın; Flanagan, Adrienne; Günel, Murat; Sezerman, O. Uğur; Yakıcıer, M. Cengiz; Pamir, M. Necmettin; Özduman, Koray

2016-01-01

The single nucleotide polymorphism rs55705857, located in a non-coding but evolutionarily conserved region at 8q24.21, is strongly associated with IDH-mutant glioma development and was suggested to be a causal variant. However, the molecular mechanism underlying this association has remained unknown. With a case control study in 285 gliomas, 316 healthy controls, 380 systemic cancers, 31 other CNS-tumors, and 120 IDH-mutant cartilaginous tumors, we identified that the association was specific to IDH-mutant gliomas. Odds-ratios were 9.25 (5.17–16.52; 95% CI) for IDH-mutated gliomas and 12.85 (5.94–27.83; 95% CI) for IDH-mutated, 1p/19q co-deleted gliomas. Decreasing strength with increasing anaplasia implied a modulatory effect. No somatic mutations were noted at this locus in 114 blood-tumor pairs, nor was there a copy number difference between risk-allele and only-ancestral allele carriers. CCDC26 RNA-expression was rare and not different between the two groups. There were only minor subtype-specific differences in common glioma driver genes. RNA sequencing and LC-MS/MS comparisons pointed to significantly altered MYC-signaling. Baseline enhancer activity of the conserved region specifically on the MYC promoter and its further positive modulation by the SNP risk-allele was shown in vitro. Our findings implicate MYC deregulation as the underlying cause of the observed association. PMID:27282637

Computer-Aided Grading of Gliomas Combining Automatic Segmentation and Radiomics

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Wei Chen

2018-01-01

Full Text Available Gliomas are the most common primary brain tumors, and the objective grading is of great importance for treatment. This paper presents an automatic computer-aided diagnosis of gliomas that combines automatic segmentation and radiomics, which can improve the diagnostic ability. The MRI data containing 220 high-grade gliomas and 54 low-grade gliomas are used to evaluate our system. A multiscale 3D convolutional neural network is trained to segment whole tumor regions. A wide range of radiomic features including first-order features, shape features, and texture features is extracted. By using support vector machines with recursive feature elimination for feature selection, a CAD system that has an extreme gradient boosting classifier with a 5-fold cross-validation is constructed for the grading of gliomas. Our CAD system is highly effective for the grading of gliomas with an accuracy of 91.27%, a weighted macroprecision of 91.27%, a weighted macrorecall of 91.27%, and a weighted macro-F1 score of 90.64%. This demonstrates that the proposed CAD system can assist radiologists for high accurate grading of gliomas and has the potential for clinical applications.

MicroRNA-195 inhibits the proliferation of human glioma cells by directly targeting cyclin D1 and cyclin E1.

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Wang Hui

Full Text Available Glioma proliferation is a multistep process during which a sequence of genetic and epigenetic alterations randomly occur to affect the genes controlling cell proliferation, cell death and genetic stability. microRNAs are emerging as important epigenetic modulators of multiple target genes, leading to abnormal cellular signaling involving cellular proliferation in cancers.In the present study, we found that expression of miR-195 was markedly downregulated in glioma cell lines and human primary glioma tissues, compared to normal human astrocytes and matched non-tumor associated tissues. Upregulation of miR-195 dramatically reduced the proliferation of glioma cells. Flow cytometry analysis showed that ectopic expression of miR-195 significantly decreased the percentage of S phase cells and increased the percentage of G1/G0 phase cells. Overexpression of miR-195 dramatically reduced the anchorage-independent growth ability of glioma cells. Furthermore, overexpression of miR-195 downregulated the levels of phosphorylated retinoblastoma (pRb and proliferating cell nuclear antigen (PCNA in glioma cells. Conversely, inhibition of miR-195 promoted cell proliferation, increased the percentage of S phase cells, reduced the percentage of G1/G0 phase cells, enhanced anchorage-independent growth ability, upregulated the phosphorylation of pRb and PCNA in glioma cells. Moreover, we show that miR-195 inhibited glioma cell proliferation by downregulating expression of cyclin D1 and cyclin E1, via directly targeting the 3'-untranslated regions (3'-UTR of cyclin D1 and cyclin E1 mRNA. Taken together, our results suggest that miR-195 plays an important role to inhibit the proliferation of glioma cells, and present a novel mechanism for direct miRNA-mediated suppression of cyclin D1 and cyclin E1 in glioma.

Thermodynamics in Gliomas: Interactions between the Canonical WNT/Beta-Catenin Pathway and PPAR Gamma

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Alexandre Vallée

2017-05-01

Full Text Available Gliomas cells are the site of numerous metabolic and thermodynamics abnormalities with an increasing entropy rate which is characteristic of irreversible processes driven by changes in Gibbs energy, heat production, intracellular acidity, membrane potential gradient, and ionic conductance. We focus our review on the opposing interactions observed in glioma between the canonical WNT/beta-catenin pathway and PPAR gamma and their metabolic and thermodynamic implications. In gliomas, WNT/beta-catenin pathway is upregulated while PPAR gamma is downregulated. Upregulation of WNT/beta-catenin signaling induces changes in key metabolic enzyme that modify their thermodynamics behavior. This leads to activation pyruvate dehydrogenase kinase 1(PDK-1 and monocarboxylate lactate transporter 1 (MCT-1. Consequently, phosphorylation of PDK-1 inhibits pyruvate dehydrogenase complex (PDH. Thus, a large part of pyruvate cannot be converted into acetyl-CoA in mitochondria and in TCA (tricarboxylic acid cycle. This leads to aerobic glycolysis despite the availability of oxygen, named Warburg effect. Cytoplasmic pyruvate is, in major part, converted into lactate. The WNT/beta-catenin pathway induces also the transcription of genes involved in cell proliferation, cell invasiveness, nucleotide synthesis, tumor growth, and angiogenesis, such as c-Myc, cyclin D1, PDK. In addition, in gliomas cells, PPAR gamma is downregulated, leading to a decrease in insulin sensitivity and an increase in neuroinflammation. Moreover, PPAR gamma contributes to regulate some key circadian genes. Abnormalities in the regulation of circadian rhythms and dysregulation in circadian clock genes are observed in gliomas. Circadian rhythms are dissipative structures, which play a key role in far-from-equilibrium thermodynamics through their interactions with WNT/beta-catenin pathway and PPAR gamma. In gliomas, metabolism, thermodynamics, and circadian rhythms are tightly interrelated.

Generation and validation of a prognostic score to predict outcome after re-irradiation of recurrent glioma

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Combs, Stephanie E.; Welzel, Thomas; Debus, Juergen [Univ. Hospital of Heidelberg, Dept. of Radiation Oncology, Heidelberg (Germany)], E-mail: Stephanie.combs@med.uni-heidelberg.de; Edler, Lutz; Rausch, Renate [German Cancer Research Center (dkfz), Dept. of Biostatistics, Heidelberg (Germany); Wick, Wolfgang [Univ. Hospital of Heidelberg, Dept. of Neurooncology, Heidelberg (Germany)

2013-01-15

Re-irradiation using high-precision radiation techniques has been established within the clinical routine for patients with recurrent gliomas. In the present work, we developed a practical prognostic score to predict survival outcome after re-irradiation. Patients and methods. Fractionated stereotactic radiotherapy (FSRT) was applied in 233 patients. Primary histology included glioblastoma (n = 89; 38%), WHO Grade III gliomas (n = 52; 22%) and low-grade glioma (n = 92; 40%). FSRT was applied with a median dose of 36 Gy in 2 Gy single fractions. We evaluated survival after re-irradiation as well as progression-free survival after re-irradiation; prognostic factors analyzed included age, tumor volume at re-irradiation, histology, time between initial radiotherapy and re-irradiation, age and Karnofsky Performance Score. Results. Median survival after FSRT was 8 months for glioblastoma, 20 months for anaplastic gliomas, and 24 months for recurrent low-grade patients. The strongest prognostic factors significantly impacting survival after re-irradiation were histology (p <0.0001) and age (<50 vs. ={>=}50, p < 0.0001) at diagnosis and the time between initial radiotherapy and re-irradiation {<=}12 vs. >12 months (p < 0.0001). We generated a four-class prognostic score to distinguish patients with excellent (0 points), good (1 point), moderate (2 points) and poor (3-4 points) survival after re-irradiation. The difference in outcome was highly significant (p < 0.0001). Conclusion. We generated a practical prognostic score index based on three clinically relevant factors to predict the benefit of patients from re-irradiation. This score index can be helpful in patient counseling, and for the design of further clinical trials. However, individual treatment decisions may include other patient-related factors not directly influencing outcome.

Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma

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2018-06-18

Constitutional Mismatch Repair Deficiency Syndrome; Lynch Syndrome; Malignant Glioma; Progressive Ependymoma; Progressive Medulloblastoma; Recurrent Brain Neoplasm; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Brain Neoplasm; Refractory Diffuse Intrinsic Pontine Glioma; Refractory Ependymoma; Refractory Medulloblastoma

CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1α

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Esencay, Mine; Sarfraz, Yasmeen; Zagzag, David

2013-01-01

Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion. In order to perform the studies, we employed optimal cell culture methods and hypoxic conditions, lentivirus-mediated knockdown of protein expression, Western Blot analysis, migration assays and immunoprecipitation. We determined statistical significance by unpaired t-test. In this report, we show that U87MG, LN229 and LN308 glioma cells express CXCR7 and that exposure to hypoxia upregulates CXCR7 protein expression in these cell lines. CXCR7-expressing U87MG, LN229 and LN308 glioma cells migrated towards stromal-derived factor (SDF)-1α/CXCL12 in hypoxic conditions in the Boyden chamber assays. While shRNA-mediated knockdown of CXCR7 expression did not affect the migration of any of the three cell lines in normoxic conditions, we observed a reduction in the migration of LN229 and LN308, but not U87MG, glioma cells towards SDF-1α in hypoxic conditions. In addition, knockdown of CXCR7 expression in LN229 and LN308 glioma cells decreased levels of SDF-1α-induced phosphorylation of ERK1/2 and Akt. Inhibiting CXCR4 in LN229 and LN308 glioma cells that were knocked down for CXCR7 did not further reduce migration towards SDF-1α in hypoxic conditions and did not affect the levels of phosphorylated ERK1/2 and Akt. Analysis of immunoprecipitated CXCR4 from LN229 and LN308 glioma cells revealed co-precipitated CXCR7. Taken together, our findings indicate that both CXCR4 and CXCR7 mediate glioma cell migration towards SDF-1α in hypoxic conditions and support the development of therapeutic agents targeting these receptors

Analysis of changes in energy and redox states in HepG2 hepatoma and C6 glioma cells upon exposure to cadmium

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Yang, M.S.; Yu, L.C.; Gupta, R.C.

2004-01-01

The energy and redox states of the HepG2 hepatoma and the C6 glioma cells were studied by quantifying the levels of ATP, ADP, AMP, GSH, and GSSG. These values were used to calculate the energy charge potential (ECP = [ATP + 0.5ADP]/TAN), total adenosine nucleotides (TAN = ATP + ADP + AMP), total glutathione (TG = [GSH + GSSG]/TAN), and the redox state (GSH/GSSG ratio). For comparison between cell types, the level of each energy metabolite (ATP, ADP, and AMP) was normalized against TAN of the respective cell. The results showed that ATP:ADP:AMP ratio was 0.76:0.11:0.13 for the HepG2 cells and 0.80:0.11:0.09 for the C6 glioma cells. ECP was 0.81 ± 0.01 and 0.85 ± 0.01 for the HepG2 and the C6 glioma cells, respectively. GSH/GSSG ratio was 2.66 ± 0.16 and 3.63 ± 0.48 for HepG2 and C6 glioma cells, respectively. TG was 3.2 ± 0.54 for the HepG2 cells and 2.43 ± 0.18 for the C6 glioma cells, indicating that the level of total glutathione is more than two to three times higher than the total energy metabolites in these cell lines. Following a 3-h incubation in medium containing different concentrations of Cd, there was a dose-dependent decrease in cell viability. The 3-h LC 50 for the HepG2 cells was 0.5 mM and that for the C6 glioma cells was 0.4 mM. Cellular TAN decreased with a decrease in cell viability. Upon careful analysis of the energy state, there was a significant increase in relative amount of ATP and decrease in ADP and AMP in both cells as Cd concentration increased from 0 to 0.1, 0.2, and 0.6 mM. However, ECP in both cell lines increased, which indicated that the level of high energy phosphate was adequate. There was also a significant increase in TG and a significant decrease in GSH/GSSG in the C6 glioma cells when cells were exposed to as low as 0.1 mM Cd, which suggested that the cellular redox state was compromised. The HepG2 cells, on the other hand, showed no significant change in both TG and GSH/GSSG level until Cd concentration reached 0.6 m

Increased catalase activity by all-trans retinoic acid and its effect on radiosensitivity in rat glioma cells

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Jin, Hua; Jeon, Ha Yeun; Park, Woo Yoon; Kim, Won Dong; Ahn, Hee Yul; Yu, Jae Ran

2005-01-01

It has been reported that all-trans retinoic acid (ATRA) can inhibit glioma growing in vitro. However, clinical trials with ATRA alone in gliomas revealed modest results. ATRA has been shown to increase radiosensitivity in other tumor types, so combining radiation and ATRA would be one of alternatives to increase therapeutic efficacy in malignant gliomas. Thus, we intended to know the role of catalase, which is induced by ATRA, for radiosensitivity. If radiation-reduced reactive oxygen species (ROS) is removed by catalase, the effect of radiation will be reduced. A rat glioma cell line (36B10) was used for this study. The change of catalase activity and radiosensitivity by ATRA, with or without 3-amino-1, 2, 4-triazole (ATZ), a chemical inhibitor of catalase were measured. Catalase activity was measured by the decomposition of H 2 O 2 spectrophotometrically. Radiosensitivity was measured with clonogenic assay. Also ROS was measured using a 2, 7-dichlorofluores-cein diacetate spectrophotometrically. When 36B10 cells were exposed to 10, 25 and 50 μ M of ATRA for 48 h, the expression of catalase activity were increased with increasing concentration and incubation time of ATRA. Catalase activity was decreased with increasing the concentration of AT (1, 10 mM) dose-dependently. ROS was increased with ATRA and it was augmented with the combination of ATRA and radiation. ATZ decreased ROS production and increased cell survival in combination of ATRA and radiation despite the reduction of catalase. The increase of ROS is one of the reasons for the increased radiosensitivity in combination with ATRA. The catalase that is induced by ATRA doesn't decrease ROS production and radiosensitivity

Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy

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Gregory J. Baker

2014-07-01

Full Text Available As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM, and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients.

Capacity of ultraviolet-induced DNA repair in human glioma cells

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Itoh, Hiroji

1987-04-01

A DNA repair abnormality is likely related to an increased incidence of neoplasms in several autosomal recessive diseases such as xeroderma pigmentosum, Fanconi's anemia, Bloom's syndrome and ataxia telangiectasia. In human glioma cells, however, there are only a few reports on DNA repair. In this study, an ultraviolet (UV)-induced DNA repair was examined systematically in many human glioma cells. Two human malignant glioma cell lines (MMG-851, U-251-MG) and 7 human glioma cell strains (4, benign; 3, malignant) of short term culture, in which glial fibrillary acidic protein (GFAP) staining were positive, were used. To investigate the capacity of DNA repair, UV sensitivity was determined by colony formation; excision repair by autoradiography and Cytosine Arabinoside (Ara-C) assay; and post-replication repair by the joining rate of newly synthesized DNA. As a result, the colony-forming abilities of malignant glioma cell lines were lower than those of normal human fibroblasts, but no difference was found between two malignant glioma cell lines. The excision repair of the malignant group (2 cell lines and 3 cell strains) was apparently lower than that of the benign group (4 cell strains). In two malignant glioma cell lines, the excision repair of MMG-851 was lower than that of U-251-MG, and the post-replication repair of MMG-851 was higher than that of U-251-MG. These results were considered to correspond well with colony-forming ability. The results indicate that there are some differences in each human malignant glioma cell in its UV-induced DNA repair mechanism, and that the excision repair of the malignant glioma cells is apparently lower than that of the benign glioma cells. These findings may be useful for diagnosis and treatment.

Association between XRCC1 polymorphism 399 G->A and glioma among Caucasians: a systematic review and meta-analysis

Directory of Open Access Journals (Sweden)

Jacobs Daniel I

2012-10-01

Full Text Available Abstract Background The x-ray cross complementing group 1 gene (XRCC1 is crucial to proper repair of DNA damage such as single-strand DNA breaks. A non-synonymous polymorphism in XRCC1, 399 G → A, has been shown to reduce effectiveness of such DNA repair and has been associated with the risk of certain cancers. The known risk for glioma from high dose ionizing radiation makes associations between this polymorphism and glioma of particular interest. Methods A systematic literature review and meta-analysis was conducted to explore the association between XRCC1 399 G → A and glioma. Subgroup analyses by grade, gender, genotyping method, country in which study was conducted, and study size were conducted when data were available and validity of the results were assessed by influence analyses and exploration of potential publication bias. Results Six studies were eligible for meta-analysis including data on 2,362 Caucasian glioma cases and 3,085 Caucasian controls. Pooled analysis yielded a significant association between the variant of interest and risk of glioma (OR = 1.17, 95% CI: 1.05-1.30 which was found to be disproportionately driven by a single study. Exclusion of this study, in an influence analysis, produced no statistically significant evidence of association with glioma (OR = 1.10, 95% CI: 0.98-1.23, and no evidence of publication bias. Conclusions This meta-analysis does not suggest a major role of the XRCC1 399 G → A polymorphism in influencing risk of glioma among Caucasians. Future studies should report data separately for glioma subtypes to permit stratified analyses for Grade III and Grade IV glioma and examine other polymorphisms in this gene.

Selective uptake of boronophenylalanine by glioma stem/progenitor cells

International Nuclear Information System (INIS)

Sun, Ting; Zhou, Youxin; Xie, Xueshun; Chen, Guilin; Li, Bin; Wei, Yongxin; Chen, Jinming; Huang, Qiang; Du, Ziwei

2012-01-01

The success of boron neutron capture therapy (BNCT) depends on the amount of boron in cells and the tumor/blood and tumor/(normal tissue) boron concentration ratios. For the first time, measurements of boron uptake in both stem/progenitor and differentiated glioma cells were performed along with measurements of boron biodistribution in suitable animal models. In glioma stem/progenitor cells, the selective accumulation of boronophenylalanine (BPA) was lower, and retention of boron after BPA removal was longer than in differentiated glioma cells in vitro. However, boron biodistribution was not statistically significantly different in mice with xenografts. - Highlights: ► Uptake of BPA was analyzed in stem/progenitor and differentiated glioma cells. ► Selective accumulation of BPA was lower in glioma stem/progenitor cells. ► Retention of boron after BPA removal was longer in glioma stem/progenitor cells. ► Boron biodistribution was not statistically different in mice with xenografts.

Binding of cetuximab to the EGFRvIII deletion mutant and its biological consequences in malignant glioma cells

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Jutten, Barry; Dubois, Ludwig; Li Younan; Aerts, Hugo; Wouters, Bradly G.; Lambin, Philippe; Theys, Jan; Lammering, Guido

2009-01-01

Background and purpose: Despite the clinical use of cetuximab, a chimeric antibody against EGFR, little is known regarding its interaction with EGFRvIII, a frequently expressed deletion mutant of EGFR. Therefore, we investigated the interaction and the functional consequences of cetuximab treatment on glioma cells stably expressing EGFRvIII. Materials and methods: The human glioma cell line U373 genetically modified to express EGFRvIII was used to measure the binding of cetuximab and its internalization using flow cytometry and confocal microscopy. Proliferation and cell survival were analyzed by cell growth and clonogenic survival assays. Results: Cetuximab is able to bind to EGFRvIII and causes an internalization of the receptor and decreases its expression levels. Furthermore, in contrast to EGF, cetuximab was able to activate EGFRvIII which was evidenced by multiple phosphorylation sites and its downstream signaling targets. Despite this activation, the growth rate and the radiosensitivity of the EGFRvIII-expressing glioma cells were not modulated. Conclusions: Cetuximab binds to EGFRvIII and leads to the initial activation, internalization and subsequent downregulation of EGFRvIII, but it does not seem to modulate the proliferation or radiosensitivity of EGFRvIII-expressing glioma cells. Thus, approaches to treat EGFRvIII-expressing glioma cells should be evaluated more carefully.

Gene expression-based molecular diagnostic system for malignant gliomas is superior to histological diagnosis.

Science.gov (United States)

Shirahata, Mitsuaki; Iwao-Koizumi, Kyoko; Saito, Sakae; Ueno, Noriko; Oda, Masashi; Hashimoto, Nobuo; Takahashi, Jun A; Kato, Kikuya

2007-12-15

Current morphology-based glioma classification methods do not adequately reflect the complex biology of gliomas, thus limiting their prognostic ability. In this study, we focused on anaplastic oligodendroglioma and glioblastoma, which typically follow distinct clinical courses. Our goal was to construct a clinically useful molecular diagnostic system based on gene expression profiling. The expression of 3,456 genes in 32 patients, 12 and 20 of whom had prognostically distinct anaplastic oligodendroglioma and glioblastoma, respectively, was measured by PCR array. Next to unsupervised methods, we did supervised analysis using a weighted voting algorithm to construct a diagnostic system discriminating anaplastic oligodendroglioma from glioblastoma. The diagnostic accuracy of this system was evaluated by leave-one-out cross-validation. The clinical utility was tested on a microarray-based data set of 50 malignant gliomas from a previous study. Unsupervised analysis showed divergent global gene expression patterns between the two tumor classes. A supervised binary classification model showed 100% (95% confidence interval, 89.4-100%) diagnostic accuracy by leave-one-out cross-validation using 168 diagnostic genes. Applied to a gene expression data set from a previous study, our model correlated better with outcome than histologic diagnosis, and also displayed 96.6% (28 of 29) consistency with the molecular classification scheme used for these histologically controversial gliomas in the original article. Furthermore, we observed that histologically diagnosed glioblastoma samples that shared anaplastic oligodendroglioma molecular characteristics tended to be associated with longer survival. Our molecular diagnostic system showed reproducible clinical utility and prognostic ability superior to traditional histopathologic diagnosis for malignant glioma.

New insights into susceptibility to glioma.

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Liu, Yanhong; Shete, Sanjay; Hosking, Fay J; Robertson, Lindsay B; Bondy, Melissa L; Houlston, Richard S

2010-03-01

The study of inherited susceptibility to cancer has been one of the most informative areas of research in the past decade. Most of the cancer genetics studies have been focused on the common tumors such as breast and colorectal cancers. As the allelic architecture of these tumors is unraveled, research attention is turning to other rare cancers such as glioma, which are also likely to have a major genetic component as the basis of their development. In this brief review we discuss emerging data on glioma whole genome-association searches to identify risk loci. Two glioma genome-wide association studies have so far been reported. Our group identified 5 risk loci for glioma susceptibility (TERT rs2736100, CCDC26 rs4295627, CDKN2A/CDKN2B rs4977756, RTEL1 rs6010620, and PHLDB1 rs498872). Wrensch and colleagues provided further evidence to 2 risk loci (CDKN2B rs1412829 and RTEL1 rs6010620) for GBM and anaplastic astrocytoma. Although these data provide the strongest evidence to date for the role of common low-risk variants in the etiology of glioma, the single-nucleotide polymorphisms identified alone are unlikely to be candidates for causality. Identifying the causal variant at each specific locus and its biological impact now poses a significant challenge, contingent on a combination of fine mapping and functional analyses. Finally, we hope that a greater understanding of the biological basis of the disease will lead to the development of novel therapeutic interventions.

A Genetically Modified Adenoviral Vector with a Phage Display-Derived Peptide Incorporated into Fiber Fibritin Chimera Prolongs Survival in Experimental Glioma.

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Kim, Julius W; Kane, J Robert; Young, Jacob S; Chang, Alan L; Kanojia, Deepak; Morshed, Ramin A; Miska, Jason; Ahmed, Atique U; Balyasnikova, Irina V; Han, Yu; Zhang, Lingjiao; Curiel, David T; Lesniak, Maciej S

2015-09-01

The dismal clinical context of advanced-grade glioma demands the development of novel therapeutic strategies with direct patient impact. Adenovirus-mediated virotherapy represents a potentially effective approach for glioma therapy. In this research, we generated a novel glioma-specific adenovirus by instituting more advanced genetic modifications that can maximize the efficiency and safety of therapeutic adenoviral vectors. In this regard, a glioma-specific targeted fiber was developed through the incorporation of previously published glioma-specific, phage-panned peptide (VWT peptide) on a fiber fibritin-based chimeric fiber, designated as "GliomaFF." We showed that the entry of this virus was highly restricted to glioma cells, supporting the specificity imparted by the phage-panned peptide. In addition, the stability of the targeting moiety presented by fiber fibritin structure permitted greatly enhanced infectivity. Furthermore, the replication of this virus was restricted in glioma cells by controlling expression of the E1 gene under the activity of the tumor-specific survivin promoter. Using this approach, we were able to explore the combinatorial efficacy of various adenoviral modifications that could amplify the specificity, infectivity, and exclusive replication of this therapeutic adenovirus in glioma. Finally, virotherapy with this modified virus resulted in up to 70% extended survival in an in vivo murine glioma model. These data demonstrate that this novel adenoviral vector is a safe and efficient treatment for this difficult malignancy.

