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Sample records for glioma bearer mouse

  1. Noninvasive Monitoring of Glioma Growth in the Mouse

    PubMed Central

    Alessandrini, Francesco; Ceresa, Davide; Appolloni, Irene; Marubbi, Daniela; Malatesta, Paolo

    2016-01-01

    Malignant gliomas are the most common and deadly primary malignant brain tumors. In vivo orthotopic models could doubtless represent an appropriate tool to test novel treatment for gliomas. However, methods commonly used to monitor the growth of glioma inside the mouse brain are time consuming and invasive. We tested the reliability of a minimally invasive procedure, based on a secreted luciferase (Gaussia luciferase), to frequently monitor the changes of glioma size. Gluc activity was evaluated from blood samples collected from the tail tip of mice twice a week, allowing to make a growth curve for the tumors. We validated the correlation between Gluc activity and tumor size by analysing the tumor after brain dissection. We found that this method is reliable for monitoring human glioma transplanted in immunodeficient mice, but it has strong limitation in immunocompetent models, where an immune response against the luciferase is developed during the first weeks after transplant.

  2. Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 m...

  3. Malignant Glioma: Lessons from Genomics, Mouse Models, and Stem Cells

    PubMed Central

    Chen, Jian; McKay, Renée M.; Parada, Luis F.

    2013-01-01

    Eighty percent of malignant tumors that develop in the central nervous system are malignant gliomas, which are essentially incurable. Here, we discuss how recent sequencing studies are identifying unexpected drivers of gliomagenesis, including mutations in isocitrate dehydrogenase 1 and the NF-κB pathway, and how genome-wide analyses are reshaping the classification schemes for tumors and enhancing prognostic value of molecular markers. We discuss the controversies surrounding glioma stem cells and explore how the integration of new molecular data allows for the generation of more informative animal models to advance our knowledge of glioma's origin, progression, and treatment. PMID:22464322

  4. Glioma

    MedlinePlus

    ... problems, as well as changes in behavior and personality, are also fairly common in mixed glioma patients. ... Cerebri: Symptoms are often nonspecific and can include personality and behavioral changes, memory disturbance, increased intracranial pressure ...

  5. A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells12

    PubMed Central

    Misuraca, Katherine L.; Hu, Guo; Barton, Kelly L.; Chung, Alexander; Becher, Oren J.

    2016-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3 +/Nestin +/Sox2 + population lining the fourth ventricle and a Pax3 +/NeuN + parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53fl/fl mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67 +, Nestin +, Olig2 +, and largely GFAP − and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease. PMID:26806352

  6. Insights Gained from Modeling High-Grade Glioma in the Mouse

    PubMed Central

    Rankin, Sherri L.; Zhu, Guo; Baker, Suzanne J.

    2011-01-01

    High grade gliomas (HGG) are devastating primary brain tumors with universally poor prognoses. Advances toward effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumor initiation, progression, and phenotype, the influence of tumor microenviroment, and the analysis of cell types that can give rise to glioma. HGGs are a highly heterogeneous group of tumors, and the complexity of diverse mutations within common signaling pathways as well as the developmental and cell-type context of transformation contribute to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely approximate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing. PMID:22035336

  7. 31 CFR 358.7 - Where do I send my bearer corpora and detached bearer coupons to be converted?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... detached bearer coupons to be converted? 358.7 Section 358.7 Money and Finance: Treasury Regulations... Where do I send my bearer corpora and detached bearer coupons to be converted? Send bearer corpora and detached bearer coupons to be converted to: Bureau of the Public Debt, Division of Customer Service, P....

  8. Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma

    PubMed Central

    Lobo, Merryl R.; Kukino, Ayaka; Tran, Huong; Schabel, Matthias C.; Springer, Charles S.; Gillespie, G. Yancey; Grafe, Marjorie R.; Woltjer, Randall L.; Pike, Martin M.

    2015-01-01

    Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the

  9. Synergistic Antivascular and Antitumor Efficacy with Combined Cediranib and SC6889 in Intracranial Mouse Glioma.

    PubMed

    Lobo, Merryl R; Kukino, Ayaka; Tran, Huong; Schabel, Matthias C; Springer, Charles S; Gillespie, G Yancey; Grafe, Marjorie R; Woltjer, Randall L; Pike, Martin M