Efficacy and toxicity of postoperative temozolomide radiochemotherapy in malignant glioma

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Kocher, M.; Kunze, S.; Eich, H.T.; Semrau, R.; Mueller, R.P. [Dept. of Radiation Oncology, Univ. of Cologne (Germany)

2005-03-01

Purpose: to evaluate the feasibility, safety and efficacy of daily temozolomide concurrent with postoperative radiotherapy in malignant glioma. Patients and methods: from 11/1999 to 03/2003, n = 81 patients aged 15-72 years (median 52 years, karnofsky score 80-100% in 83%) suffering from primary glioblastoma (n = 47), anaplastic astrocytoma (n = 6), anaplastic oligodendroglioma (n = 16), and recurrent glioma (n = 12) were treated. Patients with primary gliomas received a combination of postoperative radiotherapy (60 Gy/1.8- to 2.0-Gy fractions) and daily oral temozolomide (75 mg/m{sup 2}) at all irradiation days (30-33 doses), while recurrent tumors were treated with 45-60 Gy and temozolomide. Initially, 6/81 patients had daily temozolomide doses of 50 mg/m{sup 2}. Results: in total, 70/81 patients (86%) completed both radio- and chemotherapy. Grade 1 nausea/vomiting was seen in 28%, grade 2 in 11%, grade 3 in 1%. Antiemetics were applied in 41%. Hematologic toxicities were observed as follows: leukopenia grade 3/4 1%, lymphopenia grade 3/4 46%, thrombopenia grade 3/4 1%. Two patients under dexamethasone suffered herpes encephalitis after one and 16 doses of temozolomide (75 mg/m{sup 2}). Median survival was 15 months for glioblastoma. In oligodendroglioma patients, a 4-year survival rate of 78% was observed. Conclusion: postoperative radiochemotherapy with 30-33 daily doses of temozolomide (75 mg/m{sup 2}) is safe in patients with malignant glioma. The combined schedule is effective in oligodendroglioma patients and may prolong survival in glioblastoma. Effort should be taken to minimize corticosteroid doses, since both steroids and temozolomide lead to immunosuppression. (orig.)

Health-related quality of life in patients with high-grade gliomas

DEFF Research Database (Denmark)

Piil, K; Jakobsen, J; Christensen, Karl Bang

2015-01-01

follow-up after 1 year. Scores of Karnofsky Performance Status (KPS), physical activity, anxiety and depression and health-related quality of life (FACT-Br) are obtained. Patients' physical activity level and KPS decrease during the disease- and treatment trajectory. The majority of patients did......The diagnosis of a high-grade glioma usual is followed by functional impairment(s), cognitive decline and an impaired psycho-social well-being. This might well have a significant and negative impact on the health related quality of life. The purpose of this study was to explore physical activity...... levels, prevalence and severity of anxiety and depressive symptoms and health-related quality of life among patients with a highgrade glioma. This paper is based on a longitudinal mixed methods study. Patients (n = 30) completed questionnaires at 5 time points from time of diagnosis until the final...

Optimizing a machine learning based glioma grading system using multi-parametric MRI histogram and texture features.

Science.gov (United States)

Zhang, Xin; Yan, Lin-Feng; Hu, Yu-Chuan; Li, Gang; Yang, Yang; Han, Yu; Sun, Ying-Zhi; Liu, Zhi-Cheng; Tian, Qiang; Han, Zi-Yang; Liu, Le-De; Hu, Bin-Quan; Qiu, Zi-Yu; Wang, Wen; Cui, Guang-Bin

2017-07-18

Current machine learning techniques provide the opportunity to develop noninvasive and automated glioma grading tools, by utilizing quantitative parameters derived from multi-modal magnetic resonance imaging (MRI) data. However, the efficacies of different machine learning methods in glioma grading have not been investigated.A comprehensive comparison of varied machine learning methods in differentiating low-grade gliomas (LGGs) and high-grade gliomas (HGGs) as well as WHO grade II, III and IV gliomas based on multi-parametric MRI images was proposed in the current study. The parametric histogram and image texture attributes of 120 glioma patients were extracted from the perfusion, diffusion and permeability parametric maps of preoperative MRI. Then, 25 commonly used machine learning classifiers combined with 8 independent attribute selection methods were applied and evaluated using leave-one-out cross validation (LOOCV) strategy. Besides, the influences of parameter selection on the classifying performances were investigated. We found that support vector machine (SVM) exhibited superior performance to other classifiers. By combining all tumor attributes with synthetic minority over-sampling technique (SMOTE), the highest classifying accuracy of 0.945 or 0.961 for LGG and HGG or grade II, III and IV gliomas was achieved. Application of Recursive Feature Elimination (RFE) attribute selection strategy further improved the classifying accuracies. Besides, the performances of LibSVM, SMO, IBk classifiers were influenced by some key parameters such as kernel type, c, gama, K, etc. SVM is a promising tool in developing automated preoperative glioma grading system, especially when being combined with RFE strategy. Model parameters should be considered in glioma grading model optimization.

Chemotherapy with ACNU and radiation therapy for malignant glioma in cerebral hemisphere of adult

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Miyagami, Mitsusuke; Tsubokawa, Takashi (Nihon Univ., Tokyo (Japan). School of Medicine)

1990-08-01

Fifty four cases of malignant gliomas in adults localized in the cerebral hemisphere including the location of basal ganglia and corpus callosum in 26% were survived over one month and followed more than 2 years after operation for 10 years recently. Histologically they had 40 cases of glioblastoma multiform and 14 cases of anaplastic astrocytoma. All malignant gliomas were given an operation and radiation, classifying 4 groups due to chemotherapeutic methods: Group I (20 cases) was treated by intraarterial infusion of ACNU with 20% mannitol. The others were Group II (8 cases) treated by intraarterial infusion of ACNU only, Group III (13 cases) by intravenous infusion of ACNU only and Group IV (13 cases) by no chemotherapy. Post-operative survival rates in the malignant gliomas of Group I were that 1 year survival rate was in 16 out of 20 cases (80%), 2 years in 55%, and 5 years in 25%. In glioblastoma multiform, 1 year survival rate of Group I was recognized in 70% and 2 years in 36%, a little better than the other treatments. Two year survival rate of other treatments demonstrated 17% in Group II, 25% in Group III, and 11% in Group IV. CT findings of glioblastoma multiform in Group I showed no rest tumor in 4 cases and one case of CR, and 3 cases of PR in the follow up study of 10 cases with rest tumor on CT after operation. There were no permanent complications except for temporary mild neurological deficit in 7% of Group I improving within 2 to 3 days after intraarterial infusion of ACNU and 20% mannitol. It is suggested that chemotherapy of Group I by intraarterial infusion of ACNU and 20% mannitol demonstrated a little better therapeutic efficacy than the other Groups, at least within 2 years after operation. (author).

Loss of heterozygosity of TRIM3 in malignant gliomas

International Nuclear Information System (INIS)

Boulay, Jean-Louis; Stiefel, Urs; Taylor, Elisabeth; Dolder, Béatrice; Merlo, Adrian; Hirth, Frank

2009-01-01

Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3) encodes a structural homolog of Drosophila brain tumor (brat) implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ... Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5. Our analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3. Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene

Concurrent thermochemoradiotherapy for brain high-grade glioma

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Ryabova, A. I., E-mail: ranigor@mail.ru; Novikov, V. A.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Choinzonov, E. L. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); Siberian State Medical University, Tomsk, 634050 (Russian Federation); Gribova, O. V. [Tomsk Cancer Research Institute, Tomsk, 634050 (Russian Federation); National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation); Baranova, A. V. [National Research Tomsk Polytechnic University, Tomsk, 634050 (Russian Federation)

2016-08-02

Despite the achievements in the current strategies for treatment, the prognosis in malignant glioma patients remains unsatisfactory. Hyperthermia is currently considered to be the most effective and universal modifier of radiotherapy and chemotherapy. Preliminary treatment outcomes for 28 patients with newly diagnosed (23) and recurrent (5) high-grade gliomas were presented. All the patients received multimodality treatment including surgery, thermoche-moradiotherapy followed by 4 cycles of adjuvant chemotherapy. All the patients endured thermochemoradiotherapy well. A complication, limited skin burn (II stage), was diagnosed in two cases and treated conservatively without treatment interruption. A month after thermochemoradiotherapy the results were as follows: complete regression was achieved in 4 cases, partial regression in 4 cases, stable disease in 14 cases and disease progression in 6 cases (one of them is pseudo-progression). After completing the adjuvant chemotherapy 2 more patients demonstrated complete response and 1 patient had disease progression. Introduction of local hyperthermia in multimodal therapy of malignant glioma does not impair the combined modality treatment tolerability of patients with malignant gliomas. A small number of studied patients and short follow-up time do not allow making reliable conclusions about the impact of local hyperthermia on the treatment outcomes; however, there is a tendency towards the increase in disease-free survival in the patients with newly diagnosed malignant gliomas.

Intraoperative radiation therapy for malignant glioma

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Sakai, Noboru; Yamada, Hiromu; Andoh, Takashi; Hirata, Toshifumi; Nishimura, Yasuaki; Miwa, Yoshiaki; Shimizu, Kotoyuki; Yanagawa, Shigeo [Gifu Univ. (Japan). Faculty of Medicine

1991-11-01

Intraoperative radiation therapy (IORT) was used as part of the initial therapy for malignant glioma in 32 of 73 patients with histologically verified anaplastic astrocytoma (grade III astrocytoma) and glioblastoma multiforme. The initial treatment for all cases was subtotal or total tumor resection combined with external irradiation and chemotherapy. IORT was performed 1 week after tumor resection, with doses of 10-50 Gy (mean 26.7 Gy) in one session. Fourteen of 32 cases had IORT two times because of tumor recurrence. The IORT patients had survival rates at 24 and 36 months after initial treatment of 57.1 and 33.5% (median survival 26.2 months). The other 41 patients had 23.6 and 13.1% survivals (median survival 20.7 months), which were significantly lower (p<0.01). Tumor recurrence within the original lesion site was suspected because of clinical condition, computed tomography, and magnetic resonance imaging studies in 65.6% of the IORT group (21 cases) 12 months after initial treatment. Twenty cases of death in the IORT group, including five autopsy cases, demonstrated regional tumor recurrence with a high incidence of intraventricular tumor invasion. The authors consider IORT is beneficial for selected malignant glioma patients, including tumor recurrence, because of prolonged survival. (author).

Nuclear and Cytoplasmic Delivery of Lactoferrin in Glioma using Chitosan Nanoparticles: Cellular Location Dependent-Action of Lactoferrin.

Science.gov (United States)

Tammam, Salma N; Azzazy, Hassan M E; Lamprecht, Alf

2018-05-23

Lactoferrin (Lf) exerts anti-cancer effects on glioma, however, the exact mechanism remains unclear. Despite possessing a nuclear localization sequence (NLS), Lf was found to allocate only in the cytoplasm of glioma 261. Lf was therefore loaded into nuclear and cytoplasmic targeted nanoparticles (NPs) to determine whether nuclear delivery of Lf would enhance its anti-cancer effect. Upon treatment with 300 and 800 µg/mL Lf loaded chitosan NPs, nuclear targeted Lf-NPs showed 1.3 and 2.7 folds increase in cell viability, whereas cytoplasmic targeted Lf-NPs at 300 µg/mL decreased cell viability by 0.8 folds in comparison to free Lf and controls. Results suggest that the cytotoxicity of Lf on glioma is attributable to its cytoplasmic allocation. Nuclear delivery of Lf induced cell proliferation rather than cytotoxicity, indicating that the mode of action of Lf in glioma is cell location dependent. This calls for caution about the general use of Lf as an anti-cancer protein. Copyright © 2018. Published by Elsevier B.V.

Evaluation of Mobile Phone and Cordless Phone Use and Glioma Risk Using the Bradford Hill Viewpoints from 1965 on Association or Causation

Directory of Open Access Journals (Sweden)

Michael Carlberg

2017-01-01

Full Text Available Objective. Bradford Hill’s viewpoints from 1965 on association or causation were used on glioma risk and use of mobile or cordless phones. Methods. All nine viewpoints were evaluated based on epidemiology and laboratory studies. Results. Strength: meta-analysis of case-control studies gave odds ratio (OR = 1.90, 95% confidence interval (CI = 1.31–2.76 with highest cumulative exposure. Consistency: the risk increased with latency, meta-analysis gave in the 10+ years’ latency group OR = 1.62, 95% CI = 1.20–2.19. Specificity: increased risk for glioma was in the temporal lobe. Using meningioma cases as comparison group still increased the risk. Temporality: highest risk was in the 20+ years’ latency group, OR = 2.01, 95% CI =1.41–2.88, for wireless phones. Biological gradient: cumulative use of wireless phones increased the risk. Plausibility: animal studies showed an increased incidence of glioma and malignant schwannoma in rats exposed to radiofrequency (RF radiation. There is increased production of reactive oxygen species (ROS from RF radiation. Coherence: there is a change in the natural history of glioma and increasing incidence. Experiment: antioxidants reduced ROS production from RF radiation. Analogy: there is an increased risk in subjects exposed to extremely low-frequency electromagnetic fields. Conclusion. RF radiation should be regarded as a human carcinogen causing glioma.

Molecular Subtyping of Tumors from Patients with Familial Glioma.

Science.gov (United States)

Ruiz, Vanessa Y; Praska, Corinne E; Armstrong, Georgina; Kollmeyer, Thomas M; Yamada, Seiji; Decker, Paul A; Kosel, Matthew L; Eckel-Passow, Jeanette E; Consortium, The Gliogene; Lachance, Daniel H; Bainbridge, Matthew N; Melin, Beatrice S; Bondy, Melissa L; Jenkins, Robert B

2017-10-10

Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on IDH mutation and 1p/19q co-deletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas, and that tumors in the same family should have the same molecular subtype. Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded (FFPE) tumor was obtained for a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation (CNV) data was obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wild type, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q-codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (p=0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ=0.59): 3 IDH-mutant non-codeleted, 2 IDH-wild type, and 2 IDH-mutant and 1p/19q-codeleted gliomas. Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight about the distribution of molecular subtypes in FG. © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

miR-21 Is Linked to Glioma Angiogenesis

DEFF Research Database (Denmark)

Hermansen, Simon Kjær; Nielsen, Boye Schnack; Aaberg-Jessen, Charlotte

2016-01-01

MicroRNA-21 (miR-21) is the most consistently over-expressed microRNA (miRNA) in malignant gliomas. We have previously reported that miR-21 is upregulated in glioma vessels and subsets of glioma cells. To better understand the role of miR-21 in glioma angiogenesis and to characterize miR-21......-localized with the hypoxia- and angiogenesis-associated markers HIF-1α (p=0.0020) and VEGF (p=0.0096), whereas the putative miR-21 target, PTEN, was expressed independently of miR-21. Expression of stem cell markers Oct4, Sox2 and CD133 was not associated with miR-21. In six glioblastoma cultures, miR-21 did not correlate...... with the six markers. These findings suggest that miR-21 is linked to glioma angiogenesis, that miR-21 is unlikely to regulate PTEN, and that miR-21-positive tumor cells do not possess stem cell characteristics....

Ectopic High Expression of E2-EPF Ubiquitin Carrier Protein Indicates a More Unfavorable Prognosis in Brain Glioma.

Science.gov (United States)

Zhang, Xiaohui; Zhao, Fangbo; Zhang, Shujun; Song, Yichun

2017-04-01

Ubiquitination of proteins meant for elimination is a primary method of eukaryotic cellular protein degradation. The ubiquitin carrier protein E2-EPF is a key degradation enzyme that is highly expressed in many tumors. However, its expression and prognostic significance in brain glioma are still unclear. The aim of this study was to reveal how the level of E2-EPF relates to prognosis in brain glioma. Thirty low-grade and 30 high-grade brain glioma samples were divided into two tissue microarrays each. Levels of E2-EPF protein were examined by immunohistochemistry and immunofluorescence. Quantitative real-time polymerase chain reaction was used to analyze the level of E2-EPF in 60 glioma and 3 normal brain tissue samples. The relationship between E2-EPF levels and prognosis was analyzed by Kaplan-Meier survival curves. E2-EPF levels were low in normal brain tissue samples but high in glioma nuclei. E2-EPF levels gradually increased as glioma grade increased (p EPF levels in high-grade glioma were significantly higher than in low-grade glioma (p EPF levels was shorter than in patients with low expression (p EPF was significantly shorter than patients with only nuclear E2-EPF (p EPF levels, especially ectopic, are associated with higher grade glioma and shorter survival. E2-EPF levels may play a key role in predicting the prognosis for patients with brain glioma.

Extra-Neural Metastases of Malignant Gliomas: Myth or Reality?

Energy Technology Data Exchange (ETDEWEB)

Beauchesne, Patrick [Neuro-Oncology, CHU de NANCY, Hôpital Central, CO n°34, 54035 Nancy Cedex (France)

2011-01-27

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years— despite debulking surgery, radiotherapy and cytotoxic chemotherapy—with a median survival of 9–12 months. Virtually no patients are cured of their illness. Malignant gliomas are usually locally invasive tumors, though extra-neural metastases can sometimes occur late in the course of the disease (median of two years). They generally appear after craniotomy although spontaneous metastases have also been reported. The incidence of these metastases from primary intra-cranial malignant gliomas is low; it is estimated at less than 2% of all cases. Extra-neural metastases from gliomas frequently occur late in the course of the disease (median of two years), and generally appear after craniotomy, but spontaneous metastases have also been reported. Malignant glioma metastases usually involve the regional lymph nodes, lungs and pleural cavity, and occasionally the bone and liver. In this review, we present three cases of extra-neural metastasis of malignant gliomas from our department, summarize the main reported cases in literature, and try to understand the mechanisms underlying these systemic metastases.

Extra-Neural Metastases of Malignant Gliomas: Myth or Reality?

International Nuclear Information System (INIS)

Beauchesne, Patrick

2011-01-01

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. Prognosis for these patients has not significantly changed in recent years— despite debulking surgery, radiotherapy and cytotoxic chemotherapy—with a median survival of 9–12 months. Virtually no patients are cured of their illness. Malignant gliomas are usually locally invasive tumors, though extra-neural metastases can sometimes occur late in the course of the disease (median of two years). They generally appear after craniotomy although spontaneous metastases have also been reported. The incidence of these metastases from primary intra-cranial malignant gliomas is low; it is estimated at less than 2% of all cases. Extra-neural metastases from gliomas frequently occur late in the course of the disease (median of two years), and generally appear after craniotomy, but spontaneous metastases have also been reported. Malignant glioma metastases usually involve the regional lymph nodes, lungs and pleural cavity, and occasionally the bone and liver. In this review, we present three cases of extra-neural metastasis of malignant gliomas from our department, summarize the main reported cases in literature, and try to understand the mechanisms underlying these systemic metastases

Exploring the regulatory role of isocitrate dehydrogenase mutant protein on glioma stem cell proliferation.

Science.gov (United States)

Lu, H-C; Ma, J; Zhuang, Z; Qiu, F; Cheng, H-L; Shi, J-X

2016-08-01

Glioma is the most lethal form of cancer that originates mostly from the brain and less frequently from the spine. Glioma is characterized by abnormal regulation of glial cell differentiation. The severity of the glioma was found to be relaxed in isocitrate dehydrogenase 1 (IDH1) mutant. The present study focused on histological discrimination and regulation of cancer stem cell between IDH1 mutant and in non-IDH1 mutant glioma tissue. Histology, immunohistochemistry and Western blotting techniques are used to analyze the glioma nature and variation in glioma stem cells that differ between IDH1 mutant and in non-IDH1 mutant glioma tissue. The aggressive form of non-IDH1 mutant glioma shows abnormal cellular histological variation with prominent larger nucleus along with abnormal clustering of cells. The longer survival form of IDH1 mutant glioma has a control over glioma stem cell proliferation. Immunohistochemistry with stem cell markers, CD133 and EGFRvIII are used to demonstrate that the IDH1 mutant glioma shows limited dependence on cancer stem cells and it shows marked apoptotic signals in TUNEL assay to regulate abnormal cells. The non-IDH1 mutant glioma failed to regulate misbehaving cells and it promotes cancer stem cell proliferation. Our finding supports that the IDH1 mutant glioma has a regulatory role in glioma stem cells and their survival.

Early life exposures and the risk of adult glioma.

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Anic, Gabriella M; Madden, Melissa H; Sincich, Kelly; Thompson, Reid C; Nabors, L Burton; Olson, Jeffrey J; LaRocca, Renato V; Browning, James E; Pan, Edward; Egan, Kathleen M

2013-09-01

Exposure to common infections in early life may stimulate immune development and reduce the risk for developing cancer. Birth order and family size are proxies for the timing of exposure to childhood infections with several studies showing a reduced risk of glioma associated with a higher order of birth (and presumed younger age at infection). The aim of this study was to examine whether birth order, family size, and other early life exposures are associated with the risk of glioma in adults using data collected in a large clinic-based US case-control study including 889 glioma cases and 903 community controls. A structured interviewer-administered questionnaire was used to collect information on family structure, childhood exposures and other potential risk factors. Logistic regression was used to calculate odds ratios (OR) and corresponding 95% confidence intervals (CI) for the association between early life factors and glioma risk. Persons having any siblings were at significantly lower risk for glioma when compared to those reporting no siblings (OR=0.64; 95% CI 0.44-0.93; p=0.020). Compared to first-borns, individuals with older siblings had a significantly lower risk (OR=0.75; 95% CI 0.61-0.91; p=0.004). Birth weight, having been breast fed in infancy, and season of birth were not associated with glioma risk. The current findings lend further support to a growing body of evidence that early exposure to childhood infections reduces the risk of glioma onset in children and adults.

In vivo detection of inducible nitric oxide synthase in rodent gliomas.

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Towner, Rheal A; Smith, Nataliya; Doblas, Sabrina; Garteiser, Philippe; Watanabe, Yasuko; He, Ting; Saunders, Debra; Herlea, Oana; Silasi-Mansat, Robert; Lupu, Florea

2010-03-01

Increased iNOS expression is often found in brain tumors, such as gliomas. The goal of this study was to develop and assess a novel molecular MRI (mMRI) probe for in vivo detection of iNOS in rodent models for gliomas (intracerebral implantation of rat C6 or RG2 cells or ethyl nitrosourea-induced glioma). The probe we used incorporated a Gd-DTPA (gadolinium(III) complex of diethylenetriamine-N,N,N',N'',N''-pentaacetate) backbone with albumin and biotin moieties and covalent binding of an anti-iNOS antibody (Ab) to albumin (anti-iNOS probe). We used mMRI with the anti-iNOS probe to detect in vivo iNOS levels in gliomas. Nonimmune normal rat IgG coupled to albumin-Gd-DTPA-biotin was used as a control nonspecific contrast agent. By targeting the biotin component of the anti-iNOS probe with streptavidin Cy3, fluorescence imaging confirmed the specificity of the probe for iNOS in glioma tissue. iNOS levels in glioma tumors were also confirmed via Western blots and immunohistochemistry. The presence of plasma membrane-associated iNOS in glioma cells was established by transmission electron microscopy and gold-labeled anti-iNOS Ab. The more aggressive RG2 glioma was not found to have higher levels of iNOS compared to C6. Differences in glioma vascularization and blood-brain barrier permeability between the C6 and the RG2 gliomas are discussed. In vivo assessment of iNOS levels associated with tumor development is quite feasible in heterogeneous tissues with mMRI. (c) 2009 Elsevier Inc. All rights reserved.

Mutant IDH1 Promotes Glioma Formation In Vivo

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Beatrice Philip

2018-05-01

Full Text Available Summary: Isocitrate dehydrogenase 1 (IDH1 is the most commonly mutated gene in grade II–III glioma and secondary glioblastoma (GBM. A causal role for IDH1R132H in gliomagenesis has been proposed, but functional validation in vivo has not been demonstrated. In this study, we assessed the role of IDH1R132H in glioma development in the context of clinically relevant cooperating genetic alterations in vitro and in vivo. Immortal astrocytes expressing IDH1R132H exhibited elevated (R-2-hydroxyglutarate levels, reduced NADPH, increased proliferation, and anchorage-independent growth. Although not sufficient on its own, IDH1R132H cooperated with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote glioma development in vivo. These tumors resembled proneural human mutant IDH1 GBM genetically, histologically, and functionally. Our findings support the hypothesis that IDH1R132H promotes glioma development. This model enhances our understanding of the biology of IDH1R132H-driven gliomas and facilitates testing of therapeutic strategies designed to combat this deadly disease. : Philip et al. show that mutant IDH1 cooperates with PDGFA and loss of Cdkn2a, Atrx, and Pten to promote gliomagenesis in vivo in a mouse model of glioma. These tumors resemble proneural human mutant IDH1 glioblastoma and exhibit enhanced sensitivity to PARP inhibition in combination with chemotherapy. Keywords: IDH1, Cdkn2a, Atrx, Pten, glioma, mouse model, RCAS/TVA

Loss of heterozygosity of TRIM3 in malignant gliomas

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Dolder Béatrice

2009-02-01

Full Text Available Abstract Background Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3 encodes a structural homolog of Drosophila brain tumor (brat implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ... Methods Here we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5. Results Our analysis identifies LOH in 17 cases (24% of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3. Conclusion Loss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene.

Novel drugs in pediatric gliomas

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Zhang, Dongli; Liu, Xiaoming; Fan, Conghai; Chen, Jiao

2017-01-01

Astrocytomas (gliomas) are the most common primary brain tumors among adults and second most frequent neoplasm among children. New ideas and novel approaches are being explored world over with aim to devise better management strategeies for this deadly pathological state. We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting importance of various therapeutic drugs against gliomas. It was observed clearly that this approach of using therape...

Neutrophilia as a biomarker for overall survival in newly diagnosed high-grade glioma patients undergoing chemoradiation

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Antoine Schernberg

2018-03-01

Full Text Available Objective: To study the prognostic value of neutrophil disorders in a retrospective cohort of high-grade glioma patients receiving definitive concurrent temozolomide and radiation. Materials and methods: Clinical records of consecutive patients treated in our Institution between January 2005 and December 2010 with concurrent temozolomide (75 mg/m2 daily and radiation were collected. The prognostic value of pretreatment neutrophilia on survival, defined as a neutrophil count exceeding 7 G/L, was examined. Results: We identified 164 patients, all treated with concurrent temozolomide-based chemoradiotherapy. Initial surgery was achieved in most (75%, with resection > 90% in 55 patients (34%. Total 151 patients (92% had glioblastoma, and 13 patients (8% had WHO grade III glioma. Eighty-two patients (50% displayed pretreatment neutrophilia. Neutrophilia was not associated with concurrent or adjuvant temodal discontinuation (p > 0.3. The 2-year actuarial overall survival was 45%. Steroid consumption, i.e. 60 mg or more of daily prednisolone, increased pretreatment neutrophil count (p = 0.005. In univariate analysis, neutrophilia was associated with worse overall survival (p = 0.019, as well as age ≥ 65 years (p = 0.009, surgical resection < 90% (p = 0.003 and prednisolone consumption ≥ 60 mg/day (p = 0.016. In multivariate analysis, neutrophilia (p = 0.013, age ≥ 65 (p = 0.001, and surgical tumor resection < 90% (p = 0.010 independently decreased overall survival, while, steroid consumption was not (p = 0.088. Conclusion: In high-grade gliomas treated with concurrent temozolomide and radiation, pretreatment neutrophilia may be a significant prognosis factor for overall survival. In addition with previously available markers, this independent cost-effective biomarker could help identifying patients with worsened prognosis. Keywords: High grade gliomas, Glioblastoma

Gamma-glutamylcyclotransferase promotes the growth of human glioma cells by activating Notch-Akt signaling

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Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao; Tan, Guo-Wei; Wang, Zhan-Xiang, E-mail: md_wzx7189@163.com

2016-03-18

Glioma as an aggressive type tumor is rapidly growing and has become one of the leading cause of cancer-related death worldwide. γ-Glutamylcyclotransferase (GGCT) has been shown as a diagnostic marker in various cancers. To reveal whether there is a correlation between GGCT and human glioma, GGCT expression in human glioma tissues and cell lines was first determined. We found that GGCT expression was up-regulated in human glioma tissues and cell lines. Further, we demonstrate that GGCT knockdown inhibits glioma cell T98G and U251 proliferation and colony formation, whereas GGCT overexpression leads to oppose effects. GGCT overexpression promotes the expression of Notch receptors and activates Akt signaling in glioma cells, and Notch-Akt signaling is activated in glioma tissues with high expression of GGCT. Finally, we show that inhibition of Notch-Akt signaling with Notch inhibitor MK-0752 blocks the effects of GGCT on glioma proliferation and colony formation. In conclusion, GGCT plays a critical role in glioma cell proliferation and may be a potential cancer therapeutic target. - Highlights: • GGCT expression is up-regulated in human glioma tissues and cell lines. • GGCT promotes glioma cell growth and colony formation. • GGCT promotes the activation of Notch-Akt signaling in glioma cells and tissues. • Notch inhibition blocks the role of GGCT in human glioma cells.

Isolated optic nerve gliomas: a multicenter historical cohort study.

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Shofty, Ben; Ben-Sira, Liat; Kesler, Anat; Jallo, George; Groves, Mari L; Iyer, Rajiv R; Lassaletta, Alvaro; Tabori, Uri; Bouffet, Eric; Thomale, Ulrich-Wilhelm; Hernáiz Driever, Pablo; Constantini, Shlomi

2017-12-01

OBJECTIVE Isolated optic nerve gliomas (IONGs) constitute a rare subgroup of optic pathway gliomas (OPGs). Due to the rarity of this condition and the difficulty in differentiating IONGs from other types of OPGs in most clinical series, little is known about these tumors. Currently, due to lack of evidence, they are managed the same as any other OPG. METHODS The authors conducted a multicenter retrospective cohort study aimed at determining the natural history of IONGs. Included were patients with clear-cut glioma of the optic nerve without posterior (chiasmatic/hypothalamic) involvement. At least 1 year of follow-up, 2 MRI studies, and 2 neuro-ophthalmological examinations were required for inclusion. RESULTS Thirty-six patients with 39 tumors were included in this study. Age at diagnosis ranged between 6 months and 16 years (average 6 years). The mean follow-up time was 5.6 years. Twenty-five patients had neurofibromatosis Type 1. During the follow-up period, 59% of the tumors progressed, 23% remained stable, and 18% (all with neurofibromatosis Type 1) displayed some degree of spontaneous regression. Fifty-one percent of the patients presented with visual decline, of whom 90% experienced further deterioration. Nine patients were treated with chemotherapy, 5 of whom improved visually. Ten patients underwent operation, and no local or distal recurrence was noted. CONCLUSIONS Isolated optic nerve gliomas are highly dynamic tumors. Radiological progression and visual deterioration occur in greater percentages than in the general population of patients with OPGs. Response to chemotherapy may be better in this group, and its use should be considered early in the course of the disease.

The Value of 5-Aminolevulinic Acid in Low-grade Gliomas and High-grade Gliomas Lacking Glioblastoma Imaging Features: An Analysis Based on Fluorescence, Magnetic Resonance Imaging, 18F-Fluoroethyl Tyrosine Positron Emission Tomography, and Tumor Molecular Factors.

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Jaber, Mohammed; Wölfer, Johannes; Ewelt, Christian; Holling, Markus; Hasselblatt, Martin; Niederstadt, Thomas; Zoubi, Tarek; Weckesser, Matthias; Stummer, Walter

2016-03-01

Approximately 20% of grade II and most grade III gliomas fluoresce after 5-aminolevulinic acid (5-ALA) application. Conversely, approximately 30% of nonenhancing gliomas are actually high grade. The aim of this study was to identify preoperative factors (ie, age, enhancement, 18F-fluoroethyl tyrosine positron emission tomography [F-FET PET] uptake ratios) for predicting fluorescence in gliomas without typical glioblastomas imaging features and to determine whether fluorescence will allow prediction of tumor grade or molecular characteristics. Patients harboring gliomas without typical glioblastoma imaging features were given 5-ALA. Fluorescence was recorded intraoperatively, and biopsy specimens collected from fluorescing tissue. World Health Organization (WHO) grade, Ki-67/MIB-1 index, IDH1 (R132H) mutation status, O-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and 1p/19q co-deletion status were assessed. Predictive factors for fluorescence were derived from preoperative magnetic resonance imaging and F-FET PET. Classification and regression tree analysis and receiver-operating-characteristic curves were generated for defining predictors. Of 166 tumors, 82 were diagnosed as WHO grade II, 76 as grade III, and 8 as glioblastomas grade IV. Contrast enhancement, tumor volume, and F-FET PET uptake ratio >1.85 predicted fluorescence. Fluorescence correlated with WHO grade (P fluorescing grade III gliomas was higher than in nonfluorescing tumors, whereas in fluorescing and nonfluorescing grade II tumors, no differences were noted. Age, tumor volume, and F-FET PET uptake are factors predicting 5-ALA-induced fluorescence in gliomas without typical glioblastoma imaging features. Fluorescence was associated with an increased Ki-67/MIB-1 index and high-grade pathology. Whether fluorescence in grade II gliomas identifies a subtype with worse prognosis remains to be determined.

A prospective study of cognitive functions following conventional radiotherapy for supratentorial gliomas in young adults: 4-year results

International Nuclear Information System (INIS)

Vigliani, Maria-Claudia; Sichez, Nicole; Poisson, Michel; Delattre, Jean-Yves

1996-01-01

Purpose: To evaluate the effects of limited field conventional cerebral radiotherapy (RT) on cognitive functions of adults. Methods and Materials: A prospective neuropsychological study was performed on 17 patients who underwent conventional limited field RT for a low-grade glioma or for a good-prognosis anaplastic glioma. Results were compared with 14 control patients with low-grade gliomas who did not receive radiotherapy. Results: A transient significant decrease of performances for the Reaction Time test was observed at 6 months in the irradiated group with return to baseline values 12 months post-RT. Subsequently, no other significant changes were observed over a 48-month follow-up period in the irradiated and nonirradiated groups. Nonetheless, when the scores of each patient were considered over time instead of the mean values of the group, one irradiated patient (5.8%) experienced progressive deterioration while two irradiated patients (11.7%) experienced long-lasting improvement. Individual changes did not occur in the control group. Conclusion: This study suggests that a transient early delayed drop of neuropsychological performances at 6 months is frequent following limited field conventional RT, but the risk of long-term cognitive dysfunction after irradiation is low, at least in the first 4 years after RT and when it is administered alone in young adults

UPA-sensitive ACPP-conjugated nanoparticles for multi-targeting therapy of brain glioma.

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Zhang, Bo; Zhang, Yujie; Liao, Ziwei; Jiang, Ting; Zhao, Jingjing; Tuo, Yanyan; She, Xiaojian; Shen, Shun; Chen, Jun; Zhang, Qizhi; Jiang, Xinguo; Hu, Yu; Pang, Zhiqing

2015-01-01

Now it is well evidenced that tumor growth is a comprehensive result of multiple pathways, and glioma parenchyma cells and stroma cells are closely associated and mutually compensatory. Therefore, drug delivery strategies targeting both of them simultaneously might obtain more promising therapeutic benefits. In the present study, we developed a multi-targeting drug delivery system modified with uPA-activated cell-penetrating peptide (ACPP) for the treatment of brain glioma (ANP). In vitro experiments demonstrated nanoparticles (NP) decorated with cell-penetrating peptide (CPP) or ACPP could significantly improve nanoparticles uptake by C6 glioma cells and nanoparticles penetration into glioma spheroids as compared with traditional NP and thus enhanced the therapeutic effects of its payload when paclitaxel (PTX) was loaded. In vivo imaging experiment revealed that ANP accumulated more specifically in brain glioma site than NP decorated with or without CPP. Brain slides further showed that ACPP contributed to more nanoparticles accumulation in glioma site, and ANP could co-localize not only with glioma parenchyma cells, but also with stroma cells including neo-vascular cells and tumor associated macrophages. The pharmacodynamics results demonstrated ACPP could significantly improve the therapeutic benefits of nanoparticles by significantly prolonging the survival time of glioma bearing mice. In conclusion, the results suggested that nanoparticles modified with uPA-sensitive ACPP could reach multiple types of cells in glioma tissues and provide a novel strategy for glioma targeted therapy.

Targetome Analysis Revealed Involvement of MiR-126 in Neurotrophin Signaling Pathway: A Possible Role in Prevention of Glioma Development.

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Rouigari, Maedeh; Dehbashi, Moein; Ghaedi, Kamran; Pourhossein, Meraj

2018-07-01

For the first time, we used molecular signaling pathway enrichment analysis to determine possible involvement of miR-126 and IRS-1 in neurotrophin pathway. In this prospective study, Validated and predicted targets (targetome) of miR-126 were collected following searching miRtarbase (http://mirtarbase.mbc.nctu.edu.tw/) and miRWalk 2.0 databases, respectively. Then, approximate expression of miR-126 targeting in Glioma tissue was examined using UniGene database (http://www.ncbi. nlm.nih.gov/unigene). In silico molecular pathway enrichment analysis was carried out by DAVID 6.7 database (http://david. abcc.ncifcrf.gov/) to explore which signaling pathway is related to miR-126 targeting and how miR-126 attributes to glioma development. MiR-126 exerts a variety of functions in cancer pathogenesis via suppression of expression of target gene including PI3K, KRAS, EGFL7, IRS-1 and VEGF. Our bioinformatic studies implementing DAVID database, showed the involvement of miR-126 target genes in several signaling pathways including cancer pathogenesis, neurotrophin functions, Glioma formation, insulin function, focal adhesion production, chemokine synthesis and secretion and regulation of the actin cytoskeleton. Taken together, we concluded that miR-126 enhances the formation of glioma cancer stem cell probably via down regulation of IRS-1 in neurotrophin signaling pathway. Copyright© by Royan Institute. All rights reserved.

Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells.

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Sauvageot, Claire Marie-Elisabeth; Weatherbee, Jessica Leigh; Kesari, Santosh; Winters, Susan Elizabeth; Barnes, Jessica; Dellagatta, Jamie; Ramakrishna, Naren Raj; Stiles, Charles Dean; Kung, Andrew Li-Jen; Kieran, Mark W; Wen, Patrick Yung Chih

2009-04-01

Glioblastoma multiforme (GBM) arises from genetic and signaling abnormalities in components of signal transduction pathways involved in proliferation, survival, and the cell cycle axis. Studies to date with single-agent targeted molecular therapy have revealed only modest effects in attenuating the growth of these tumors, suggesting that targeting multiple aberrant pathways may be more beneficial. Heat-shock protein 90 (HSP90) is a molecular chaperone that is involved in the conformational maturation of a defined group of client proteins, many of which are deregulated in GBM. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is a well-characterized HSP90 inhibitor that should be able to target many of the aberrant signal transduction pathways in GBM. We assessed the ability of 17-AAG to inhibit the growth of glioma cell lines and glioma stem cells both in vitro and in vivo and assessed its ability to synergize with radiation and/or temozolomide, the standard therapies for GBM. Our results reveal that 17-AAG is able to inhibit the growth of both human glioma cell lines and glioma stem cells in vitro and is able to target the appropriate proteins within these cells. In addition, 17-AAG can inhibit the growth of intracranial tumors and can synergize with radiation both in tissue culture and in intracranial tumors. This compound was not found to synergize with temozolomide in any of our models of gliomas. Our results suggest that HSP90 inhibitors like 17-AAG may have therapeutic potential in GBM, either as a single agent or in combination with radiation.

The change of p16 gene expression in glioma cell line C6 after radiation with gamma knife

International Nuclear Information System (INIS)

Zhao Xingli; Zhao Conghai; Tian Yu

2002-01-01

Objective: T observe the change of expression of p16 gene product, P16 protein, after treated by gamma knife on glioma cell line C6. Methods: Glioma C6 cells proliferated in vitro, treated by γ-knife in dose of 5.00 and 6.22 Gy, respectively. P16 protein was detected by immunohistochemical technique and image analysis. Results: The P16 protein in glioma C6 cells was notably increased after treatment with γ knife (P < 0.01). The grey number in C6 group (control group) was 167.1 +- 6.2 and was 155.4 +- 2.0 and 124.9 +- 7.1, respectively, in 5.00 Gy and 6.22 Gy gamma knife treated group. Conclusion: It is suggests that one of the mechanisms of glioma cell C6 apoptosis induced by γ-knife radiation may be associated with activation of p16 gene and increase of P16 protein expression

F11R is a novel monocyte prognostic biomarker for malignant glioma.

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Winnie W Pong

Full Text Available Brain tumors (gliomas contain large populations of infiltrating macrophages and recruited microglia, which in experimental murine glioma models promote tumor formation and progression. Among the barriers to understanding the contributions of these stromal elements to high-grade glioma (glioblastoma; GBM biology is the relative paucity of tools to characterize infiltrating macrophages and resident microglia. In this study, we leveraged multiple RNA analysis platforms to identify new monocyte markers relevant to GBM patient outcome.High-confidence lists of mouse resident microglia- and bone marrow-derived macrophage-specific transcripts were generated using converging RNA-seq and microarray technologies and validated using qRT-PCR and flow cytometry. Expression of select cell surface markers was analyzed in brain-infiltrating macrophages and resident microglia in an induced GBM mouse model, while allogeneic bone marrow transplantation was performed to trace the origins of infiltrating and resident macrophages. Glioma tissue microarrays were examined by immunohistochemistry, and the Gene Expression Omnibus (GEO database was queried to determine the prognostic value of identified microglia biomarkers in human GBM.We generated a unique catalog of differentially-expressed bone marrow-derived monocyte and resident microglia transcripts, and demonstrated that brain-infiltrating macrophages acquire F11R expression in GBM and following bone-marrow transplantation. Moreover, mononuclear cell F11R expression positively correlates with human high-grade glioma and additionally serves as a biomarker for GBM patient survival, regardless of GBM molecular subtype.These studies establish F11R as a novel monocyte prognostic marker for GBM critical for defining a subpopulation of stromal cells for future potential therapeutic intervention.

Developing chemotherapy for diffuse pontine intrinsic gliomas (DIPG).

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Gwak, Ho-Shin; Park, Hyeon Jin

2017-12-01

Prognosis of diffuse intrinsic pontine glioma (DIPG) is poor, with a median survival of 10 months after radiation. At present, chemotherapy has failed to show benefits over radiation. Advances in biotechnology have enabled the use of autopsy specimens for genomic analyses and molecular profiling of DIPG, which are quite different from those of supratentorial high grade glioma. Recently, combined treatments of cytotoxic agents with target inhibitors, based on biopsied tissue, are being examined in on-going trials. Spontaneous DIPG mice models have been recently developed that is useful for preclinical studies. Finally, the convection-enhanced delivery could be used to infuse drugs directly into the brainstem parenchyma, to which conventional systemic administration fails to achieve effective concentration. The WHO glioma classification defines a diffuse midline glioma with a H3-K27M-mutation, and we expect increase of tissue confirmation of DIPG, which will give us the biological information helping the development of a targeted therapy. Copyright © 2017 Elsevier B.V. All rights reserved.

Fotemustine: A Third-Generation Nitrosourea for the Treatment of Recurrent Malignant Gliomas

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Beauchesne, Patrick

2012-01-01

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas

Fotemustine: A Third-Generation Nitrosourea for the Treatment of Recurrent Malignant Gliomas

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Patrick Beauchesne

2012-02-01

Full Text Available Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas.

Fotemustine: A Third-Generation Nitrosourea for the Treatment of Recurrent Malignant Gliomas

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Beauchesne, Patrick [Neuro-oncology/Neurology, University Hospital of Nancy, Hôpital CENTRAL, CO N 34,54035 Nancy cedex (France)

2012-02-01

Malignant gliomas account for approximately 60% of all primary brain tumors in adults. The prognosis for patients with malignant glioma has not changed significantly in recent years. Despite debulking surgery, radiotherapy and cytotoxic chemotherapy, the median survival time is nine to 12 months, and very few, if any, patients are cured from this illness. Fotemustine is an alkylating agent characterized by the grafting of a phosphonoalanine group onto the nitrosourea radical with consequent high lipophilicity and improved diffusion through the cell membrane and the blood-brain barrier. Fotemustine has been registered for use in two indications: disseminated malignant melanoma, including cerebral metastases, and primary brain tumors. Fotemustine is currently used in Europe, particularly in France and Italy, as a salvage therapy for recurrent malignant gliomas. Myelosuppression, leucopenia and thrombocytopenia are the most frequent side effects of treatment with fotemustine. The objective response to this treatment is between 26% and 70%, and the reported median survival time is 10 months. New drug combinations containing fotemustine and angiogenesis inhibitors, such as bevacizumab, are currently under development. In this review, we describe all the combinations of fotemustine currently used in clinical practice for recurrent malignant gliomas.

Tipifarnib in Treating Young Patients With Recurrent or Progressive High-Grade Glioma, Medulloblastoma, Primitive Neuroectodermal Tumor, or Brain Stem Glioma

Science.gov (United States)

2013-10-07

Childhood High-grade Cerebral Astrocytoma; Childhood Oligodendroglioma; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma

Decreased interleukin-20 expression in scleroderma skin contributes to cutaneous fibrosis.

Science.gov (United States)

Kudo, Hideo; Jinnin, Masatoshi; Asano, Yoshihide; Trojanowska, Maria; Nakayama, Wakana; Inoue, Kuniko; Honda, Noritoshi; Kajihara, Ikko; Makino, Katsunari; Fukushima, Satoshi; Ihn, Hironobu

2014-06-01

To clarify the role of interleukin-20 (IL-20) in the regulatory mechanism of extracellular matrix expression and to determine the contribution of IL-20 to the phenotype of systemic sclerosis (SSc). Protein and messenger RNA (mRNA) levels of collagen, Fli-1, IL-20, and IL-20 receptor (IL-20R) were analyzed using polymerase chain reaction (PCR) array, immunoblotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time PCR. PCR array revealed that IL-20 decreased gene expression of α2(I) collagen (0.03-fold), Smad3 (0.02-fold), and endoglin (0.05-fold) in cultured normal dermal fibroblasts. Fli-1 protein expression was induced by IL-20 (~2-fold). The inhibition of collagen by IL-20, the induction of Fli-1 by IL-20, and the reduction of Smad3 and endoglin by IL-20 were also observed in SSc fibroblasts. Serum IL-20 levels were reduced only slightly in SSc patients but were significantly decreased in patients with scleroderma spectrum disorders (the prodromal stage of SSc) compared with those in normal subjects (111.3 pg/ml versus 180.4 pg/ml; P value of IL-20 and IL-20R, their function and expression in vivo should be further studied. Copyright © 2014 by the American College of Rheumatology.

Proton magnetic resonance spectroscopy in the distinction of high-grade cerebral gliomas from single metastatic brain tumors

International Nuclear Information System (INIS)

Server, Andres; Schellhorn, Till; Haakonsen, Monika; Nakstad, Per H.; Josefsen, Roger; Kulle, Bettina; Maehlen, Jan; Kumar, Theresa; Gadmar, Oeystein; Langberg, Carl W.

2010-01-01

Background: Brain metastases and primary high-grade gliomas, including glioblastomas multiforme (GBM) and anaplastic astrocytomas (AA), may be indistinguishable by conventional magnetic resonance (MR) imaging. Identification of these tumors may have therapeutic consequences. Purpose: To assess the value of MR spectroscopy (MRS) using short and intermediate echo time (TE) in differentiating solitary brain metastases and high-grade gliomas on the basis of differences in metabolite ratios in the intratumoral and peritumoral region. Material and Methods: We performed MR imaging and MRS in 73 patients with histologically verified intraaxial brain tumors: 53 patients with high-grade gliomas (34 GBM and 19 AA) and 20 patients with metastatic brain tumors. The metabolite ratios of Cho/Cr, Cho/NAA, and NAA/Cr at intermediate TE and the presence of lipids at short TE were assessed from spectral maps in the tumoral core, peritumoral edema, and contralateral normal-appearing white matter. The differences in the metabolite ratios between high-grade gliomas/GBM/AA and metastases were analyzed statistically. Cutoff values of Cho/Cr, Cho/NAA, and NAA/Cr ratios in the peritumoral edema, as well as Cho/Cr and NAA/Cr ratios in the tumoral core for distinguishing high-grade gliomas/GBM/AA from metastases were determined by receiver operating characteristic (ROC) curve analysis. Results: Significant differences were noted in the peritumoral Cho/Cr, Cho/NAA, and NAA/ Cr ratios between high-grade gliomas/GBM/AA and metastases. ROC analysis demonstrated a cutoff value of 1.24 for peritumoral Cho/Cr ratio to provide sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of 100%, 88.9%, 80.0%, and 100%, respectively, for discrimination between high-grade gliomas and metastases. By using a cutoff value of 1.11 for peritumoral Cho/NAA ratio, the sensitivity was 100%, the specificity was 91.1%, the PPV was 83.3%, and the NPV was 100%. Conclusion: The results of this

Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes.

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Auvergne, Romane M; Sim, Fraser J; Wang, Su; Chandler-Militello, Devin; Burch, Jaclyn; Al Fanek, Yazan; Davis, Danielle; Benraiss, Abdellatif; Walter, Kevin; Achanta, Pragathi; Johnson, Mahlon; Quinones-Hinojosa, Alfredo; Natesan, Sridaran; Ford, Heide L; Goldman, Steven A

2013-06-27

Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning World Health Organization grades II-IV. Messenger RNA profiling identified a cohort of genes that distinguished A2B5+ glioma tumor progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, which included the transcription factor SIX1 and its principal cofactors, EYA1 and DACH2. Small hairpin RNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs with those of normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood and more specifically targeted. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Tissue pO2 of Orthotopic 9L and C6 Gliomas and Tumor-Specific Response to Radiotherapy and Hyperoxygenation

International Nuclear Information System (INIS)

Khan, Nadeem; Li Hongbin; Hou, Huagang; Lariviere, Jean P.; Gladstone, David J.; Demidenko, Eugene; Swartz, Harold M.

2009-01-01

Purpose: Tumor hypoxia is a well-known therapeutic problem; however, a lack of methods for repeated measurements of glioma partial pressure of oxygen (pO 2 ) limits the ability to optimize the therapeutic approaches. We report the effects of 9.3 Gy of radiation and carbogen inhalation on orthotopic 9L and C6 gliomas and on the contralateral brain pO 2 in rats using a new and potentially widely useful method, multisite in vivo electron paramagnetic resonance oximetry. Methods and Materials: Intracerebral 9L and C6 tumors were established in the left hemisphere of syngeneic rats, and electron paramagnetic resonance oximetry was successfully used for repeated tissue pO 2 measurements after 9.3 Gy of radiation and during carbogen breathing for 5 consecutive days. Results: Intracerebral 9L gliomas had a pO 2 of 30-32 mm Hg and C6 gliomas were relatively hypoxic, with a pO 2 of 12-14 mm Hg (p 2 of the contralateral brain was 40-45 mm Hg in rats with either 9L or C6 gliomas. Irradiation resulted in a significant increase in pO 2 of the 9L gliomas only. A significant increase in the pO 2 of the 9L and C6 gliomas was observed in rats breathing carbogen, but this effect decreased during 5 days of repeated experiments in the 9L gliomas. Conclusion: These results highlight the tumor-specific effect of radiation (9.3.Gy) on tissue pO 2 and the different responses to carbogen inhalation. The ability of electron paramagnetic resonance oximetry to provide direct repeated measurements of tissue pO 2 could have a vital role in understanding the dynamics of hypoxia during therapy that could then be optimized by scheduling doses at times of improved tumor oxygenation

111Indium (DTPA-octreotide) scintigraphy in patients with cerebral gliomas

International Nuclear Information System (INIS)

Luyken, C.; Hildebrandt, G.; Klug, N.; Scheidhauer, K.; Schicha, H.; Krisch, B.

1994-01-01

Somatostatin receptors (SR) have been identified in vitro in normal brain tissue, in neuro-endocrine tumours and in cerebral gliomas WHO grade 1 or 2 by autoradiography or using somatostatin-gold conjugates. In vivo, SR detection has become possible by scintigraphy applying the somatostatin analogue octreotide, radio-labelled with 111 indium. It was supposed that expression of SR in cerebral gliomas corresponds to low grade tumour malignancy and that, in vivo, somatostatin receptor scintigraphy (SRS) could refine and improve the WHO grading system for cerebral gliomas. Nineteen patients with cerebral gliomas (grade 2: n=8, grade 3: n=3, grade 4: n=8) were examined with 111 In (DTPA-octreotide) to evaluate, whether SRS could improve the pre-operative estimation of tumour biology and the postoperative management. The results of SRS were related with the histological findings and with the in vitro demonstration of somatostatin-binding sites on cultured tumour cells incubated with a somatostatin-gold conjugate. In vivo, none of the patients with glioma grade 2 showed enhanced tracer uptake in the SRS, whereas in vitro SR were detected in cultured tumour tissue in 5 out of 5 cases. Every patient with glioma grade 3 or 4 demonstrated a high focal uptake of 111 In (DTPA-octreotide), as shown by SRS. Three patients with glioma grade 4, additionally examined with 99mTc-DTPA, showed an increased tracer uptake within the tumour area when compared with results of SRS. In vitro, SR were detected on tumour cell surface in 5 out of 6 tissue samples from patients with gliomas grade 3 or 4. One patient harbouring a cerebral abscess with a high focal tracer uptake in the SRS but with absence of somatostatin-binding sites in vitro. We conclude, that in glioma patients enhanced tracer uptake in receptor scintigraphy with 111 In (DTPA-octreotide) does not depend on the presence of SR in tumour but on the dysfunction of the blood-brain barrier. Thus, SRS dose not improve the

Immunotherapy Approaches for Malignant Glioma From 2007 to 2009

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Sampson, John H.

2012-01-01

Malignant glioma is a deadly disease for which there have been few therapeutic advances over the past century. Although previous treatments were largely unsuccessful, glioma may be an ideal target for immune-based therapy. Recently, translational research led to several clinical trials based on tumor immunotherapy to treat patients with malignant glioma. Here we review 17 recent glioma immunotherapy clinical trials, published over the past 3 years. Various approaches were used, including passive transfer of naked and radiolabeled antibodies, tumor antigen-specific peptide immunization, and the use of patient tumor cells with or without dendritic cells as vaccines. We compare and discuss the current state of the art of clinical immunotherapy treatment, as well as its limited successes, pitfalls, and future potential. PMID:20424975

Paclitaxel poliglumex, temozolomide, and radiation for newly diagnosed high-grade glioma: a Brown University Oncology Group Study.

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Jeyapalan, Suriya; Boxerman, Jerrold; Donahue, John; Goldman, Marc; Kinsella, Timothy; Dipetrillo, Thomas; Evans, Devon; Elinzano, Heinrich; Constantinou, Maria; Stopa, Edward; Puthawala, Yakub; Cielo, Deus; Santaniello, Alyson; Oyelese, Adetokunbo; Mantripragada, Kalyan; Rosati, Kayla; Isdale, Debora; Safran, Howard

2014-10-01

Paclitaxel poliglumex (PPX), a drug conjugate that links paclitaxel to poly-L-glutamic acid, is a potent radiation sensitizer. Prior studies in esophageal cancer have demonstrated that PPX (50 mg/m/wk) can be administered with concurrent radiation with acceptable toxicity. The primary objective of this study was to determine the safety of the combination of PPX with temozolomide and concurrent radiation for high-grade gliomas. Eligible patients were required to have WHO grade 3 or 4 gliomas. Patients received weekly PPX (50 mg/m/wk) combined with standard daily temozolomide (75 mg/m) for 6 weeks with concomitant radiation (2.0 Gy, 5 d/wk for a total dose of 60 Gy). Twenty-five patients were enrolled, 17 with glioblastoma and 8 with grade 3 gliomas. Seven of 25 patients had grade 4 myelosuppression. Hematologic toxicity lasted up to 5 months suggesting a drug interaction between PPX and temozolomide. For patients with glioblastoma, the median progression-free survival was 11.5 months and the median overall survival was 18 months. PPX could not be safely combined with temozolomide due to grade 4 hematologic toxicity. However, the favorable progression-free and overall survival suggest that PPX may enhance radiation for glioblastoma. A randomized study of single agent PPX/radiation versus temozolomide/radiation for glioblastoma without MGMT methylation is underway.

Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells.

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Ge, Peng-Fei; Zhang, Ji-Zhou; Wang, Xiao-Fei; Meng, Fan-Kai; Li, Wen-Chen; Luan, Yong-Xin; Ling, Feng; Luo, Yi-Nan

2009-07-01

The ubiquitin-proteasome system (UPS) and lysosome-dependent macroautophagy (autophagy) are two major intracellular pathways for protein degradation. Recent studies suggest that proteasome inhibitors may reduce tumor growth and activate autophagy. Due to the dual roles of autophagy in tumor cell survival and death, the effect of autophagy on the destiny of glioma cells remains unclear. In this study, we sought to investigate whether inhibition of the proteasome can induce autophagy and the effects of autophagy on the fate of human SHG-44 glioma cells. The proteasome inhibitor MG-132 was used to induce autophagy in SHG-44 glioma cells, and the effect of autophagy on the survival of SHG-44 glioma cells was investigated using an autophagy inhibitor 3-MA. Cell viability was measured by MTT assay. Apoptosis and cell cycle were detected by flow cytometry. The expression of autophagy related proteins was determined by Western blot. MG-132 inhibited cell proliferation, induced cell death and cell cycle arrest at G(2)/M phase, and activated autophagy in SHG-44 glioma cells. The expression of autophagy-related Beclin-1 and LC3-I was significantly up-regulated and part of LC3-I was converted into LC3-II. However, when SHG-44 glioma cells were co-treated with MG-132 and 3-MA, the cells became less viable, but cell death and cell numbers at G(2)/M phase increased. Moreover, the accumulation of acidic vesicular organelles was decreased, the expression of Beclin-1 and LC3 was significantly down-regulated and the conversion of LC3-II from LC3-I was also inhibited. Inhibition of the proteasome can induce autophagy in human SHG-44 glioma cells, and inhibition of autophagy increases cell death. This discovery may shed new light on the effect of autophagy on modulating the fate of SHG-44 glioma cells.Acta Pharmacologica Sinica (2009) 30: 1046-1052; doi: 10.1038/aps.2009.71.

RasGRP3 regulates the migration of glioma cells via interaction with Arp3

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Lee, Hae Kyung; Finniss, Susan; Cazacu, Simona; Xiang, Cunli; Poisson, Laila M.; Blumberg, Peter M.; Brodie, Chaya

2015-01-01

Glioblastoma (GBM), the most aggressive primary brain tumors, are highly infiltrative. Although GBM express high Ras activity and Ras proteins have been implicated in gliomagenesis, Ras-activating mutations are not frequent in these tumors. RasGRP3, an important signaling protein responsive to diacylglycerol (DAG), increases Ras activation. Here, we examined the expression and functions of RasGRP3 in GBM and glioma cells. RasGRP3 expression was upregulated in GBM specimens and glioma stem cells compared with normal brains and neural stem cells, respectively. RasGRP3 activated Ras and Rap1 in glioma cells and increased cell migration and invasion partially via Ras activation. Using pull-down assay and mass spectroscopy we identified the actin-related protein, Arp3, as a novel interacting protein of RasGRP3. The interaction of RasGRP3 and Arp3 was validated by immunofluorescence staining and co-immunoprecipitation, and PMA, which activates RasGRP3 and induces its translocation to the peri-nuclear region, increased the association of Arp3 and RasGRP3. Arp3 was upregulated in GBM, regulated cell spreading and migration and its silencing partially decreased these effects of RasGRP3 in glioma cells. In summary, RasGRP3 acts as an important integrating signaling protein of the DAG and Ras signaling pathways and actin polymerization and represents an important therapeutic target in GBM. PMID:25682201

Hypoxic regulation of the expression of genes encoded estrogen related proteins in U87 glioma cells: eff ect of IRE1 inhibition.

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Minchenko, D O; Riabovol, O O; Ratushna, O O; Minchenko, O H

2017-01-01

The aim of the present study was to examine the effect of inhibition of endoplasmic reticulum stress signaling, mediated by IRE1 (inositol requiring enzyme 1), which is a central mediator of the unfolded protein response on the expression of genes encoded estrogen related proteins (NRIP1/RIP140, TRIM16/EBBP, ESRRA/NR3B1, FAM162A/E2IG5, PGRMC2/PMBP, and SLC39A6/LIV-1) and their hypoxic regulation in U87 glioma cells for evaluation of their possible significance in the control of glioma cells proliferation. The expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells, transfected by empty vector pcDNA3.1 (control) and cells without IRE1 signaling enzyme function (transfected by dnIRE1) upon hypoxia, was studied by a quantitative polymerase chain reaction. Inhibition of both enzymatic activities (kinase and endoribonuclease) of IRE1 signaling enzyme function up-regulates the expression of EBBP, E2IG5, PGRMC2, and SLC39A6 genes is in U87 glioma cells in comparison with the control glioma cells, with more significant changes for E2IG5 and PGRMC2 genes. At the same time, the expression of NRIP1 and ESRRA genes is strongly down-regulated in glioma cells upon inhibition of IRE1. We also showed that hypoxia increases the expression of E2IG5, PGRMC2, and EBBP genes and decreases NRIP1 and ESRRA genes expression in control glioma cells. Furthermore, the inhibition of IRE1 in U87 glioma cells decreases the eff ect of hypoxia on the expression of E2IG5 and PGRMC2 genes, eliminates hypoxic regulation of NRIP1 gene, and enhances the sensitivity of ESRRA gene to hypoxic condition. Furthermore, the expression of SLC39A6 gene is resistant to hypoxia in both the glioma cells with and without IRE1 signaling enzyme function. Results of this investigation demonstrate that inhibition of IRE1 signaling enzyme function affects the expression of NRIP1, EBBP, ESRRA, E2IG5, PGRMC2, and SLC39A6 genes in U87 glioma cells in gene specific manner and these changes

Upregulation of B23 promotes tumor cell proliferation and predicts poor prognosis in glioma

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Chen, Jianguo [Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province (China); Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province (China); Sun, Jie; Yang, Liu; Yan, Yaohua; Shi, Wei; Shi, Jinlong; Huang, Qingfeng; Chen, Jian [Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001, Jiangsu Province (China); Lan, Qing, E-mail: lanqingsj@163.com [Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, Jiangsu Province (China)

2015-10-09

B23 (also known as Nucleophosmin, NPM, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. In this study we intended to investigate the clinical significance of B23 expression in human glioma and its biological function in glioma cells. Western blot and immunohistochemistry analysis showed that B23 was overexpressed in glioma tissues and glioma cell lines. In addition, the expression level of B23 was positively correlated with glioma pathological grade and Ki-67 expression. Kaplan–Meier analysis revealed that a higher B23 expression in patients with glioma was associated with a poorer prognosis. In vitro, after the release of glioma cell lines from serum starvation, the expression of B23 was upregulated, as well as PCNA (Proliferating Cell Nuclear Antigen) and cyclin A. In addition, knockdown of B23 by small interfering RNA transfection diminished the expression of PCNA, cyclin D1 and arrested cell growth at G1 phase. Taken together, our results implied that B23 could be a candidate prognostic biomarker as well as a potential therapeutical target of glioma. - Highlights: • B23 expression increased as the malignant degree of glioma increased, which was consistent with Ki-67 expression. • High expression of B23 could be a strong determinant of poor prognosis in glioma. • B23 may be involved in the proliferation of glioma in a cell-cycle-dependent pathway. • Knockdown of B23 expression by siRNA could affect the progression of glioma. • B23 may be a potential prognosis biomarker and a possible therapeutic target for glioma.

Utility of multiparametric 3-T MRI for glioma characterization

International Nuclear Information System (INIS)

Roy, Bhaswati; Gupta, Rakesh K.; Maudsley, Andrew A.; Sheriff, Sulaiman; Awasthi, Rishi; Mohakud, Sudipta; Gu, Meng; Spielman, Daniel M.; Husain, Nuzhat; Behari, Sanjay; Pandey, Chandra M.; Rathore, Ram K.S.; Alger, Jeffry R.

2013-01-01

Accurate grading of cerebral glioma using conventional structural imaging techniques remains challenging due to the relatively poor sensitivity and specificity of these methods. The purpose of this study was to evaluate the relative sensitivity and specificity of structural magnetic resonance imaging and MR measurements of perfusion, diffusion, and whole-brain spectroscopic parameters for glioma grading. Fifty-six patients with radiologically suspected untreated glioma were studied with T1- and T2-weighted MR imaging, dynamic contrast-enhanced MR imaging, diffusion tensor imaging, and volumetric whole-brain MR spectroscopic imaging. Receiver-operating characteristic analysis was performed using the relative cerebral blood volume (rCBV), apparent diffusion coefficient, fractional anisotropy, and multiple spectroscopic parameters to determine optimum thresholds for tumor grading and to obtain the sensitivity, specificity, and positive and negative predictive values for identifying high-grade gliomas. Logistic regression was performed to analyze all the parameters together. The rCBV individually classified glioma as low and high grade with a sensitivity and specificity of 100 and 88 %, respectively, based on a threshold value of 3.34. On combining all parameters under consideration, the classification was achieved with 2 % error and sensitivity and specificity of 100 and 96 %, respectively. Individually, CBV measurement provides the greatest diagnostic performance for predicting glioma grade; however, the most accurate classification can be achieved by combining all of the imaging parameters. (orig.)

MRI in Glioma Immunotherapy: Evidence, Pitfalls, and Perspectives

Directory of Open Access Journals (Sweden)

Domenico Aquino

2017-01-01

Full Text Available Pseudophenomena, that is, imaging alterations due to therapy rather than tumor evolution, have an important impact on the management of glioma patients and the results of clinical trials. RANO (response assessment in neurooncology criteria, including conventional MRI (cMRI, addressed the issues of pseudoprogression after radiotherapy and concomitant chemotherapy and pseudoresponse during antiangiogenic therapy of glioblastomas (GBM and other gliomas. The development of cancer immunotherapy forced the identification of further relevant response criteria, summarized by the iRANO working group in 2015. In spite of this, the unequivocal definition of glioma progression by cMRI remains difficult particularly in the setting of immunotherapy approaches provided by checkpoint inhibitors and dendritic cells. Advanced MRI (aMRI may in principle address this unmet clinical need. Here, we discuss the potential contribution of different aMRI techniques and their indications and pitfalls in relation to biological and imaging features of glioma and immune system interactions.

Proposal for development of a system for planning radiotherapy of gliomas

International Nuclear Information System (INIS)

Caldeira, Alexandre D.

2015-01-01

In the last three years, discussions were held on several topics in Nuclear Medicine area, starting with the nuclear data processing, passing by deterministic and stochastic mathematical methods, and finalizing with computer simulations of the following phenomena: neutron transport, applied to boron neutron capture therapy, and neutron diffusion, to study growth of tumor cells. From a mathematical model applied to radiotherapy of gliomas available in literature, it is proposed a strategy for development of a computer system to assist the planning radiotherapy of gliomas. (author)

Berberine enhances inhibition of glioma tumor cell migration and invasiveness mediated by arsenic trioxide

International Nuclear Information System (INIS)

Lin, Tseng-Hsi; Kuo, Hsing-Chun; Chou, Fen-Pi; Lu, Fung-Jou

2008-01-01

Arsenic trioxide (As 2 O 3 ) exhibits promising anticarcinogenic activity in acute promyelocytic leukemic patients and induces apoptosis in various tumor cells in vitro. Here, we investigated the effect of the natural alkaloid berberine on As 2 O 3 -mediated inhibition of cancer cell migration using rat and human glioma cell lines. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to determine the viability of rat C6 and human U-87 glioma cells after treatment with As 2 O 3 or berberine, and after co-treatment with As 2 O 3 and berberine. The wound scratch and Boyden chamber assays were applied to determine the effect of As 2 O 3 and berberine on the migration capacity and invasiveness of glioma cancer cells. Zymography and Western blot analyses provided information on the effect of As 2 O 3 and berberine on the intracellular translocation and activation of protein kinase C (PKC), and some PKC-related downstream factors. Most assays were performed three times, independently, and data were analyzed using ANOVA. The cell viability studies demonstrated that berberine enhances As 2 O 3 -mediated inhibition of glioma cell growth after 24 h incubation. Untreated control cells formed a confluent layer, the formation of which was inhibited upon incubation with 5 μM As 2 O 3 . The latter effect was even more pronounced in the presence of 10 μM berberine. The As 2 O 3 -mediated reduction in motility and invasion of glioma cells was enhanced upon co-treatment with berberine. Furthermore, it has been reported that PKC isoforms influence the morphology of the actin cytoskeleton, as well as the activation of metalloproteases MT1-MMP and MMP-2, reported to be involved in cancer cell migration. Treatment of glioma cells with As 2 O 3 and berberine significantly decreased the activation of PKC α and ε and led to actin cytoskeleton rearrangements. The levels of two downstream transcription factors, myc and jun, and MT1-MMP and MMP-2 were also

Tumor-infiltrating lymphocytes (TILs) from patients with glioma

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Liu, Zhenjiang; Meng, Qingda; Bartek, Jiri

2017-01-01

Tumor-infiltrating lymphocytes (TILs) may represent a viable source of T cells for the biological treatment of patients with gliomas. Glioma tissue was obtained from 16 patients, tumor cell lines were established, and TILs were expanded in 16/16 cases using a combination of IL-2/IL-15/IL-21...

The value of intraoperative sonography in low grade glioma surgery.

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Petridis, Athanasios K; Anokhin, Maxim; Vavruska, Jan; Mahvash, Mehran; Scholz, Martin

2015-04-01

There is a number of different methods to localize a glioma intraoperatively. Neuronavigation, intraoperative MRI, 5-aminolevulinic acid, as well as intraoperative sonography. Every method has its advantages and disadvantages. Low grade gliomas do not show a specific signal with 5-aminolevulinic acid and are difficult to distinguish macroscopically from normal tissue. In the present study we stress out the importance of intraoperative diagnostic ultrasound for localization of low grade gliomas. We retrospectively evaluated the charts and MRIs of 34 patients with low grade gliomas operated in our department from 2011 until December 2014. The efficacy of ultrasound as an intraoperative navigational tool was assessed. In 15 patients ultrasound was used and in 19 not. Only histologically proven low grades gliomas (astrocytomas grade II) were evaluated. In none of the patients where ultrasound (combined with neuronavigation) was used (N=15) to find the tumors, the target was missed, whereas the exclusive use of neuronavigation missed the target in 5 of 19 cases of small subcortical low grade gliomas. Intraoperative ultrasound is an excellent tool in localizing low grade gliomas intraoperatively. It is an inexpensive, real time neuronavigational tool, which overcomes brain shift. Even when identifying the tumors with ultrasound is very reliable, the extend of resection and the decision to remove any residual tumor with the help of ultrasound is at the moment unreliable. Copyright © 2015 Elsevier B.V. All rights reserved.

RTEL1 tagging SNPs and haplotypes were associated with glioma development.

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Li, Gang; Jin, Tianbo; Liang, Hongjuan; Zhang, Zhiguo; He, Shiming; Tu, Yanyang; Yang, Haixia; Geng, Tingting; Cui, Guangbin; Chen, Chao; Gao, Guodong

2013-05-17

As glioma ranks as the first most prevalent solid tumors in primary central nervous system, certain single-nucleotide polymorphisms (SNPs) may be related to increased glioma risk, and have implications in carcinogenesis. The present case-control study was carried out to elucidate how common variants contribute to glioma susceptibility. Ten candidate tagging SNPs (tSNPs) were selected from seven genes whose polymorphisms have been proven by classical literatures and reliable databases to be tended to relate with gliomas, and with the minor allele frequency (MAF)>5% in the HapMap Asian population. The selected tSNPs were genotyped in 629 glioma patients and 645 controls from a Han Chinese population using the multiplexed SNP MassEXTEND assay calibrated. Two significant tSNPs in RTEL1 gene were observed to be associated with glioma risk (rs6010620, P=0.0016, OR: 1.32, 95% CI: 1.11-1.56; rs2297440, P=0.001, OR: 1.33, 95% CI: 1.12-1.58) by χ2 test. It was identified the genotype "GG" of rs6010620 acted as the protective genotype for glioma (OR, 0.46; 95% CI, 0.31-0.7; P=0.0002), while the genotype "CC" of rs2297440 as the protective genotype in glioma (OR, 0.47; 95% CI, 0.31-0.71; P=0.0003). Furthermore, haplotype "GCT" in RTEL1 gene was found to be associated with risk of glioma (OR, 0.7; 95% CI, 0.57-0.86; Fisher's P=0.0005; Pearson's P=0.0005), and haplotype "ATT" was detected to be associated with risk of glioma (OR, 1.32; 95% CI, 1.12-1.57; Fisher's P=0.0013; Pearson's P=0.0013). Two single variants, the genotypes of "GG" of rs6010620 and "CC" of rs2297440 (rs6010620 and rs2297440) in the RTEL1 gene, together with two haplotypes of GCT and ATT, were identified to be associated with glioma development. And it might be used to evaluate the glioma development risks to screen the above RTEL1 tagging SNPs and haplotypes. The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1993021136961998.

Beyond Alkylating Agents for Gliomas: Quo Vadimus?

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Puduvalli, Vinay K; Chaudhary, Rekha; McClugage, Samuel G; Markert, James

2017-01-01

Recent advances in therapies have yielded notable success in terms of improved survival in several cancers. However, such treatments have failed to improve outcome in patients with gliomas for whom surgery followed by radiation therapy and chemotherapy with alkylating agents remain the standard of care. Genetic and epigenetic studies have helped identify several alterations specific to gliomas. Attempts to target these altered pathways have been unsuccessful due to various factors, including tumor heterogeneity, adaptive resistance of tumor cells, and limitations of access across the blood-brain barrier. Novel therapies that circumvent such limitations have been the focus of intense study and include approaches such as immunotherapy, targeting of signaling hubs and metabolic pathways, and use of biologic agents. Immunotherapeutic approaches including tumor-targeted vaccines, immune checkpoint blockade, antibody-drug conjugates, and chimeric antigen receptor-expressing cell therapies are in various stages of clinical trials. Similarly, identification of key metabolic pathways or converging hubs of signaling pathways that are tumor specific have yielded novel targets for therapy of gliomas. In addition, the failure of conventional therapies against gliomas has led to a growing interest among patients in the use of alternative therapies, which in turn has necessitated developing evidence-based approaches to the application of such therapies in clinical studies. The development of these novel approaches bears potential for providing breakthroughs in treatment of more meaningful and improved outcomes for patients with gliomas.

Plant thymidine kinase 1: a novel efficient suicide gene for malignant glioma therapy

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Khan, Z.; Knecht, Wolfgang; Willer, Mette

2010-01-01

The prognosis for malignant gliomas remains poor, and new treatments are urgently needed. Targeted suicide gene therapy exploits the enzymatic conversion of a prodrug, such as a nucleoside analog, into a cytotoxic compound. Although this therapeutic strategy has been considered a promising regimen...... suicide gene therapy system in combination with stem cell mediated gene delivery promises new treatment of malignant gliomas....

Treating malignant glioma in Chinese patients: update on temozolomide

Directory of Open Access Journals (Sweden)

Chang L

2014-02-01

Full Text Available Liang Chang,1 Jun Su,1 Xiuzhi Jia,2,3 Huan Ren2,3 1Department of Neurosurgery, The Tumor Hospital of Harbin Medical University, 2Department of Immunology, Harbin Medical University, 3Key Lab Infection and Immunity, Heilongjiang Province, Harbin, People's Republic of China Abstract: Malignant glioma, ie, anaplastic astrocytoma and glioblastoma, is the most common type of primary malignant brain tumor in the People's Republic of China, and is particularly aggressive. The median survival of patients with newly diagnosed glioblastoma is only 12–14 months despite advanced therapeutic strategies. Treatment of malignant glioma consists mainly of surgical resection followed by adjuvant radiation and chemotherapy. Temozolomide (TMZ, a second-generation oral alkylating agent, is playing an increasingly important role in the treatment of malignant glioma in Chinese patients. Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ. However, as a relatively new agent, the history and development of TMZ for malignant glioma is not well documented in Chinese patients. Multicenter, randomized controlled trials including appropriately sized patient populations investigating multiple aspects of TMZ therapy and related combination therapies are warranted in patients with malignant glioma. This review provides an update on the efficacy, mechanism of action, adverse reactions, and clinical role of TMZ in the treatment of malignant glioma in Chinese patients. Keywords: malignant glioma, chemotherapy, temozolomide, efficacy, side effect, People's Republic of China

Tumor-specific binding of radiolabeled G-22 monoclonal antibody in glioma patients

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Yoshida, Jun; Wakabayashi, Toshihiko; Mizuno, Masaaki; Sugita, Kenichiro; Oshima, Motoo; Tadokoro, Masanori; Sakuma, Sadayuki [Nagoya Univ. (Japan). Faculty of Medicine; Seo, Hisao

1992-03-01

Iodine-131-labeled G-22 monoclonal antibody F(ab'){sub 2} fragment reacting specifically with a glioma-associated surface glycoprotein was administered to 12 glioma patients to investigate its use in radioimaging of intracranial gliomas. No immediate or delayed side effects were attributable to antibody injection. Nine patients received the radiolabeled complex intravenously. The images of low-grade gliomas were generally poor and disappeared within 4 days. High-contrast images were obtained beyond the 7th day in high-grade gliomas except one case in the pineal region. Three patients received intraventricular or intratumoral administration. Clear images of all tumors were demonstrated from the 2nd until later than the 7th day. One patient with cerebrospinal fluid (CSF) dissemination of brainstem glioma demonstrated negative CSF cytology after intraventricular administration. (author).

Targeting the erythropoietin receptor on glioma cells reduces tumour growth

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Peres, Elodie A.; Valable, Samuel; Guillamo, Jean-Sebastien; Marteau, Lena; Bernaudin, Jean-Francois; Roussel, Simon; Lechapt-Zalcman, Emmanuele; Bernaudin, Myriam; Petit, Edwige

2011-01-01

Hypoxia has been shown to be one of the major events involved in EPO expression. Accordingly, EPO might be expressed by cerebral neoplastic cells, especially in glioblastoma, known to be highly hypoxic tumours. The expression of EPOR has been described in glioma cells. However, data from the literature remain descriptive and controversial. On the basis of an endogenous source of EPO in the brain, we have focused on a potential role of EPOR in brain tumour growth. In the present study, with complementary approaches to target EPO/EPOR signalling, we demonstrate the presence of a functional EPO/EPOR system on glioma cells leading to the activation of the ERK pathway. This EPO/EPOR system is involved in glioma cell proliferation in vitro. In vivo, we show that the down-regulation of EPOR expression on glioma cells reduces tumour growth and enhances animal survival. Our results support the hypothesis that EPOR signalling in tumour cells is involved in the control of glioma growth.

Roles of sphingosine-1-phosphate (S1P) receptors in malignant behavior of glioma cells. Differential effects of S1P2 on cell migration and invasiveness

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Young, Nicholas; Van Brocklyn, James R.

2007-01-01

Sphingosine-1-phosphate (S1P) is a bioactive lipid that signals through a family of five G-protein-coupled receptors, termed S1P 1-5 . S1P stimulates growth and invasiveness of glioma cells, and high expression levels of the enzyme that forms S1P, sphingosine kinase-1, correlate with short survival of glioma patients. In this study we examined the mechanism of S1P stimulation of glioma cell proliferation and invasion by either overexpressing or knocking down, by RNA interference, S1P receptor expression in glioma cell lines. S1P 1 , S1P 2 and S1P 3 all contribute positively to S1P-stimulated glioma cell proliferation, with S1P 1 being the major contributor. Stimulation of glioma cell proliferation by these receptors correlated with activation of ERK MAP kinase. S1P 5 blocks glioma cell proliferation, and inhibits ERK activation. S1P 1 and S1P 3 enhance glioma cell migration and invasion. S1P 2 inhibits migration through Rho activation, Rho kinase signaling and stress fiber formation, but unexpectedly, enhances glioma cell invasiveness by stimulating cell adhesion. S1P 2 also potently enhances expression of the matricellular protein CCN1/Cyr61, which has been implicated in tumor cell adhesion, and invasion as well as tumor angiogenesis. A neutralizing antibody to CCN1 blocked S1P 2 -stimulated glioma invasion. Thus, while S1P 2 decreases glioma cell motility, it may enhance invasion through induction of proteins that modulate glioma cell interaction with the extracellular matrix

Identification of molecular pathways facilitating glioma cell invasion in situ.

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Ido Nevo

Full Text Available Gliomas are mostly incurable secondary to their diffuse infiltrative nature. Thus, specific therapeutic targeting of invasive glioma cells is an attractive concept. As cells exit the tumor mass and infiltrate brain parenchyma, they closely interact with a changing micro-environmental landscape that sustains tumor cell invasion. In this study, we used a unique microarray profiling approach on a human glioma stem cell (GSC xenograft model to explore gene expression changes in situ in Invading Glioma Cells (IGCs compared to tumor core, as well as changes in host cells residing within the infiltrated microenvironment relative to the unaffected cortex. IGCs were found to have reduced expression of genes within the extracellular matrix compartment, and genes involved in cell adhesion, cell polarity and epithelial to mesenchymal transition (EMT processes. The infiltrated microenvironment showed activation of wound repair and tissue remodeling networks. We confirmed by protein analysis the downregulation of EMT and polarity related genes such as CD44 and PARD3 in IGCs, and EFNB3, a tissue-remodeling agent enriched at the infiltrated microenvironment. OLIG2, a proliferation regulator and glioma progenitor cell marker upregulated in IGCs was found to function in enhancing migration and stemness of GSCs. Overall, our results unveiled a more comprehensive picture of the complex and dynamic cell autonomous and tumor-host interactive pathways of glioma invasion than has been previously demonstrated. This suggests targeting of multiple pathways at the junction of invading tumor and microenvironment as a viable option for glioma therapy.

MTSS1 is epigenetically regulated in glioma cells and inhibits glioma cell motility

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Daniel Luxen

2017-02-01

Full Text Available Epigenetic silencing by DNA methylation in brain tumors has been reported for many genes, however, their function on pathogenesis needs to be evaluated. We investigated the MTSS1 gene, identified as hypermethylated by differential methylation hybridization (DMH. Fifty-nine glioma tissue samples and seven glioma cell lines were examined for hypermethylation of the MTSS1 promotor, MTSS1 expression levels and gene dosage. GBM cell lines were treated with demethylating agents and interrogated for functional consequences of MTSS1 expression after transient transfection. Hypermethylation was significantly associated with IDH1/2 mutation. Comparative SNP analysis indicates higher incidence of loss of heterozygosity of MTSS1 in anaplastic astrocytomas and secondary glioblastomas as well as hypermethylation of the remaining allele. Reversal of promoter hypermethylation results in an increased MTSS1 expression. Cell motility was significantly inhibited by MTSS1 overexpression without influencing cell growth or apoptosis. Immunofluorescence analysis of MTSS1 in human astrocytes indicates co-localization with actin filaments. MTSS1 is down-regulated by DNA methylation in glioblastoma cell lines and is part of the G-CIMP phenotype in primary glioma tissues. Our data on normal astrocytes suggest a function of MTSS1 at focal contact structures with an impact on migratory capacity but no influence on apoptosis or cellular proliferation.

ALDH1A3: A Marker of Mesenchymal Phenotype in Gliomas Associated with Cell Invasion.

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Wenlong Zhang

Full Text Available Aldehyde dehydrogenases (ALDH is a family of enzymes including 19 members. For now, ALDH activity had been wildly used as a marker of cancer stem cells (CSCs. But biological functions of relevant isoforms and their clinical applications are still controversial. Here, we investigate the clinical significance and potential function of ALDH1A3 in gliomas. By whole-genome transcriptome microarray and mRNA sequencing analysis, we compared the expression of ALDH1A3 in high- and low- grade gliomas as well as different molecular subtypes. Microarray analysis was performed to identify the correlated genes of ALDH1A3. We further used Gene Ontology (GO and Kyoto Encyclopedia of Genes and Genomes (KEGG pathways analysis to explore the biological function of ALDH1A3. Finally, by mRNA knockdown we revealed the relationship between ALDH1A3 and the ability of tumor invasion. ALDH1A3 overexpression was significantly associated with high grade as well as the higher mortality of gliomas in survival analysis. ALDH1A3 was characteristically highly expressed in Mesenchymal (Mes subtype gliomas. Moreover, we found that ALDH1A3 was most relevant to extracellular matrix organization and cell adhesion biological process, and the ability of tumor invasion was suppressed after ALDH1A3 knockdown in vitro. In conclusion, ALDH1A3 can serve as a novel marker of Mes phenotype in gliomas with potential clinical prognostic value. The expression of ALDH1A3 is associated with tumor cell invasion.

Effects of anticancer drugs on glia-glioma brain tumor model characterized by acoustic impedance microscopy

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Soon, Thomas Tiong Kwong; Chean, Tan Wei; Yamada, Hikari; Takahashi, Kenta; Hozumi, Naohiro; Kobayashi, Kazuto; Yoshida, Sachiko

2017-07-01

An ultrasonic microscope is a useful tool for observing living tissue without chemical fixation or histochemical processing. Two-dimensional (2D) acoustic impedance microscopy developed in our previous study for living cell observation was employed to visualize intracellular changes. We proposed a brain tumor model by cocultivating rat glial cells and C6 gliomas to quantitatively analyze the effects of two types of anticancer drugs, cytochalasin B (CyB) and temozolomide (TMZ), when they were applied. We reported that CyB treatment (25 µg/ml, T = 90 min) significantly reduced the acoustic impedance of gliomas and has little effect on glial cells. Meanwhile, TMZ treatment (2 mg/ml, T = 90 min) impacted both cells equally, in which both cells’ acoustic impedances were decreased. As CyB targets the actin filament polymerization of the cells, we have concluded that the decrease in acoustic impedance was in fact due to actin filament depolymerization and the data can be quantitatively assessed for future studies in novel drug development.

Clinical characteristics associated with the intracranial dissemination of gliomas.

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Cai, Xu; Qin, Jun-Jie; Hao, Shu-Yu; Li, Huan; Zeng, Chun; Sun, Sheng-Jun; Yu, Lan-Bing; Gao, Zhi-Xian; Xie, Jian

2018-03-01

Glioma is the most common malignant tumor of the brain and the intracranial dissemination of gliomas is the late stage of the development of the tumor. However, there is little research in literature on the occurrence of intracranial dissemination of gliomas. In order to provide a reference for clinical work, we carried out this study on intracranial dissemination of glioma. A total of 629 patients with gliomas received tumor resection by the same surgeon from August 2010 to September 2015 were included in this study. The authors performed a retrospective review of the patients and the information regarding clinical features, histopathological results, molecular pathologic results and clinical outcomes was collected and analyzed. In this retrospective study, we found that the intracranial dissemination phenomenon occurred in 53 patients (8.43%). We analyzed the clinical characteristics of patients and found that the age at diagnosis (P = 0.011), WHO grade of the tumor (P dissemination. The higher grade of the tumor, the more prone to disseminate. Deletion of 1p/19q had no significant correlation with the intracranial dissemination. MMP9, Ki-67, and EGFR were highly expressed in tumor cells that caused dissemination, and the level of Ki-67 expression had significance in statistics (P 40 years), high pathological grade, invasion of the corpus callosum and high levels of Ki-67 expression were risk factors associated with the intracranial dissemination of gliomas. Copyright © 2018 Elsevier B.V. All rights reserved.

Ibuprofen and Diclofenac Restrict Migration and Proliferation of Human Glioma Cells by Distinct Molecular Mechanisms

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Leidgens, Verena; Seliger, Corinna; Jachnik, Birgit; Welz, Tobias; Leukel, Petra; Vollmann-Zwerenz, Arabel; Bogdahn, Ulrich; Kreutz, Marina; Grauer, Oliver M.; Hau, Peter

2015-01-01

Background Non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with anti-tumorigenic effects in different tumor entities. For glioma, research has generally focused on diclofenac; however data on other NSAIDs, such as ibuprofen, is limited. Therefore, we performed a comprehensive investigation of the cellular, molecular, and metabolic effects of ibuprofen and diclofenac on human glioblastoma cells. Methods Glioma cell lines were treated with ibuprofen or diclofenac to investigate functional effects on proliferation and cell motility. Cell cycle, extracellular lactate levels, lactate dehydrogenase-A (LDH-A) expression and activity, as well as inhibition of the Signal Transducer and Activator of Transcription 3 (STAT-3) signaling pathway, were determined. Specific effects of diclofenac and ibuprofen on STAT-3 were investigated by comparing their effects with those of the specific STAT-3 inhibitor STATTIC. Results Ibuprofen treatment led to a stronger inhibition of cell growth and migration than treatment with diclofenac. Proliferation was affected by cell cycle arrest at different checkpoints by both agents. In addition, diclofenac, but not ibuprofen, decreased lactate levels in all concentrations used. Both decreased STAT-3 phosphorylation; however, diclofenac led to decreased c-myc expression and subsequent reduction in LDH-A activity, whereas treatment with ibuprofen in higher doses induced c-myc expression and less LDH-A alteration. Conclusions This study indicates that both ibuprofen and diclofenac strongly inhibit glioma cells, but the subsequent metabolic responses of both agents are distinct. We postulate that ibuprofen may inhibit tumor cells also by COX- and lactate-independent mechanisms after long-term treatment in physiological dosages, whereas diclofenac mainly acts by inhibition of STAT-3 signaling and downstream modulation of glycolysis. PMID:26485029

The translocator protein radioligand 18F-DPA-714 monitors antitumor effect of erufosine in a rat 9L intracranial glioma model

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Awde, Ali R.; Boisgard, Raphael; Theze, Benoit; Dubois, Albertine; Zheng, Jinzi; Winkeler, Alexandra; Dolle, Frederic; Jacobs, Andreas H.; Tavitian, Bertrand

2013-01-01

On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2- 18 F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a] pyrimidin-3-yl)acetamide ( 18 F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkyl-phosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using 18 F-DPA-714 PET. Methods: In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with 18 F-DPA-714 for the time of treatment. Results: A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in 18 F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive micro-glia/macrophages and glial fibrillary acidic protein-positive astrocytes. Conclusion: Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using 18 F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas. (authors)

Use of peri-operative anti-epileptic drugs in patients with newly diagnosed high grade malignant glioma: a single center experience.

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Lwu, Shelly; Hamilton, Mark G; Forsyth, Peter A; Cairncross, J Gregory; Parney, Ian F

2010-02-01

An American Academy of Neurology practice parameter recommends that long-term prophylactic anti-epileptic drugs (AED) should not be routine in patients with newly diagnosed brain tumors. However, prospective multi-center North American data shows that most newly diagnosed glioma patients receive prophylactic AED. We examined our own peri-operative AED practice patterns in newly-diagnosed patients with malignant glioma to determine if we deviate from published guidelines. A retrospective chart review was performed in adult patients with newly diagnosed malignant gliomas undergoing surgery in southern Alberta between January 2003 and December 2005. Demographic information, AED use, seizure incidence, adverse effects, tumor size, and tumor location were recorded. Of 164 eligible patients, 54 (33%) presented with seizures and all received AED. Prophylactic AED were given to 44 patients (27%). Peri-operative seizures (within 1 week) occurred in two patients without (3%) and no patients with seizure prophylaxis. Adverse AED reactions and adverse effects attributable to seizures were both rare. Prophylactic AED were continued >1 week post-op in 30 patients (18%). Patients receiving prophylactic AED were more likely to have had tumors involving the temporal lobe than those who did not (50 vs. 20%; P < 0.01). Patients receiving peri-operative AED prophylaxis were common, had a trend to reduced peri-operative seizures, and had few adverse effects. However, most of these patients were maintained on prophylactic AED continued beyond the first peri-operative week, contradicting published guidelines. Increased awareness of practice guidelines may help modify AED prescription patterns in malignant glioma patients.

LncRNA TUG1 acts as a tumor suppressor in human glioma by promoting cell apoptosis.

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Li, Jun; Zhang, Meng; An, Gang; Ma, Qingfang

2016-03-01

Previous studies have revealed multiple functional roles of long non-coding RNA taurine upregulated gene 1 in different types of malignant tumors, except for human glioma. Here, it was designed to study the potential function of taurine upregulated gene 1 in glioma pathogenesis focusing on its regulation on cell apoptosis. The expression of taurine upregulated gene 1 in glioma tissues was detected by quantitative RT-PCR and compared with that in adjacent normal tissues. Further correlation analysis was conducted to show the relationship between taurine upregulated gene 1 expression and different clinicopathologic parameters. Functional studies were performed to investigate the influence of taurine upregulated gene 1 on apoptosis and cell proliferation by using Annexin V/PI staining and cell counting kit-8 assays, respectively. And, caspase activation and Bcl-2 expression were analyzed to explore taurine upregulated gene 1-induced mechanism. taurine upregulated gene 1 expression was significantly inhibited in glioma and showed significant correlation with WHO Grade, tumor size and overall survival. Further experiments revealed that the dysregulation of taurine upregulated gene 1 affected the apoptosis and cell proliferation of glioma cells. Moreover, taurine upregulated gene 1 could induce the activation of caspase-3 and-9, with inhibited expression of Bcl-2, implying the mechanism in taurine upregulated gene 1-induced apoptosis. taurine upregulated gene 1 promoted cell apoptosis of glioma cells by activating caspase-3 and -9-mediated intrinsic pathways and inhibiting Bcl-2-mediated anti-apoptotic pathways, acting as a tumor suppressor in human glioma. This study provided new insights for the function of taurine upregulated gene 1 in cancer biology, and suggested a potent application of taurine upregulated gene 1 overexpression for glioma therapy. © 2016 by the Society for Experimental Biology and Medicine.

Intracellular targeting of mercaptoundecahydrododecaborate (BSH) to malignant glioma by transferrin-PEG liposomes for boron neutron capture therapy (BNCT)

International Nuclear Information System (INIS)

Doi, Atsushi; Miyatake, Shin-ichi; Iida, Kyouko

2006-01-01

Malignant glioma is one of the most difficult tumor to control with usual therapies. In our institute, we select boron neutron capture therapy (BNCT) as an adjuvant radiation therapy after surgical resection. This therapy requires the selective delivery of high concentration of 10 B to malignant tumor tissue. In this study, we focused on a tumor-targeting 10 B delivery system (BDS) for BNCT that uses transferrin-conjugated polyethylene-glycol liposome encapsulating BSH (TF-PEG liposome-BSH) and compared 10 B uptake of the tumor among BSH, PEG liposome-BSH and TF-PEG liposome-BSH. In vitro, we analyzed 10 B concentration of the cultured human U87Δ glioma cells incubated in medium containing 20 μg 10 B/ml derived from each BDS by inductively coupled plasma atomic emission spectrometry (ICP-AES). In vivo, human U87Δ glioma-bearing nude mice were administered with each BDS (35mg 10 B/kg) intravenously. We analyzed 10 B concentration of tumor, normal brain and blood by ICP-AES. The TF-PEG liposome-BSH showed higher absolute concentration more than the other BDS. Moreover, TF-PEG liposome-BSH decreased 10 B concentration in blood and normal tissue while it maintained high 10 B concentration in tumor tissue for a couple of days. This showed the TF-PEG liposome-BSH caused the selective delivery of high concentration of 10 B to malignant tumor tissue. The TF-PEG liposome-BSH is more potent BDS for BNCT to obtain absolute high 10 B concentration and good contrast between tumor and normal tissue than BSH and PEG liposome-BSH. (author)

ACE I/D sequence variants but not MTHFR C677T, is strongly linked to malignant glioma risk and its variant DD genotype may act as a promising predictive biomarker for overall survival of glioma patients.

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Pandith, Arshad A; Qasim, Iqbal; Zahoor, Wani; Shah, Parveen; Bhat, Abdul R

2018-01-10

ACE I/D and MTHFR C677T gene polymorphisms can be seen as candidate genes for glioma on the basis of their biological functions and their involvement in different cancers. The aim of this study was to analyze potential association and overall survival between MTHFR C677T and ACE I/D polymorphism in glioma patients in our population. We tested genotype distribution of 112 glioma patients against 141 cancer-free controls from the same region. Kaplan-Meier survival analysis was performed to evaluate overall survival of patients for both genes. No significant differences were found among MTHFR C677T wild type C and variant genotypes CT/TT with glioma patients. In ACE, the distribution of variant ID and DD was found to be significantly higher in glioma cases as compared to controls (pACE DD genotypes were highly presented in glioma cases 26.8% versus 10.6% in controls (pACE DD genotypes had the least estimated overall survival of 13.4months in comparison to 21. 7 and 17.6months for ACE II and I/D genotypes respectively. We conclude ACE I/D polymorphism plays a vital role in predisposition of higher risk for glioma. We also suggest that ACE DD genotypes may act as an important predictive biomarker for overall survival of glioma patients. Copyright © 2017. Published by Elsevier B.V.

Benefits of adjuvant chemotherapy in high-grade gliomas.

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DeAngelis, Lisa M

2003-12-01

The current standard of care for patients with high-grade glioma is resection followed by radiotherapy. Adjuvant chemotherapy is not widely accepted because of the low sensitivity of gliomas to traditional antineoplastic agents, the poor penetration of most drugs across the blood-brain barrier, and the significant systemic toxicity associated with current agents. However, nitrosoureas and, subsequently, temozolomide (Temodar [US], Temodal [international]; Schering-Plough Corporation, Kenilworth, NJ), a novel alkylating agent, cross the blood-brain barrier and have activity against gliomas. Nitrosoureas have been studied in phase III trials in the adjuvant setting. In individual trials, chemotherapy did not increase median survival but did increase the proportion of patients surviving >/=18 months by 15%. Only with large meta-analyses did the addition of chemotherapy achieve a statistically significant improvement in median survival. Currently there is no means of identifying which patients will benefit from adjuvant chemotherapy, but nitrosoureas and temozolomide are well tolerated in most patients, justifying the administration of adjuvant chemotherapy to all newly diagnosed patients with malignant glioma.

Synergistic anti-glioma effect of a coloaded nano-drug delivery system

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Xu H

2016-12-01

Full Text Available Huae Xu,1,* Feng Jia,2,* Pankaj Kumar Singh,3 Shu Ruan,4 Hao Zhang,5,* Xiaolin Li5 1Department of Pharmacy, The First Affiliated Hospital with Nanjing Medical University, Nanjing, 2Department of Neurosurgery, Yancheng City No 1 People’s Hospital, The Fourth Affiliated Hospital of Nantong Medical College, Yancheng, People’s Republic of China; 3Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Department of Endocrinology, Yancheng Third Hospital, The Affiliated Hospital of Southeast University Medical College, Yancheng, 5Department of Geriatrics, The First Affiliated Hospital with Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: The anti-glioma effect of temozolomide (Tem is sometimes undermined by the emerging resistance. Recently, resveratrol (Res, herbal medicine extracted from grape seeds, has been demonstrated for its potential use in chemosensitization. In the current study, both these drugs were loaded simultaneously into nanoparticles with methoxy poly(ethylene glycol-poly epsilon caprolactone (mPEG-PCL as drug carriers in order to achieve better antitumor efficiency. Tem/Res-coloaded mPEG-PCL nanoparticles were constructed, characterized, and tested for antitumor effect on glioma cells by using in vitro and xenograft model system. The nanoparticle constructs were satisfactory with drug loading content (Res =~12.4%; Tem =~9.3% and encapsulation capacity of >85% for both the drugs. In addition, the coencapsulation led to better in vitro stability of the nanoparticles than Tem-loaded nanoparticles. An in vitro uptake study demonstrated a high uptake efficiency of the nanoparticles by glioma cells. The synergistic antitumor effect against glioma cells was observed in the combinational treatment of Res and Tem. Tem/Res-coloaded nanoparticles induced higher apoptosis in U87 glioma cells as

Voxel-based clustered imaging by multiparameter diffusion tensor images for glioma grading.

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Inano, Rika; Oishi, Naoya; Kunieda, Takeharu; Arakawa, Yoshiki; Yamao, Yukihiro; Shibata, Sumiya; Kikuchi, Takayuki; Fukuyama, Hidenao; Miyamoto, Susumu

2014-01-01

Gliomas are the most common intra-axial primary brain tumour; therefore, predicting glioma grade would influence therapeutic strategies. Although several methods based on single or multiple parameters from diagnostic images exist, a definitive method for pre-operatively determining glioma grade remains unknown. We aimed to develop an unsupervised method using multiple parameters from pre-operative diffusion tensor images for obtaining a clustered image that could enable visual grading of gliomas. Fourteen patients with low-grade gliomas and 19 with high-grade gliomas underwent diffusion tensor imaging and three-dimensional T1-weighted magnetic resonance imaging before tumour resection. Seven features including diffusion-weighted imaging, fractional anisotropy, first eigenvalue, second eigenvalue, third eigenvalue, mean diffusivity and raw T2 signal with no diffusion weighting, were extracted as multiple parameters from diffusion tensor imaging. We developed a two-level clustering approach for a self-organizing map followed by the K-means algorithm to enable unsupervised clustering of a large number of input vectors with the seven features for the whole brain. The vectors were grouped by the self-organizing map as protoclusters, which were classified into the smaller number of clusters by K-means to make a voxel-based diffusion tensor-based clustered image. Furthermore, we also determined if the diffusion tensor-based clustered image was really helpful for predicting pre-operative glioma grade in a supervised manner. The ratio of each class in the diffusion tensor-based clustered images was calculated from the regions of interest manually traced on the diffusion tensor imaging space, and the common logarithmic ratio scales were calculated. We then applied support vector machine as a classifier for distinguishing between low- and high-grade gliomas. Consequently, the sensitivity, specificity, accuracy and area under the curve of receiver operating characteristic

DELETION AND 5'CPG ISLAND METHYLATION OF p15 GENE IN BRAIN GLIOMA

Institute of Scientific and Technical Information of China (English)

无

2000-01-01

Objective: To investigate the abnormality of p15 gene in brain glioma and the correlation of it with occurrence or malignant progression of brain glioma. Methods: Deletion and 5'CPG island methylation of p15 gene were detected by the methods of PCR and PCR-based methylation in 56 cases of brain glioma. Results: Out of 43 cases of high grade glioma, 14 cases were found to have homozygous deletion of p15E1, while none of the 13 cases of low grade glioma was found to have deletion of p15E1 (P<0.05). Methylation of 5'CPG Island of p15 gene was found only in four cases of glioma. Conclusion: Abnormality of p15 gene may involved in the occurrence and malignant progression of brain glioma. Homozygous deletion of gene is the major mechanism of inactivation for p15 gene in brain glioma.

Glioma-targeting micelles for optical/magnetic resonance dual-mode imaging

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Zhou Q

2015-03-01

Full Text Available Qing Zhou,1,* Ketao Mu,2,* Lingyu Jiang,1 Hui Xie,3 Wei Liu,1 Zhengzheng Li,1 Hui Qi,1 Shuyan Liang,1 Huibi Xu,1 Yanhong Zhu,1 Wenzhen Zhu,2 Xiangliang Yang11National Engineering Research Center for Nanomedicine, College of Life Science and Technology, 2Radiology Department, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 3Department of Information Processing, China Patent Information Center, Wuhan, People’s Republic of China*These authors contributed equally to this workAbstract: Surgical resection is the primary mode for glioma treatment, while gross total resection is difficult to achieve, due to the invasiveness of the gliomas. Meanwhile, the tumor-resection region is closely related to survival rate and life quality. Therefore, we developed optical/magnetic resonance imaging (MRI bifunctional targeted micelles for glioma so as to delineate the glioma location before and during operation. The micelles were constructed through encapsulation of hydrophobic superparamagnetic iron oxide nanoparticles (SPIONs with polyethylene glycol-block-polycaprolactone (PEG-b-PCL by using a solvent-evaporation method, and modified with a near-infrared fluorescent probe, Cy5.5, in addition to the glioma-targeting ligand lactoferrin (Lf. Being encapsulated by PEG-b-PCL, the hydrophobic SPIONs dispersed well in phosphate-buffered saline over 4 weeks, and the relaxivity (r2 of micelles was 215.4 mM–1·s–1, with sustained satisfactory fluorescent imaging ability, which might have been due to the interval formed by PEG-b-PCL for avoiding the fluorescence quenching caused by SPIONs. The in vivo results indicated that the nanoparticles with Lf accumulated efficiently in glioma cells and prolonged the duration of hypointensity at the tumor site over 48 hours in the MR image compared to the nontarget group. Corresponding with the MRI results, the margin of the glioma was clearly demarcated in the fluorescence image

High bone sialoprotein (BSP expression correlates with increased tumor grade and predicts a poorer prognosis of high-grade glioma patients.

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Tao Xu

Full Text Available OBJECTIVES: To investigate the expression and prognostic value of bone sialoprotein (BSP in glioma patients. METHODS: We determined the expression of BSP using real-time RT-PCR and immunohistochemistry in tissue microarrays containing 15 normal brain and 270 glioma samples. Cumulative survival was calculated by the Kaplan-Meier method and analyzed by the log-rank test. Univariate and multivariate analyses were performed by the stepwise forward Cox regression model. RESULTS: Both BSP mRNA and protein levels were significantly elevated in high-grade glioma tissues compared with those of normal brain and low-grade glioma tissues, and BSP expression positively correlated with tumor grade (P<0.001. Univariate and multivariate analysis showed high BSP expression was an independent prognostic factor for a shorter progression-free survival (PFS and overall survival (OS in both grade III and grade IV glioma patients [hazard ratio (HR = 2.549 and 3.154 for grade III glioma, and HR = 1.637 and 1.574 for grade IV glioma, respectively]. Patients with low BSP expression had a significantly longer median OS and PFS than those with high BSP expression. Small extent of resection and lineage of astrocyte served as independent risk factors of both shorter PFS and OS in grade III glioma patients; GBM patients without O(6-methylguanine (O(6-meG DNA methyltransferase (MGMT methylation and Karnofsky performance score (KPS less than 70 points were related to poor prognosis. Lack of radiotherapy related to shorter OS but not affect PFS in both grade III and grade IV glioma patients. CONCLUSION: High BSP expression occurs in a significant subset of high-grade glioma patients and predicts a poorer outcome. The study identifies a potentially useful molecular marker for the categorization and targeted therapy of gliomas.

Astrocytes protect glioma cells from chemotherapy and upregulate survival genes via gap junctional communication.

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Lin, Qingtang; Liu, Zhao; Ling, Feng; Xu, Geng

2016-02-01

Gliomas are the most common type of primary brain tumor. Using current standard treatment regimens, the prognosis of patients with gliomas remains poor, which is predominantly due to the resistance of glioma cells to chemotherapy. The organ microenvironment has been implicated in the pathogenesis and survival of tumor cells. Thus, the aim of the present study was to test the hypothesis that astrocytes (the housekeeping cells of the brain microenvironment) may protect glioma cells from chemotherapy and to investigate the underlying mechanism. Immunofluorescent and scanning electron microscopy demonstrated that glioma cells were surrounded and infiltrated by activated astrocytes. In vitro co-culture of glioma cells with astrocytes significantly reduced the cytotoxic effects on glioma cells caused by various chemotherapeutic agents, as demonstrated by fluorescein isothiocyanate-propidium iodide flow cytometry. Transwell experiments indicated that this protective effect was dependent on physical contact and the gap junctional communication (GJC) between astrocytes and glioma cells. Microarray expression profiling further revealed that astrocytes upregulated the expression levels of various critical survival genes in the glioma cells via GJC. The results of the present study indicated that the organ microenvironment may affect the biological behavior of tumor cells and suggest a novel mechanism of resistance in glioma cells, which may be of therapeutic relevance clinically.

Uptake of iodine-123-α-methyl tyrosine by gliomas and non-neoplastic brain lesions

International Nuclear Information System (INIS)

Kuwert, T.; Morgenroth, C.; Woesler, B.; Matheja, P.; Palkovic, S.; Vollet, B.; Samnick, S.; Maasjosthusmann, U.; Lerch, H.; Gildehaus, F.J.; Wassmann, H.; Schober, O.

1996-01-01

Using single-photon emission tomography (SPET), the radiopharmaceutical L-3-iodine-123-α-methyl tyrosine (IMT) has been applied to the imaging of amino acid transport into brain tumours. It was the aim of this study to investigate whether IMT SPET is capable of differentiating between high-grade gliomas, low-grade gliomas and non-neoplastic brain lesions. To this end, IMT uptake was determined in 53 patients using the triple-headed SPET camera MULTISPECT 3. Twenty-eight of these subjects suffered from high-grade gliomas (WHO grade III or IV), 12 from low-grade gliomas (WHO grade II), and 13 from non-neoplastic brain lesions, including lesions after effective therapy of a glioma (five cases), infarctions (four cases), inflammatory lesions (three cases), infarctions (four cases), inflammatory lesions (three cases) and traumatic haematoma (one case). IMT uptake was significantly higher in high-grade gliomas than in low-grade gliomas and non-neoplastic lesions. IMT uptake by low-grade gliomas was not significantly different from that by non-neoplastic lesions. Diagnostic sensitivity and specificity were 71% and 83% for differentiating high-grade from low-grade gliomas, 82% and 100% for distinguishing high-grade gliomas from non-neoplastic lesions, and 50% and 100% for discriminating low-grade gliomas from non-neoplastic lesions. Analogously to positron emission tomography with radioactively labelled amino acids and fluorine-18 deoxyglucose, IMT SPET may aid in differentiating higc-grade gliomas from histologically benign brain tumours and non-neoplastic brain lesions; it is of only limited value in differentiating between non-neoplastic lesions and histologically benign brain tumours. (orig.)

NUMB does not impair growth and differentiation status of experimental gliomas

International Nuclear Information System (INIS)

Euskirchen, Philipp; Skaftnesmo, Kai-Ove; Huszthy, Peter C.; Brekkå, Narve; Bjerkvig, Rolf; Jacobs, Andreas H.; Miletic, Hrvoje

2011-01-01

The cell fate determinant NUMB orchestrates asymmetric cell division in flies and mammals and has lately been suggested to have a tumor suppressor function in breast and lung cancer. Here, we studied NUMB in the context of malignant gliomas. We used ectopic expression of NUMB in order to inhibit proliferation and induce differentiation in glioma cells by alteration of Notch, Hedgehog and p53 signaling. We found that NUMB is consistently expressed in glioma biopsies with predominance of NUMB2/4 isoforms as determined by isoform-specific real-time PCR and Western blotting. Upon lentiviral overexpression, in vitro proliferation rate and the grade of differentiation as assessed by morphology and expression of neural and glial markers remained unchanged. Orthotopic xenografts of NUMB-transduced human U87 glioma cells could be established in nude rats without impairing engraftment or causing significant changes in morphology based on magnetic resonance imaging (MRI). The previously reported alteration of Hedgehog and p53 signaling by NUMB could not be recapitulated in glioma cells. We thus show that in experimental gliomas, NUMB overexpression most likely does not exert a tumor suppressor function such as seen in epithelial cancers.

JS-K, a glutathione S-transferase-activated nitric oxide donor with antineoplastic activity in malignant gliomas.

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Weyerbrock, Astrid; Osterberg, Nadja; Psarras, Nikolaos; Baumer, Brunhilde; Kogias, Evangelos; Werres, Anna; Bette, Stefanie; Saavedra, Joseph E; Keefer, Larry K; Papazoglou, Anna

2012-02-01

Glutathione S-transferases (GSTs) control multidrug resistance and are upregulated in many cancers, including malignant gliomas. The diazeniumdiolate JS-K generates nitric oxide (NO) on enzymatic activation by glutathione and GST, showing promising NO-based anticancer efficacy. To evaluate the role of NO-based antitumor therapy with JS-K in U87 gliomas in vitro and in vivo. U87 glioma cells and primary glioblastoma cell lines were exposed to JS-K and a variety of inhibitors to study cell death by necrosis, apoptosis, and other mechanisms. GST expression was evaluated by immunocytochemistry, polymerase chain reaction, and Western blot, and NO release from JS-K was studied with a NO assay. The growth-inhibitory effect of JS-K was studied in a U87 xenograft model in vivo. Dose-dependent inhibition of cell proliferation was observed in human U87 glioma cells and primary glioblastoma cells in vitro. Cell death was partially induced by caspase-dependent apoptosis, which could be blocked by Z-VAD-FMK and Q-VD-OPH. Inhibition of GST by sulfasalazine, cGMP inhibition by ODQ, and MEK1/2 inhibition by UO126 attenuated the antiproliferative effect of JS-K, suggesting the involvement of various intracellular death signaling pathways. Response to JS-K correlated with mRNA and protein expression of GST and the amount of NO released by the glioma cells. Growth of U87 xenografts was reduced significantly, with immunohistochemical evidence for increased necrosis and apoptosis and reduced proliferation. Our data show for the first time the potent antiproliferative effect of JS-K in gliomas in vitro and in vivo. These findings warrant further investigation of this novel NO-releasing prodrug in gliomas.

Glucose consumption and rate constants for 18F-fluorodeoxyglucose in human gliomas

International Nuclear Information System (INIS)

Ishikawa, Masatsune; Kikuchi, Haruhiko; Nagata, Izumi; Yamagata, Sen; Taki, Waro; Yonekura, Yoshiharu; Nishizawa, Sadahiko; Iwasaki, Yasushi; Mukai, Takao

1990-01-01

To investigate the value of direct measurement of the rate constants by performing 18 F-labeled fluorodeoxyglucose (FDG) studies of glucose consumption in human gliomas in vivo, a kinetic method with 3- and 4-parameter rate constant models for FDG uptake was used to analyze data from dynamic scans obtained by positron emission tomography after injection of FDG into 14 patients with glioma. The results were compared with those obtained by the autoradiographic method using 3- and 4-parameter rate constant models. There were no significant differences in the glucose consumption calculated by the four different methods both in the gliomas and in the contralateral intact cortex. It was found that the rate constant k4 could be neglected in calculation of glucose consumption in gliomas as well as in the contralateral intact cortex. The rate constant k3, an index of hexokinase function, was higher in malignant gliomas than in benign gliomas and was close to that in the contralateral cortex. This study indicates that the 3-parameter autoradiographic method, which is the most common one used in clinical practice, is reliable for the calculation of glucose consumption in human gliomas. Furthermore, direct measurement of the regional rate constants for FDG by the kinetic method was found to be useful for evaluation of the biochemical and physiological characteristics of human gliomas in vivo. (author)

EMMPRIN is an independent negative prognostic factor for patients with astrocytic glioma.

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Li Tian

Full Text Available Extracellular matrix metalloproteinase inducer (EMMPRIN, also known as CD147, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs. It has been proved to be associated with tumor invasion and metastasis in various human malignancies. In our study, the protein expression level of EMMPRIN in 306 cases of astrocytic glioma is investigated by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of EMMPRIN with clinicopathological characteristics and prognosis of patients. It was proved that EMMPRIN protein expression was increased in glioma compared with that in normal brain tissue. Moreover, EMMPRIN immunohistochemical staining was correlated with WHO grade and Karnofsky performance score for strong positive EMMPRIN staining is more frequently detected in glioma of advanced grade or low KPS score. It is also demonstrated that EMMPRIN could be an independent negative prognostic factor in glioma for patients with glioma of strong EMMPRIN staining tend to have high risk of death. These results proved that EMMPRIN is associated with prognosis of glioma, which may also suggest the potential role of EMMPRIN in glioma management.

EMMPRIN is an independent negative prognostic factor for patients with astrocytic glioma.

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Tian, Li; Zhang, Yang; Chen, Yu; Cai, Min; Dong, Hailong; Xiong, Lize

2013-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN), also known as CD147, is a member of the immunoglobulin superfamily that is present on the surface of tumor cells and stimulates adjacent fibroblasts to produce matrix metalloproteinases (MMPs). It has been proved to be associated with tumor invasion and metastasis in various human malignancies. In our study, the protein expression level of EMMPRIN in 306 cases of astrocytic glioma is investigated by immunohistochemistry assay. Statistical analysis was utilized to evaluate the association of EMMPRIN with clinicopathological characteristics and prognosis of patients. It was proved that EMMPRIN protein expression was increased in glioma compared with that in normal brain tissue. Moreover, EMMPRIN immunohistochemical staining was correlated with WHO grade and Karnofsky performance score for strong positive EMMPRIN staining is more frequently detected in glioma of advanced grade or low KPS score. It is also demonstrated that EMMPRIN could be an independent negative prognostic factor in glioma for patients with glioma of strong EMMPRIN staining tend to have high risk of death. These results proved that EMMPRIN is associated with prognosis of glioma, which may also suggest the potential role of EMMPRIN in glioma management.

Season of Birth and Risk for Adult Onset Glioma

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Jimmy T. Efird

2010-04-01

Full Text Available Adult onset glioma is a rare cancer which occurs more frequently in Caucasians than African Americans, and in men than women. The etiology of this disease is largely unknown. Exposure to ionizing radiation is the only well established environmental risk factor, and this factor explains only a small percentage of cases. Several recent studies have reported an association between season of birth and glioma risk. This paper reviews the plausibility of evidence focusing on the seasonal interrelation of farming, allergies, viruses, vitamin D, diet, birth weight, and handedness. To date, a convincing explanation for the occurrence of adult gliomas decades after a seasonal exposure at birth remains elusive.

A population-based study of low-grade gliomas and mutated isocitrate dehydrogenase 1 (IDH1)

DEFF Research Database (Denmark)

Dahlrot, Rikke H; Kristensen, Bjarne W; Hjelmborg, Jacob

2013-01-01

Low-grade gliomas (LGG) have a slow growth rate, but transformations into malignant gliomas with a rapid deterioration occur in many patients. The aim of this study was to evaluate clinical prognostic factors in a population-based cohort of patients with LGG. In addition we investigated the expre...

The immunohistochemical expression of calcitonin receptor-like receptor (CRLR) in human gliomas.

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Benes, L; Kappus, C; McGregor, G P; Bertalanffy, H; Mennel, H D; Hagner, S

2004-02-01

Gliomas are the most common primary tumours of the central nervous system and exhibit rapid growth that is associated with neovascularisation. Adrenomedullin is an important tumour survival factor in human carcinogenesis. It has growth promoting effects on gliomas, and blockade of its actions has been experimentally shown to reduce the growth of glioma tissues and cell lines. There is some evidence that the calcitonin receptor-like receptor (CRLR) mediates the tumorigenic actions of adrenomedullin. To determine whether CRLR is expressed in human gliomas and the probable cellular targets of adrenomedullin. Biopsies from 95 human gliomas of varying grade were processed for immunohistochemical analysis using a previously developed and characterised antibody to CRLR. All tumour specimens were positive for CRLR. As previously found in normal peripheral tissues, CRLR immunostaining was particularly intense in the endothelial cells. This was evident in all the various vascular conformations that were observed, and which are typical of gliomas. In addition, clear immunostaining of tumour cells with astrocyte morphology was observed. These were preferentially localised around vessels. This study has shown for the first time that the CRLR protein is present in human glioma tissue. The expression of the receptor in endothelial cells and in astrocytic tumour cells is consistent with the evidence that its endogenous ligand, adrenomedullin, may influence glioma growth by means of both direct mitogenic and indirect angiogenic effects. CRLR may be a valuable target for effective therapeutic intervention in these malignant tumours.

PEGylated Polyamidoamine dendrimer conjugated with tumor homing peptide as a potential targeted delivery system for glioma.

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Jiang, Yan; Lv, Lingyan; Shi, Huihui; Hua, Yabing; Lv, Wei; Wang, Xiuzhen; Xin, Hongliang; Xu, Qunwei

2016-11-01

Glioblastoma multiforme (GBM) is the most common and aggressive primary central nervous system (CNS) tumor with a short survival time. The failure of chemotherapy is ascribed to the low transport of chemotherapeutics across the Blood Brain Tumor Barrier (BBTB) and poor penetration into tumor tissue. In order to overcome the two barriers, small nanoparticles with active targeted capability are urgently needed for GBM drug delivery. In this study, we proposed PEGylated Polyamidoamine (PAMAM) dendrimer nanoparticles conjugated with glioma homing peptides (Pep-1) as potential glioma targeting delivery system (Pep-PEG-PAMAM), where PEGylated PAMAM dendrimer nanoparticle was utilized as carrier due to its small size and perfect penetration into tumor and Pep-1 was used to overcome BBTB via interleukin 13 receptor α2 (IL-13Rα2) mediated endocytosis. The preliminary availability and safety of Pep-PEG-PAMAM as a nanocarrier for glioma was evaluated. In vitro results indicated that a significantly higher amount of Pep-PEG-PAMAM was endocytosed by U87 MG cells. In vivo fluorescence imaging of U87MG tumor-bearing mice confirmed that the fluorescence intensity at glioma site of targeted group was 2.02 folds higher than that of untargeted group (**p<0.01), and glioma distribution experiment further revealed that Pep-PEG-PAMAM exhibited a significantly enhanced accumulation and improved penetration at tumor site. In conclusion, Pep-1 modified PAMAM was a promising nanocarrier for targeted delivery of brain glioma. Copyright © 2016 Elsevier B.V. All rights reserved.

Comparative genomic and proteomic analysis of high grade glioma primary cultures and matched tumor in situ.

LENUS (Irish Health Repository)

Howley, R

2012-10-15

Developing targeted therapies for high grade gliomas (HGG), the most common primary brain tumor in adults, relies largely on glioma cultures. However, it is unclear if HGG tumorigenic signaling pathways are retained under in-vitro conditions. Using array comparative genomic hybridization and immunohistochemical profiling, we contrasted the epidermal and platelet-derived growth factor receptor (EGFR\\/PDGFR) in-vitro pathway status of twenty-six primary HGG cultures with the pathway status of their original HGG biopsies. Genomic gains or amplifications were lost during culturing while genomic losses were more likely to be retained. Loss of EGFR amplification was further verified immunohistochemically when EGFR over expression was decreased in the majority of cultures. Conversely, PDGFRα and PDGFRβ were more abundantly expressed in primary cultures than in the original tumor (p<0.05). Despite these genomic and proteomic differences, primary HGG cultures retained key aspects of dysregulated tumorigenic signaling. Both in-vivo and in-vitro the presence of EGFR resulted in downstream activation of P70s6K while reduced downstream activation was associated with the presence of PDGFR and the tumor suppressor, PTEN. The preserved pathway dysregulation make this glioma model suitable for further studies of glioma tumorigenesis, however individual culture related differences must be taken into consideration when testing responsiveness to chemotherapeutic agents.

Childhood Brain Stem Glioma Treatment (PDQ®)—Patient Version

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Childhood brain stem glioma can be a benign (not cancer) or malignant (cancer) condition where abnormal cells form in the tissues of the brain stem. Get information about the symptoms, diagnosis, prognosis, and treatment of newly diagnosed and recurrent childhood brain stem glioma in this expert-reviewed summary.

Contemporary management of high-grade gliomas.

Science.gov (United States)

Sim, Hao-Wen; Morgan, Erin R; Mason, Warren P

2018-01-01

High-grade gliomas, including glioblastoma, are the most common malignant brain tumors in adults. Despite intensive efforts to develop new therapies for these diseases, treatment options remain limited and prognosis is poor. Recently, there have been important advances in our understanding of the molecular basis of glioma, leading to refinements in our diagnostic and management approach. There is new evidence to guide the treatment of elderly patients. A multitude of new agents have been investigated, including targeted therapies, immunotherapeutics and tumor-treating fields. This review summarizes the key findings from this research, and presents a perspective on future opportunities to advance the field.

Anatomic mapping of molecular subtypes in diffuse glioma.

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Tang, Qisheng; Lian, Yuxi; Yu, Jinhua; Wang, Yuanyuan; Shi, Zhifeng; Chen, Liang

2017-09-15

Tumor location served as an important prognostic factor in glioma patients was considered to postulate molecular features according to cell origin theory. However, anatomic distribution of unique molecular subtypes was not widely investigated. The relationship between molecular phenotype and histological subgroup were also vague based on tumor location. Our group focuses on the study of glioma anatomic location of distinctive molecular subgroups and histology subtypes, and explores the possibility of their consistency based on clinical background. We retrospectively reviewed 143 cases with both molecular information (IDH1/TERT/1p19q) and MRI images diagnosed as cerebral diffuse gliomas. The anatomic distribution was analyzed between distinctive molecular subgroups and its relationship with histological subtypes. The influence of tumor location, molecular stratification and histology diagnosis on survival outcome was investigated as well. Anatomic locations of cerebral diffuse glioma indicate varied clinical outcome. Based on that, it can be stratified into five principal molecular subgroups according to IDH1/TERT/1p19q status. Triple-positive (IDH1 and TERT mutation with 1p19q codeletion) glioma tended to be oligodendroglioma present with much better clinical outcome compared to TERT mutation only group who is glioblastoma inclined (median overall survival 39 months VS 18 months). Five molecular subgroups were demonstrated with distinctive locational distribution. This kind of anatomic feature is consistent with its corresponding histological subtypes. Each molecular subgroup in glioma has unique anatomic location which indicates distinctive clinical outcome. Molecular diagnosis can be served as perfect complementary tool for the precise diagnosis. Integration of histomolecular diagnosis will be much more helpful in routine clinical practice in the future.

Identifying novel glioma associated pathways based on systems biology level meta-analysis.

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Hu, Yangfan; Li, Jinquan; Yan, Wenying; Chen, Jiajia; Li, Yin; Hu, Guang; Shen, Bairong

2013-01-01

With recent advances in microarray technology, including genomics, proteomics, and metabolomics, it brings a great challenge for integrating this "-omics" data to analysis complex disease. Glioma is an extremely aggressive and lethal form of brain tumor, and thus the study of the molecule mechanism underlying glioma remains very important. To date, most studies focus on detecting the differentially expressed genes in glioma. However, the meta-analysis for pathway analysis based on multiple microarray datasets has not been systematically pursued. In this study, we therefore developed a systems biology based approach by integrating three types of omics data to identify common pathways in glioma. Firstly, the meta-analysis has been performed to study the overlapping of signatures at different levels based on the microarray gene expression data of glioma. Among these gene expression datasets, 12 pathways were found in GeneGO database that shared by four stages. Then, microRNA expression profiles and ChIP-seq data were integrated for the further pathway enrichment analysis. As a result, we suggest 5 of these pathways could be served as putative pathways in glioma. Among them, the pathway of TGF-beta-dependent induction of EMT via SMAD is of particular importance. Our results demonstrate that the meta-analysis based on systems biology level provide a more useful approach to study the molecule mechanism of complex disease. The integration of different types of omics data, including gene expression microarrays, microRNA and ChIP-seq data, suggest some common pathways correlated with glioma. These findings will offer useful potential candidates for targeted therapeutic intervention of glioma.

Genome-wide comparison of paired fresh frozen and formalin-fixed paraffin-embedded gliomas by custom BAC and oligonucleotide array comparative genomic hybridization: facilitating analysis of archival gliomas

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Mohapatra, Gayatry; Engler, David A.; Starbuck, Kristen D.; Kim, James C.; Bernay, Derek C.; Scangas, George A.; Rousseau, Audrey; Batchelor, Tracy T.; Betensky, Rebecca A.; Louis, David N.

2010-01-01

Molecular genetic analysis of cancer is rapidly evolving as a result of improvement in genomic technologies and the growing applicability of such analyses to clinical oncology. Array based comparative genomic hybridization (aCGH) is a powerful tool for detecting DNA copy number alterations (CNA), particularly in solid tumors, and has been applied to the study of malignant gliomas. In the clinical setting, however, gliomas are often sampled by small biopsies and thus formalin-fixed paraffin-embedded (FFPE) blocks are often the only tissue available for genetic analysis, especially for rare types of gliomas. Moreover, the biological basis for the marked intratumoral heterogeneity in gliomas is most readily addressed in FFPE material. Therefore, for gliomas, the ability to use DNA from FFPE tissue is essential for both clinical and research applications. In this study, we have constructed a custom bacterial artificial chromosome (BAC) array and show excellent sensitivity and specificity for detecting CNAs in a panel of paired frozen and FFPE glioma samples. Our study demonstrates a high concordance rate between CNAs detected in FFPE compared to frozen DNA. We have also developed a method of labeling DNA from FFPE tissue that allows efficient hybridization to oligonucleotide arrays. This labeling technique was applied to a panel of biphasic anaplastic oligoastrocytomas (AOA) to identify genetic changes unique to each component. Together, results from these studies suggest that BAC and oligonucleotide aCGH are sensitive tools for detecting CNAs in FFPE DNA, and can enable genome-wide analysis of rare, small and/or histologically heterogeneous gliomas. PMID:21080181

A super gene expression system enhances the anti-glioma effects of adenovirus-mediated REIC/Dkk-3 gene therapy

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Oka, Tetsuo; Kurozumi, Kazuhiko; Shimazu, Yosuke; Ichikawa, Tomotsugu; Ishida, Joji; Otani, Yoshihiro; Shimizu, Toshihiko; Tomita, Yusuke; Sakaguchi, Masakiyo; Watanabe, Masami; Nasu, Yasutomo; Kumon, Hiromi; Date, Isao

2016-09-01

Reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is a tumor suppressor and therapeutic gene in many human cancers. Recently, an adenovirus REIC vector with the super gene expression system (Ad-SGE-REIC) was developed to increase REIC/Dkk-3 expression and enhance therapeutic effects compared with the conventional adenoviral vector (Ad-CAG-REIC). In this study, we investigated the in vitro and in vivo effects of Ad-SGE-REIC on malignant glioma. In U87ΔEGFR and GL261 glioma cells, western blotting confirmed that robust upregulation of REIC/Dkk-3 expression occurred in Ad-SGE-REIC-transduced cells, most notably after transduction at a multiplicity of infection of 10. Cytotoxicity assays showed that Ad-SGE-REIC resulted in a time-dependent and significant reduction in the number of malignant glioma cells attaching to the bottom of culture wells. Xenograft and syngeneic mouse intracranial glioma models treated with Ad-SGE-REIC had significantly longer survival than those treated with the control vector Ad-LacZ or with Ad-CAG-REIC. This study demonstrated the anti-glioma effect of Ad-SGE-REIC, which may represent a promising strategy for the treatment of malignant glioma.

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

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Camila Ferreira de Souza

2018-04-01

Full Text Available Summary: Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed. To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified. We previously reported that the IDH mutant G-CIMP-high subtype would be a predecessor to the G-CIMP-low subtype. Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas. Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease. G-CIMP-low recurrence appeared in 9.5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability. Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression. : IDH-mutant lower-grade glioma glioblastoma often progresses to a more aggressive phenotype upon recurrence. de Souza et al. examines the intra-subtype heterogeneity of initial G-CIMP-high and use this information to identify predictive biomarkers for assessing the risk of recurrence and malignant transformation. Keywords: longitudinal gliomas, DNA methylation, IDH mutation, G-CIMP-high, intra-subtype heterogeneity, malignant transformation and recurrence, G-CIMP-low, stem cell-like glioblastoma, predictive biomarkers

An Updated and Comprehensive Meta-Analysis of Association Between Seven Hot Loci Polymorphisms from Eight GWAS and Glioma Risk.

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Wu, Qiang; Peng, Yanyan; Zhao, Xiaotao

2016-09-01

Eight genome-wide association studies (GWASs) found that seven loci (rs2736100, rs4295627, rs4977756, rs498872, rs11979158, rs2252586, rs6010620) polymorphisms could elevate the risk of glioma, one of the most common types of primary brain cancer in adults. However, the replication studies about these seven loci obtained inconsistent results. In order to derive a more accurate estimation about the relationship between the selected single-nucleotide polymorphism (SNP) and susceptibility to glioma, we conducted a meta-analysis containing all eligible published case control studies to evaluate the association. An overall literature search was conducted using the database of PubMed, Science Direct, China national knowledge infrastructure (CNKI), and Embase. Seventeen articles with 25 studies were included in the meta-analysis. Glioma risk (odds ratio, OR; 95 % confidential interval, 95 %CI) was estimated with the random-effect model or the fixed-effects model. STATA 12.0 was applied to analyze all statistical data. Results showed that seven hot loci were all associated with increased risk of glioma (rs2736100, OR = 1.28, 95 %CI = 1.23-1.32; rs4295627, OR = 1.34, 95 %CI = 1.21-1.47; rs4977756, OR = 1.24, 95 %CI = 1.20-1.28; rs498872, OR = 1.24, 95 %CI = 1.15-1.33; rs6010620, OR = 1.29, 95 %CI = 1.24-1.35; rs11979158: OR = 1.18, 95 %CI = 1.10-1.25; rs2252586: OR = 1.18, 95 %CI = 1.10-1.25). Additionally, subgroup analysis by stages of glioma found that variation of rs11979158 had stronger relationship with high-grade (OR = 1.32, 95 %CI = 1.19-1.45) than low-grade glioma (OR = 1.12, 95 % CI = 1.03-1.21). Similarly, stratified analysis of rs2252586 by stages revealed the similar trend, with OR of 1.26 (95 %CI = 1.17-1.35) in high-grade glioma and OR of 1.15 (95 %CI = 1.08-1.22) in low-grade glioma. In summary, the present study showed that mutations of the seven loci could elevate

Seizure control following radiotherapy in patients with diffuse gliomas: a retrospective study

Science.gov (United States)

Rudà, Roberta; Magliola, Umberto; Bertero, Luca; Trevisan, Elisa; Bosa, Chiara; Mantovani, Cristina; Ricardi, Umberto; Castiglione, Anna; Monagheddu, Chiara; Soffietti, Riccardo

2013-01-01

Background Little information is available regarding the effect of conventional radiotherapy on glioma-related seizures. Methods In this retrospective study, we analyzed the seizure response and outcome following conventional radiotherapy in a cohort of 43 patients with glioma (33 grade II, 10 grade III) and medically intractable epilepsy. Results At 3 months after radiotherapy, seizure reduction was significant (≥50% reduction of frequency compared with baseline) in 31/43 patients (72%) of the whole series and in 25/33 patients (76%) with grade II gliomas, whereas at 12 months seizure reduction was significant in 26/34 (76%) and in 19/25 (76%) patients, respectively. Seizure reduction was observed more often among patients displaying an objective tumor response on MRI, but patients with no change on MRI also had a significant seizure reduction. Seizure freedom (Engel class I) was achieved at 12 months in 32% of all patients and in 38% of patients with grade II tumors. Timing of radiotherapy and duration of seizures prior to radiotherapy were significantly associated with seizure reduction. Conclusions This study showed that a high proportion of patients with medically intractable epilepsy from diffuse gliomas derive a significant and durable benefit from radiotherapy in terms of epilepsy control and that this positive effect is not strictly associated with tumor shrinkage as shown on MRI. Radiotherapy at tumor progression seems as effective as early radiotherapy after surgery. Prospective studies must confirm and better characterize the response to radiotherapy. PMID:23897633

Glioma-derived mutations in isocitrate dehydrogenase 2 beneficial to traditional chemotherapy

International Nuclear Information System (INIS)

Fu, Yuejun; Huang, Rui; Zheng, Yali; Zhang, Zhiyun; Liang, Aihua

2011-01-01

Highlights: → IDH1 and IDH2 mutations are not detected in the rat C6 glioma cell line model. → IDH2 mutations are not required for the tumorigenesis of glioma. → IDH2 R172G can sensitize glioma sensitivity to chemotherapy through NADPH levels. → IDH2 R172G can give a benefit to traditional chemotherapy of glioma. → This finding serves as an important complement to existing research on this topic. -- Abstract: Heterozygous mutations in either the R132 residue of isocitrate dehydrogenase I (IDH1) or the R172 residue of IDH2 in human gliomas were recently highlighted. In the present study, we report that mutations of IDH1 and IDH2 are not detected in the rat C6 glioma cell line model, which suggests that these mutations are not required for the development of glioblastoma induced by N,N'-nitroso-methylurea. The effects of IDH2 and IDH2 R172G on C6 cells proliferation and sensitivity to chemotherapy and the possible mechanism are analyzed at the cellular level. IDH1 and IDH2 mutations lead to simultaneous loss and gain of activities in the production of α-ketoglutarate (α-KG) and 2-hydroxyglutarate (2HG), respectively, and result in lowering NADPH levels even further. The low NADPH levels can sensitize tumors to chemotherapy, and account for the prolonged survival of patients harboring the mutations. Our data extrapolate potential importance of the in vitro rat C6 glioma cell model, show that the IDH2 R172G mutation in gliomas may give a benefit to traditional chemotherapy of this cancer and serve as an important complement to existing research on this topic.

CURRENT APPROACHES TO CHEMORADIOTHERAPY FOR MALIGNANT GLIOMAS

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Ye. L. Choinzonov

2014-01-01

Full Text Available High-grade malignant gliomas (WHO grade G III–IV account for more than 50% of all primary brain tumors. Despite aggressive treatment, survival rates are still very low with a median reported survival of no more than 1.5 years.Radiation therapy is an integral part of the combined treatment, but often does not influence lethally on resistant tumor cells. Thereby, in recent decades there has been an active search for novel approaches to the treatment of malignant gliomas (chemotherapeutic drugs, biological modifiers, local hyperthermia. Experimental data showed that the effect of high temperatures has both a direct damaging effect on tumor cells and a sensitizing effect. Significant advantages are achieved when the complex treatment of different malignant tumorsincludes local hyperthermia. However data on the treatment of patients with primary and recurrent gliomas G III–IV using local hyperthermia are scarce.The literature review is given in the article provides an overview of the existing treatment methods for brain tumors.

Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.

Science.gov (United States)

Malta, Tathiane M; de Souza, Camila F; Sabedot, Thais S; Silva, Tiago C; Mosella, Maritza S; Kalkanis, Steven N; Snyder, James; Castro, Ana Valeria B; Noushmehr, Houtan

2018-04-09

Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.

A Technique for Resecting Occipital Pole Gliomas Using a Keyhole Lobectomy.

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Conner, Andrew K; Baker, Cordell M; Briggs, Robert G; Burks, Joshua D; Glenn, Chad A; Smitherman, Adam D; Morgan, Jake P; Pittman, Nathan A; Sughrue, Michael E

2017-10-01

Our purpose is to describe a method of resecting occipital pole gliomas through a keyhole lobectomy and share the patient outcomes of this technique. We performed a retrospective review of data obtained on all patients who underwent resection of occipital pole gliomas by the senior author between 2012 and 2016. We describe our technique for resecting these tumors using a keyhole lobectomy and share the patient outcomes of this operation. Eight patients were included in this study. Four patients (50%) had not received previous surgery. One patient (13%) was diagnosed with a World Health Organization grade II tumor, and 7 patients (88%) were diagnosed with glioblastoma. Two tumors (25%) were left sided and 6 (75%) right sided. The median size of resection was 28 cm 3 . The median extent of resection was 96%, and at least 90% of the tumor was resected in all cases. None of the patients experienced permanent postoperative complications. Temporary neurologic complications included 3 patients (38%) with encephalopathy and 1 patient (13%) with aphasia. There were no neurosurgical complications. Our study provides details on the technical aspects of occipital keyhole lobectomies and gives the outcomes of patients who have received an operation for tumors in this uncommon location. Taking white matter tract anatomy into consideration, we show that the keyhole method can be applied to gliomas of the occipital lobe. Copyright © 2017 Elsevier Inc. All rights reserved.

The accuracy of survival time prediction for patients with glioma is improved by measuring mitotic spindle checkpoint gene expression.

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Li Bie

Full Text Available Identification of gene expression changes that improve prediction of survival time across all glioma grades would be clinically useful. Four Affymetrix GeneChip datasets from the literature, containing data from 771 glioma samples representing all WHO grades and eight normal brain samples, were used in an ANOVA model to screen for transcript changes that correlated with grade. Observations were confirmed and extended using qPCR assays on RNA derived from 38 additional glioma samples and eight normal samples for which survival data were available. RNA levels of eight major mitotic spindle assembly checkpoint (SAC genes (BUB1, BUB1B, BUB3, CENPE, MAD1L1, MAD2L1, CDC20, TTK significantly correlated with glioma grade and six also significantly correlated with survival time. In particular, the level of BUB1B expression was highly correlated with survival time (p<0.0001, and significantly outperformed all other measured parameters, including two standards; WHO grade and MIB-1 (Ki-67 labeling index. Measurement of the expression levels of a small set of SAC genes may complement histological grade and other clinical parameters for predicting survival time.

KDM2B overexpression correlates with poor prognosis and regulates glioma cell growth

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Wang Y

2018-01-01

Full Text Available Yiwei Wang,1 Jin Zang,1 Dongyong Zhang,2 Zhenxiang Sun,1 Bo Qiu,2 Xiaojie Wang1 1Department of Human Anatomy, Shenyang Medical College, Huanggu District, Shenyang City, 2Department of Neurosurgery, First Affiliated Hospital of China Medical University, Heping District, Shenyang City, Liaoning Province, ChinaBackground: Gliomas are one of the most lethal cancers in the human central nervous system. Despite clinical treatment advancements, the prognosis of patients with glioma remains poor. KDM2B is a histone lysine demethylase, which has been observed in multiple tumors. But the concrete role of KDM2B in gliomas remains to be further illustrated.Methods: The KDM2B expression in gliomas was detected with immunohistochemistry and Western blot assay. Furthermore, knockdown of KDM2B in U87 and U251 glioma cell lines, the proliferation capacity was evaluated by cell viability assay, colon formation assay and flow cytometry in vitro. Western blot assay was used to analyze the p21, EZH2 and cyclinD1 changes followed by knockdown of KDM2B.Results: KDM2B was upregulated in tissues of glioma patients, and the expression was correlated to cancer progression. Downregulation of KDM2B in U87 and U251 glioma cell lines inhibited cell proliferation and arrested cell cycle in G0/G1 phase. In addition, silencing KDM2B promoted the upregulation of p21 while reduced the expression of EZH2 and cyclinD1.Conclusion: Taken together, our results revealed that KDM2B might influence gliomas growth and act as a novel therapeutic target for glioma patients.Keywords: EZH2, glioma, KDM2B, P21

Comparative magnetic resonance imaging findings between gliomas and presumed cerebrovascular accidents in dogs.

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Cervera, Vicente; Mai, Wilfried; Vite, Charles H; Johnson, Victoria; Dayrell-Hart, Betsy; Seiler, Gabriela S

2011-01-01

Cerebrovascular accidents, or strokes, and gliomas are common intraaxial brain lesions in dogs. An accurate differentiation of these two lesions is necessary for prognosis and treatment decisions. The magnetic resonance (MR) imaging characteristics of 21 dogs with a presumed cerebrovascular accident and 17 with a glioma were compared. MR imaging findings were reviewed retrospectively by three observers unaware of the final diagnosis. Statistically significant differences between the appearance of gliomas and cerebrovascular accidents were identified based on lesion location, size, mass effect, perilesional edema, and appearance of the apparent diffusion coefficient map. Gliomas were predominantly located in the cerebrum (76%) compared with presumed cerebrovascular accidents that were located mainly in the cerebellum, thalamus, caudate nucleus, midbrain, and brainstem (76%). Gliomas were significantly larger compared with presumed cerebrovascular accidents and more commonly associated with mass effect and perilesional edema. Wedge-shaped lesions were seen only in 19% of presumed cerebrovascular accidents. Between the three observers, 10-47% of the presumed cerebrovascular accidents were misdiagnosed as gliomas, and 0-12% of the gliomas were misdiagnosed as cerebrovascular accidents. Diffusion weighted imaging increased the accuracy of the diagnosis for both lesions. Agreement between observers was moderate (kappa = 0.48, P < 0.01).

Electrophysiology of glioma: a Rho GTPase-activating protein reduces tumor growth and spares neuron structure and function.

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Vannini, Eleonora; Olimpico, Francesco; Middei, Silvia; Ammassari-Teule, Martine; de Graaf, Erik L; McDonnell, Liam; Schmidt, Gudula; Fabbri, Alessia; Fiorentini, Carla; Baroncelli, Laura; Costa, Mario; Caleo, Matteo

2016-12-01

Glioblastomas are the most aggressive type of brain tumor. A successful treatment should aim at halting tumor growth and protecting neuronal cells to prevent functional deficits and cognitive deterioration. Here, we exploited a Rho GTPase-activating bacterial protein toxin, cytotoxic necrotizing factor 1 (CNF1), to interfere with glioma cell growth in vitro and vivo. We also investigated whether this toxin spares neuron structure and function in peritumoral areas. We performed a microarray transcriptomic and in-depth proteomic analysis to characterize the molecular changes triggered by CNF1 in glioma cells. We also examined tumor cell senescence and growth in vehicle- and CNF1-treated glioma-bearing mice. Electrophysiological and morphological techniques were used to investigate neuronal alterations in peritumoral cortical areas. Administration of CNF1 triggered molecular and morphological hallmarks of senescence in mouse and human glioma cells in vitro. CNF1 treatment in vivo induced glioma cell senescence and potently reduced tumor volumes. In peritumoral areas of glioma-bearing mice, neurons showed a shrunken dendritic arbor and severe functional alterations such as increased spontaneous activity and reduced visual responsiveness. CNF1 treatment enhanced dendritic length and improved several physiological properties of pyramidal neurons, demonstrating functional preservation of the cortical network. Our findings demonstrate that CNF1 reduces glioma volume while at the same time maintaining the physiological and structural properties of peritumoral neurons. These data indicate a promising strategy for the development of more effective antiglioma therapies. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Overexpression of NIMA-related kinase 2 is associated with poor prognoses in malignant glioma.

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Liu, Huajie; Liu, Bin; Hou, Xianzeng; Pang, Bo; Guo, Pengbo; Jiang, Wanli; Ding, Qian; Zhang, Rui; Xin, Tao; Guo, Hua; Xu, Shangchen; Pang, Qi

2017-05-01

Eleated expression of NIMA-related kinase 2 (NEK2) was frequently observed in a variety of malignant cancers, and it appears to be involved in the initiation, maintenance, progression, metastasis of cancer and is positively associated with poor prognosis. We sought to investigate NEK2 expression and its predictive roles in malignant gliomas, and study the correlation of NEK2 protein expression with proliferation, clinical parameters, overall survival and some other parameters. We investigate NEK2 protein expression in 99 samples of malignant gliomas, including 35 WHO grade II, 22 grade III, and 42 grade IV gliomas, by immunohistochemistry and western blot (n = 50). We then made correlative analysis of protein overexpression using the Kaplan-Meier method, Log rank test, and Cox proportional-hazards model analysis. NEK2 protein was overexpressed in malignant gliomas, but not in normal brain tissues. Overexpression of NEK2 correlated with malignancy, proliferation and adverse overall survival in gliomas. Moreover, chemotherapy, resection extent and WHO grade also correlate with overall survival in gliomas. However, within WHO grade II glioma subgroup, NEK2 overexpression showed no impact on overall survival. The present study firstly reveals that NEK2 protein is widely overexpressed in gliomas. NEK2 overexpression correlates significantly with malignancy (WHO grades), proliferation (Ki-67) and prognosis in malignant gliomas. NEK2 is a potential gene therapy target and prognostic indicator.

Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma

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Ceccarelli, Michele; Barthel, Floris P.; Malta, Tathiane M.; Sabedot, Thais S.; Salama, Sofie R.; Murray, Bradley A.; Morozova, Olena; Newton, Yulia; Radenbaugh, Amie; Pagnotta, Stefano M.; Anjum, Samreen; Wang, Jiguang; Manyam, Ganiraju; Zoppoli, Pietro; Ling, Shiyung; Rao, Arjun A.; Grifford, Mia; Cherniack, Andrew D.; Zhang, Hailei; Poisson, Laila; Carlotti, Carlos Gilberto; Pretti da Cunha Tirapelli, Daniela; Rao, Arvind; Mikkelsen, Tom; Lau, Ching C.; Yung, W.K. Alfred; Rabadan, Raul; Huse, Jason; Brat, Daniel J.; Lehman, Norman L.; Barnholtz-Sloan, Jill S.; Zheng, Siyuan; Hess, Kenneth; Rao, Ganesh; Meyerson, Matthew; Beroukhim, Rameen; Cooper, Lee; Akbani, Rehan; Wrensch, Margaret; Haussler, David; Aldape, Kenneth D.; Laird, Peter W.; Gutmann, David H.; Noushmehr, Houtan; Iavarone, Antonio; Verhaak, Roel G.W.

2015-01-01

SUMMARY Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH-mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wildtype diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes. PMID:26824661

Leveraging ethnic group incidence variation to investigate genetic susceptibility to glioma: A novel candidate SNP approach

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Daniel Ian Jacobs

2012-10-01

Full Text Available Objectives: Using a novel candidate SNP approach, we aimed to identify a possible genetic basis for the higher glioma incidence in Whites relative to East Asians and African-Americans. Methods: We hypothesized that genetic regions containing SNPs with extreme differences in allele frequencies across ethnicities are most likely to harbor susceptibility variants. We used International HapMap Project data to identify 3,961 candidate SNPs with the largest allele frequency differences in Whites compared to East Asians and Africans and tested these SNPs for association with glioma risk in a set of White cases and controls. Top SNPs identified in the discovery dataset were tested for association with glioma in five independent replication datasets. Results: No SNP achieved statistical significance in either the discovery or replication datasets after accounting for multiple testing. However, the most strongly associated SNP, rs879471, was found to be in linkage disequilibrium with a previously identified risk SNP, rs6010620, in RTEL1. We estimate rs6010620 to account for a glioma incidence rate ratio of 1.34 for Whites relative to East Asians. Conclusions: We explored genetic susceptibility to glioma using a novel candidate SNP method which may be applicable to other diseases with appropriate epidemiologic patterns.

Low-Grade Glioma Segmentation Based on CNN with Fully Connected CRF

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Zeju Li

2017-01-01

Full Text Available This work proposed a novel automatic three-dimensional (3D magnetic resonance imaging (MRI segmentation method which would be widely used in the clinical diagnosis of the most common and aggressive brain tumor, namely, glioma. The method combined a multipathway convolutional neural network (CNN and fully connected conditional random field (CRF. Firstly, 3D information was introduced into the CNN which makes more accurate recognition of glioma with low contrast. Then, fully connected CRF was added as a postprocessing step which purposed more delicate delineation of glioma boundary. The method was applied to T2flair MRI images of 160 low-grade glioma patients. With 59 cases of data training and manual segmentation as the ground truth, the Dice similarity coefficient (DSC of our method was 0.85 for the test set of 101 MRI images. The results of our method were better than those of another state-of-the-art CNN method, which gained the DSC of 0.76 for the same dataset. It proved that our method could produce better results for the segmentation of low-grade gliomas.

Tumor localization of boronated porphyrins in an intracerebral model of glioma

International Nuclear Information System (INIS)

Hill, J.S.; Kaye, A.H.; Gonzales, M.F.; Stylli, S.S.; Nakamura, Y.; Kahl, S.B.; Vardaxis, N.J.; Johnson, C.I.

1992-01-01

Treatment of the most common cerebral tumor, cerebral glioma, is unsatisfactory as the tumor recurs due to inadequate local control. Photodynamic therapy (PDT) and Boron Neutron Capture Therapy (BNCT) offer some promise as adjuvant treatments for cerebral glioma. Several clinical trials have been reported utilizing PDT and BNCT to treat the high grade glioma, glioblastoma multiforme. The authors have investigated the pharmacokinetic tissue distribution of the photosensitizer Haematoporphyrin derivative (HpD), the nido carboranyl porphyrin, boron tetraphenyl porphine (BTPP) and the closo carboranyl monomeric protoporphyrin (BOPP) in CBA mice bearing the intracerebral C6 glioma xenograft

Response-predictive gene expression profiling of glioma progenitor cells in vitro.

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Sylvia Moeckel

Full Text Available High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist.In this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a to enrich specimens for brain tumor initiating cells and (b to confront cells with a therapeutic agent before expression profiling.As a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro.For the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.

Metabolic impact of anti-angiogenic agents on U87 glioma cells.

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Tanja Mesti

Full Text Available BACKGROUND: Glioma cells not only secrete high levels of vascular endothelial growth factor (VEGF but also express VEGF receptors (VEGFR, supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev or VEGFR Tyrosine Kinase Inhibitor (TKI, is poorly known. MATERIAL AND METHODS: U87 cells were treated with Bev or SU1498, a selective VEGFR2 TKI. VEGFR expression was checked with FACS flow cytometry and Quantitative Real-Time PCR. VEGF secretion into the medium was assessed with an ELISA kit. Metabolomic studies on cells were performed using High Resolution Magic Angle Spinning Spectroscopy (HR-MAS. RESULTS: U87 cells secreted VEGF and expressed low level of VEGFR2, but no detectable VEGFR1. Exposure to SU1498, but not Bev, significantly impacted cell proliferation and apoptosis. Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine. Accordingly, accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells. CONCLUSION: Although both drugs target the VEGF pathway, only SU1498 showed a clear impact on cell proliferation, cell morphology and metabolism. Bevacizumab is thus less likely to modify glioma cells phenotype due to a direct therapeutic pressure on the VEGF autocrine loop. In patients treated with VEGFR TKI, monitoring lipids with magnetic resonance spectroscopic (MRS might be a valuable marker to assess drug cytotoxicity.

Antitumor effect of a new nano-vector with miRNA-135a on malignant glioma

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Liang C

2017-12-01

Full Text Available Chaofeng Liang,1,* Weitong Sun,2,* Haiyong He,1,* Baoyu Zhang,1 Cong Ling,1 Bocheng Wang,1 Tengchao Huang,1 Bo Hou,1 Ying Guo1 1Department of Neurosurgery, 3rd Affiliated Hospital of Sun Yat-sen University, Sun Yat-sen University, Guangdong, China; 2The Pharmaceutical College of Jiamusi University, Jiamusi University, Jiamusi, China *These authors contributed equally to this work Introduction: MiR-135a is found to selectively induce apoptosis in glioma cell but not in normal neurons and glial cells. However, low transfection efficacy limits its application in vivo as other miRNAs. We prepared a new kind of nano-vector based on polyethylene glycol methyl ether (mPEG and hyper-branched polyethylenimine (hy-PEI in order to improve the miRNA delivery system into the glioma cells. Methods: The mPEG-g-PEI/miR-135a was constructed and detected by 1H NMR and FTIR analyses. Transmission electron microscope was utilized for its characteristics. Stability and release efficiency was assessed by electrophoresis. Biocompatibility was observed and analyzed through co-culture with astrocytes and malignant glioma cells (C6. Transfection rate was monitored by laser confocal microscopy and flow cytometry. The antitumor effect of mPEG-g-PEI/miR-135a to C6 was confirmed in vivo by MR scanning, pathology and survival curve. RT-PCR was used to assay transfection efficiency of mPEG-g-PEI/miR-135a in vitro and in vivo. And Western blotting was used to assess the expressions of the targeted proteins of miR-135a.Results: In this experiment, we found the optimal N/P ratio of mPEG-g-PEI/miR-135a was about 6 judged by Zeta potential, particle size and encapsulation ability. The stability of mPEG-g-PEI/miR-135a in serum and the release efficiency in acid(pH=5.0 of mPEG-g-PEI/miR-135a were simulated the environment in vivo and in tumor. The mPEG-g-PEI nano-vector was co-cultured with malignant glioma cell C6 and normal astrocytes in vitro and showed good biocompatibility

Anti-invasive and antiangiogenic effects of MMI-166 on malignant glioma cells

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Nakabayashi, Hiromichi; Yawata, Toshio; Shimizu, Keiji

2010-01-01

The constitutive overexpression of matrix metalloproteinases (MMPs) is frequently observed in malignant tumours. In particular, MMP-2 and MMP-9 have been reported to be closely associated with invasion and angiogenesis in malignant gliomas. Our study aimed to evaluate the antitumour effects of MMI-166 (Nalpha-[4-(2-Phenyl-2H- tetrazole-5-yl) phenyl sulfonyl]-D-tryptophan), a third generation MMP inhibitor, on three human glioma cell lines (T98G, U87MG, and ONS12) in vitro and in vivo. The effects of MMI-166 on the gelatinolytic activity was analysed by gelatine zymography. The anti-invasive effect of MMI-166 was analysed by an in vitro invasion assay. An in vitro angiogenesis assay was also performed. In vitro growth inhibition of glioma cells by MMI-166 was determined by the MTT assay. The effect of MMI-166 on an orthotropic implantation model using athymic mice was also evaluated. Gelatine zymography revealed that MMP-2 and MMP-9 activities were suppressed by MMI-166. The invasion of glioma cells was suppressed by MMI-166. The angiogenesis assay showed that MMI-166 had a suppressive effect on glioma cell-induced angiogenesis. However, MMI-166 did not suppress glioma cell proliferation in the MTT assay. In vivo, MMI-166 suppressed tumour growth in athymic mice implanted orthotropically with T98G cells and showed an inhibitory effect on tumour-induced angiogenesis and tumour growth. This is the first report of the effect of a third generation MMP inhibitor on malignant glioma cells. These results suggest that MMI-166 may have potentially suppressive effects on the invasion and angiogenesis of malignant gliomas

Possible novel therapy for malignant gliomas with secretable trimeric TRAIL.

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Moonsup Jeong

Full Text Available Malignant gliomas are the most common primary brain tumors. Despite intensive clinical investigation and many novel therapeutic approaches, average survival for the patients with malignant gliomas is only about 1 year. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL has shown potent and cancer-selective killing activity and drawn considerable attention as a promising therapy for cancers, but concerns over delivery and toxicity have limited progress. We have developed a secretable trimeric TRAIL (stTRAIL and here evaluated the therapeutic potential of this stTRAIL-based gene therapy in brain tumors. An adenovirus (Ad-stTRAIL delivering stTRAIL was injected into intra-cranial human glioma tumors established in nude mice and tumor growth monitored using the magnetic resonance imaging (MRI. Ad-stTRAIL gene therapy showed potent tumor suppressor activity with no toxic side effects at therapeutically effective doses. When compared with 1, 3-bis(2-chloroethyl-1-nitrosourea (BCNU, a conventional therapy for malignant gliomas, Ad-stTRAIL suppressed tumor growth more potently. The combination of Ad-stTRAIL and BCNU significantly increased survival compared to the control mice or mice receiving Ad-stTRAIL alone. Our data indicate that Ad-stTRAIL, either alone or combined with BCNU, has promise as a novel therapy for malignant gliomas.

“...those left behind.” Biology and Oncology of Invasive Glioma Cells

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Michael E Berens

1999-08-01

Full Text Available Although significant technical advances in surgical and radiation treatment for brain tumors have emerged in recent years, their impact on clinical outcome for patients has been disappointing. A fundamental source of the management challenge presented by glioma patients is the insidious propensity of the malignant cells to invade into adjacent normal brain. Invasive tumor cells escape surgical removal and geographically dodge lethal radiation exposure. Recent improved understanding of the biochemistry and molecular determinants of glioma cell invasion provide valuable insight to the underlying biological features of the disease, as well as illuminating possible new therapeutic targets. Heightened commitment to migrate and invade is accompanied by a glioma cell's reduced proliferative activity. The microenvironmental manipulations coincident to invasion and migration may also impact the glioma cell's response to cytotoxic treatments. These collateral aspects of the glioma cell invasive phenotype should be further explored and exploited as novel antiglioma therapies.

CD133 positive U87 glioma stem cell radiosensitivity and DNA double-strand break repair

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Li Ping; Zong Tianzhou; Ji Xiaoqin; Lu Xueguan

2013-01-01

Objective: To explore the radiosensitivity and DNA double-strand break repair of CD133 + U87 glioma stem cell. Methods: CD133 + and CD133 - cells were isolated from glioma U87 cell lines by flow cytometry sorter system. After irradiated vertically by 4 Gy X-rays, the radiosensitivity of cells was determined by clonogenic assay. The radiation-induced DNA double-strand break repair of CD133 + and CD133 - cells was determined by the neutral comet assay,and the expression of phosphorylated histone H2AX (γ-H2AX) and Rad51 foci were measured by immunofluorescence. Results: The clone forming rate of CD133 + cells was higher than CD133 - cells (t=3.66, P<0.01) with no radiation. The clone forming rate of CD133 + cells irradiated by 4 Gy X-rays has no significant changes compared to that of the non-irradiation cells (t=0.71, P>0.05), but for CD133 - cells, it decreased compared to non-irradiation cells (t=2.91, P<0.05). The tailmoment between CD133 + cells and CD133 - cells had no difference at 0.5 h after irradiation (t=1.44, P>0.05); the tailmoment of CD133 + cells was lower than CD133 - cells at 6 and 24 h after irradiation,respectively (t=5.31 and 8.09, P<0.01). There was no significant difference in the expression of γ-H2AX foci between CD133 + and CD133 - cells at 0.5 and 6 h after irradiation (t=0.12 and 0.99, P>0.05), γ-H2AX foci of CD133 + cells was significantly decreased compared to CD133 - cells at 24 h after irradiation (t=4.99, P<0.01). For Rad 51 foci, there was no difference between CD133 + and CD133 - cells at 0.5 h after irradiation (t=1.12, P>0.05). The expression of Rad 51 foci of CD133 - cells was decreased compared to that of CD133 + cells at 6 and 24 h after irradiation,respectively (t=22.88 and 12.43, P<0.01). And the expression of Rad51 foci of CD133 + cells had no significant changes at 6-24 h after irradiation. Conclusions: Glioma stem cells is more radioresistive than glioma non-stem cells. The probable mechanism is that the DNA double

TGF-b and a specific TGF-b inhibitor regulate pericentrin B and MYH9 in glioma cell lines

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Óscar Álzate

2006-01-01

Full Text Available Malignant gliomas are heterogeneous, highly invasive vascular tumours. The multifunctional cytokine, transforming growth factor-beta (TGF-P, is expressed by grade III/IV gliomas and promotes tumour angiogenesis, invasión and immune escape. It has been shown previously that a small TGF-P receptor type I (TGF-(3-RI molecule inhibitor (SB-431542 blocks TGF-(3-mediated signal transduction, induction of angiogenic factor expression and cellular motility. As glioma cell lines display differential sensitivity to TGF-P, it was expected that they would also be differentially impacted by disruption of TGF-P signalling. Differential in gel expression (DIGE analysis and mass spectrometry was used in this work for determining protein regulation effects of both TGF-P and SB-431542 on human glioma cell lines. It was found that pericentrin B and non muscle myosin were differentially expressed in fragments which likely resulted from protease activation by the tumour growth mechanism. These results suggest that both pericentrin B and non-muscle myosin might be potential glioma biomarkers. Key words: DIGE, proteomics, glioma, TGF-P, mass spectrometry, non muscle myosin, pericentrin B.

Atypical nuclear localization of VIP receptors in glioma cell lines and patients

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Barbarin, Alice; Séité, Paule [Equipe Récepteurs, Régulations et Cellules Tumorales, Université de Poitiers, PBS bât 36, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9 (France); Godet, Julie [Laboratoire d’anatomie et de cytologie pathologiques, CHU de Poitiers, 2 rue de la Milétrie, 86000 Poitiers (France); Bensalma, Souheyla; Muller, Jean-Marc [Equipe Récepteurs, Régulations et Cellules Tumorales, Université de Poitiers, PBS bât 36, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9 (France); Chadéneau, Corinne, E-mail: corinne.chadeneau@univ-poitiers.fr [Equipe Récepteurs, Régulations et Cellules Tumorales, Université de Poitiers, PBS bât 36, 1 rue Georges Bonnet, TSA 51106, 86073 Poitiers Cedex 9 (France)

2014-11-28

Highlights: • The VIP receptor VPAC1 contains a putative NLS signal. • VPAC1 is predominantly nuclear in GBM cell lines but not VPAC2. • Non-nuclear VPAC1/2 protein expression is correlated with glioma grade. • Nuclear VPAC1 is observed in 50% of stage IV glioma (GBM). - Abstract: An increasing number of G protein-coupled receptors, like receptors for vasoactive intestinal peptide (VIP), are found in cell nucleus. As VIP receptors are involved in the regulation of glioma cell proliferation and migration, we investigated the expression and the nuclear localization of the VIP receptors VPAC1 and VPAC2 in this cancer. First, by applying Western blot and immunofluorescence detection in three human glioblastoma (GBM) cell lines, we observed a strong nuclear staining for the VPAC1 receptor and a weak nuclear VPAC2 receptor staining. Second, immunohistochemical staining of VPAC1 and VPAC2 on tissue microarrays (TMA) showed that the two receptors were expressed in normal brain and glioma tissues. Expression in the non-nuclear compartment of the two receptors significantly increased with the grade of the tumors. Analysis of nuclear staining revealed a significant increase of VPAC1 staining with glioma grade, with up to 50% of GBM displaying strong VPAC1 nuclear staining, whereas nuclear VPAC2 staining remained marginal. The increase in VPAC receptor expression with glioma grades and the enhanced nuclear localization of the VPAC1 receptors in GBM might be of importance for glioma progression.

Glucose consumption and rate constants for sup 18 F-fluorodeoxyglucose in human gliomas

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Ishikawa, Masatsune; Kikuchi, Haruhiko; Nagata, Izumi; Yamagata, Sen; Taki, Waro; Yonekura, Yoshiharu; Nishizawa, Sadahiko; Iwasaki, Yasushi; Mukai, Takao [Kyoto Univ. (Japan). Faculty of Medicine

1990-06-01

To investigate the value of direct measurement of the rate constants by performing {sup 18}F-labeled fluorodeoxyglucose (FDG) studies of glucose consumption in human gliomas in vivo, a kinetic method with 3- and 4-parameter rate constant models for FDG uptake was used to analyze data from dynamic scans obtained by positron emission tomography after injection of FDG into 14 patients with glioma. The results were compared with those obtained by the autoradiographic method using 3- and 4-parameter rate constant models. There were no significant differences in the glucose consumption calculated by the four different methods both in the gliomas and in the contralateral intact cortex. It was found that the rate constant k4 could be neglected in calculation of glucose consumption in gliomas as well as in the contralateral intact cortex. The rate constant k3, an index of hexokinase function, was higher in malignant gliomas than in benign gliomas and was close to that in the contralateral cortex. This study indicates that the 3-parameter autoradiographic method, which is the most common one used in clinical practice, is reliable for the calculation of glucose consumption in human gliomas. Furthermore, direct measurement of the regional rate constants for FDG by the kinetic method was found to be useful for evaluation of the biochemical and physiological characteristics of human gliomas in vivo. (author).

Characterization of infectivity of knob-modified adenoviral vectors in glioma

NARCIS (Netherlands)

C.P.L. Paul (C. P L); M. Everts (M.); J.N. Glasgow (J.); P. Dent (P.); P.B. Fisher (P.); I.V. Ulasov (I.); M.S. Lesniak (M.); M.A. Stoff-Khalili (M.); J.C. Roth (J.); M. Preuss (Michael); C.M.F. Dirven (Clemens); M.L.M. Lamfers (Martine); T. Siegal (Tali); Z.B. Zhu (Z.); R.E. Curiel (Rafael E.)

2008-01-01

textabstractMalignant glioma continues to be a major target for gene therapy and virotherapy due to its aggressive growth and the current lack of effective treatment. However, these approaches have been hampered by inefficient infection of glioma cells by viral vectors, particularly vectors derived

Autophagy contributes to gefitinib-induced glioma cell growth inhibition

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Chang, Cheng-Yi [Department of Surgery, Fong-Yuan Hospital, Taichung 420, Taiwan (China); Graduate Institute of Pharmaceutical Science and Technology, Central Taiwan University of Science and Technology, Taichung 406, Taiwan (China); Kuan, Yu-Hsiang [Department of Pharmacology, School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan (China); Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 402, Taiwan (China); Ou, Yen-Chuan; Li, Jian-Ri [Division of Urology, Taichung Veterans General Hospital, Taichung 407, Taiwan (China); Wu, Chih-Cheng [Department of Anesthesiology, Taichung Veterans General Hospital, Taichung 407, Taiwan (China); Department of Financial and Computational Mathematics, Providence University, Taichung 433, Taiwan (China); Pan, Pin-Ho [Department of Pediatrics, Tungs’ Taichung MetroHarbor Hospital, Taichung 435, Taiwan (China); Chen, Wen-Ying [Department of Veterinary Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Huang, Hsuan-Yi [Department of Surgery, Fong-Yuan Hospital, Taichung 420, Taiwan (China); Chen, Chun-Jung, E-mail: cjchen@vghtc.gov.tw [Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan (China); Institute of Biomedical Sciences, National Chung Hsing University, Taichung 402, Taiwan (China); Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan (China); Center for General Education, Tunghai University, Taichung 407, Taiwan (China); Department of Nursing, HungKuang University, Taichung 433, Taiwan (China)

2014-09-10

Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK.

Autophagy contributes to gefitinib-induced glioma cell growth inhibition

International Nuclear Information System (INIS)

Chang, Cheng-Yi; Kuan, Yu-Hsiang; Ou, Yen-Chuan; Li, Jian-Ri; Wu, Chih-Cheng; Pan, Pin-Ho; Chen, Wen-Ying; Huang, Hsuan-Yi; Chen, Chun-Jung

2014-01-01

Epidermal growth factor receptor tyrosine kinase inhibitors, including gefitinib, have been evaluated in patients with malignant gliomas. However, the molecular mechanisms involved in gefitinib-mediated anticancer effects against glioma are incompletely understood. In the present study, the cytostatic potential of gefitinib was demonstrated by the inhibition of glioma cell growth, long-term clonogenic survival, and xenograft tumor growth. The cytostatic consequences were accompanied by autophagy, as evidenced by monodansylcadaverine staining of acidic vesicle formation, conversion of microtubule-associated protein-1 light chain 3-II (LC3-II), degradation of p62, punctate pattern of GFP-LC3, and conversion of GFP-LC3 to cleaved-GFP. Autophagy inhibitor 3-methyladenosine and chloroquine and genetic silencing of LC3 or Beclin 1 attenuated gefitinib-induced growth inhibition. Gefitinib-induced autophagy was not accompanied by the disruption of the Akt/mammalian target of rapamycin signaling. Instead, the activation of liver kinase-B1/AMP-activated protein kinase (AMPK) signaling correlated well with the induction of autophagy and growth inhibition caused by gefitinib. Silencing of AMPK suppressed gefitinib-induced autophagy and growth inhibition. The crucial role of AMPK activation in inducing glioma autophagy and growth inhibition was further supported by the actions of AMP mimetic AICAR. Gefitinib was shown to be capable of reducing the proliferation of glioma cells, presumably by autophagic mechanisms involving AMPK activation. - Highlights: • Gefitinib causes cytotoxic and cytostatic effect on glioma. • Gefitinib induces autophagy. • Gefitinib causes cytostatic effect through autophagy. • Gefitinib induces autophagy involving AMPK

PAI-1 and EGFR expression in adult glioma tumors: toward a molecular prognostic classification

International Nuclear Information System (INIS)

Muracciole, Xavier; Romain, Sylvie; Dufour, Henri; Palmari, Jacqueline; Chinot, Olivier; Ouafik, L'Houcine; Grisoli, Francois; Figarella-Branger, Dominique; Martin, Pierre-Marie

2002-01-01

Purpose: Molecular classification of gliomas is a major challenge in the effort to improve therapeutic decisions. The plasminogen activator system, including plasminogen activator inhibitor type 1 (PAI-1), plays a key role in tumor invasion and neoangiogenesis. Epidermal growth factor receptor (EGFR) is involved in the control of proliferation. The contribution of PAI-1 and EGFR to the survival of gliomas was retrospectively investigated. Methods and Materials: Fifty-nine adult gliomas treated by neurosurgery and conventional irradiation were analyzed, including 9 low-grade (2) and 50 high-grade (3-4) tumors (WHO classification). PAI-1 was measured on cytosols and EGFR on solubilized membranes using ELISA methods. Results: High PAI-1 levels were strongly associated with high histologic grade (p<0.001) and histologic necrosis (p<0.001). PAI-1 also correlated positively with patient age (p=0.05) and negatively with Karnofsky index (p=0.01). By univariate analysis of the high-grade population, higher PAI-1 (p<0.0001) and EGFR values (p=0.02) were associated with shorter overall survival. Only PAI-1 was an independent factor in multivariate analysis. Grade 3 tumors with low PAI-1 (100% 3-year overall survival rate) presented the same clinical outcome as the low-grade tumors. Conclusions: In this prognostic study, PAI-1 and EGFR expression revealed similarities and differences between high-grade gliomas that were not apparent by traditional clinical criteria. These data strongly support that biologic factors should be included in glioma classification and the design of clinical trials to treat more homogeneous populations

Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma

International Nuclear Information System (INIS)

Qin, Tian; Wang, Chenlong; Chen, Xuewei; Duan, Chenfan; Zhang, Xiaoyan; Zhang, Jing; Chai, Hongyan; Tang, Tian; Chen, Honglei; Yue, Jiang; Li, Ying; Yang, Jing

2015-01-01

Dopamine (DA), a monoamine catecholamine neurotransmitter with antiangiogenic activity, stabilizes tumor vessels in colon, prostate and ovarian cancers, thus increases chemotherapeutic efficacy. Here, in the rat C6 glioma models, we investigated the vascular normalization effects of DA and its mechanisms of action. DA (25, 50 mg/kg) inhibited tumor growth, while a precursor of DA (levodopa) prolonged the survival time of rats bearing orthotopic C6 glioma. DA improved tumor perfusion, with significant effects from day 3, and a higher level at days 5 to 7. In addition, DA decreased microvessel density and hypoxia-inducible factor-1α expression in tumor tissues, while increasing the coverage of pericyte. Conversely, an antagonist of dopamine receptor 2 (DR2) (eticlopride) but not DR1 (butaclamol) abrogated DA-induced tumor regression and vascular normalization. Furthermore, DA improved the delivery and efficacy of temozolomide therapy. Importantly, DA increased representative M1 markers (iNOS, CXCL9, etc.), while decreasing M2 markers (CD206, arginase-1, etc.). Depletion of macrophages by clodronate or zoledronic acid attenuated the effects of DA. Notably, DA treatment induced M2-to-M1 polarization in RAW264.7 cells and mouse peritoneal macrophages, and enhanced the migration of pericyte-like cells (10T1/2), which was reversed by eticlopride or DR2-siRNA. Such changes were accompanied by the downregulation of VEGF/VEGFR2 signaling. In summary, DA induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages. Thus, targeting the tumor microvasculature by DA represents a promising strategy for human glioma therapy. - Highlights: • Dopamine induces tumor growth inhibition and vascular normalization in rat C6 glioma. • Dopamine switches macrophage phenotype from M2 to M1. • Dopamine-induced vascular normalization is mediated by macrophage polarization. • Dopamine is a promising agent targeting the microvasculature in tumor

Dopamine induces growth inhibition and vascular normalization through reprogramming M2-polarized macrophages in rat C6 glioma