    2015-01-01

    Prognosis remains extremely poor for malignant glioma. Targeted therapeutic approaches, including single agent anti-angiogenic and proteasome inhibition strategies, have not resulted in sustained anti-glioma clinical efficacy. We tested the anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib and the novel proteasome inhibitor SC68896, in combination and as single agents. To assess anti-angiogenic effects and evaluate efficacy we employed 4C8 intracranial mouse glioma and a dual-bolus perfusion MRI approach to measure Ktrans, relative cerebral blood flow and volume (rCBF, rCBV), and relative mean transit time (rMTT) in combination with anatomical MRI measurements of tumor growth. While single agent cediranib or SC68896 treatment did not alter tumor growth or survival, combined cediranib/SC68896 significantly delayed tumor growth and increased median survival by 2-fold, compared to untreated. This was accompanied by substantially increased tumor necrosis in the cediranib/SC68896 group (p<0.01), not observed with single agent treatments. Mean vessel density was significantly lower, and mean vessel lumen area was significantly higher, for the combined cediranib/SC68896 group versus untreated. Consistent with our previous findings, cediranib alone did not significantly alter mean tumor rCBF, rCBV, rMTT, or Ktrans. In contrast, SC68896 reduced rCBF in comparison to untreated, but without concomitant reductions in rCBV, rMTT, or Ktrans. Importantly, combined cediranib/SC68896 substantially reduced rCBF, rCBV. rMTT, and Ktrans. A novel analysis of Ktrans/rCBV suggests that changes in Ktrans with time and/or treatment are related to altered total vascular surface area. The data suggest that combined cediranib/SC68896 induced potent anti-angiogenic effects, resulting in increased vascular efficiency and reduced extravasation, consistent with a process of vascular normalization. The study represents the first demonstration that the

  10. Toward Distinguishing Recurrent Tumor From Radiation Necrosis: DWI and MTC in a Gamma Knife–Irradiated Mouse Glioma Model

    SciTech Connect

    Perez-Torres, Carlos J.; Engelbach, John A.; Cates, Jeremy; Thotala, Dinesh; Yuan, Liya; Schmidt, Robert E.; Rich, Keith M.; Drzymala, Robert E.; Ackerman, Joseph J.H.; Garbow, Joel R.

    2014-10-01

    Purpose: Accurate noninvasive diagnosis is vital for effective treatment planning. Presently, standard anatomical magnetic resonance imaging (MRI) is incapable of differentiating recurring tumor from delayed radiation injury, as both lesions are hyperintense in both postcontrast T1- and T2-weighted images. Further studies are therefore necessary to identify an MRI paradigm that can differentially diagnose these pathologies. Mouse glioma and radiation injury models provide a powerful platform for this purpose. Methods and Materials: Two MRI contrasts that are widely used in the clinic were chosen for application to a glioma/radiation-injury model: diffusion weighted imaging, from which the apparent diffusion coefficient (ADC) is obtained, and magnetization transfer contrast, from which the magnetization transfer ratio (MTR) is obtained. These metrics were evaluated longitudinally, first in each lesion type alone–glioma versus irradiation – and then in a combined irradiated glioma model. Results: MTR was found to be consistently decreased in all lesions compared to nonlesion brain tissue (contralateral hemisphere), with limited specificity between lesion types. In contrast, ADC, though less sensitive to the presence of pathology, was increased in radiation injury and decreased in tumors. In the irradiated glioma model, ADC also increased immediately after irradiation, but decreased as the tumor regrew. Conclusions: ADC is a better metric than MTR for differentiating glioma from radiation injury. However, MTR was more sensitive to both tumor and radiation injury than ADC, suggesting a possible role in detecting lesions that do not enhance strongly on T1-weighted images.

  11. 31 CFR 358.6 - What is the procedure for converting bearer corpora and detached bearer coupons to book-entry?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... bearer corpora and detached bearer coupons to book-entry? 358.6 Section 358.6 Money and Finance: Treasury... PUBLIC DEBT REGULATIONS GOVERNING BOOK-ENTRY CONVERSION OF BEARER CORPORA AND DETACHED BEARER COUPONS § 358.6 What is the procedure for converting bearer corpora and detached bearer coupons to...

  12. Optic glioma

    MedlinePlus

    Glioma - optic; Optic nerve glioma; Juvenile pilocytic astrocytoma; Brain cancer - optic glioma ... Optic gliomas are rare. The cause of optic gliomas is unknown. Most optic gliomas are slow-growing ...

  13. Dynamics of Circulating γδ T Cell Activity in an Immunocompetent Mouse Model of High-Grade Glioma

    PubMed Central

    O’Brien, Rebecca; Jadus, Martin R.; Gillespie, G. Yancey; Cloud, Gretchen A.; Hoa, Neil T.; Langford, Catherine P.; Lopez, Richard D.; Harkins, Lualhati E.; Lamb Jr., Lawrence S.

    2015-01-01

    Human γδ T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 mice and measured circulating γδ T cell count, phenotype, Vγ/Vδ repertoire, tumor histopathology, NKG2D ligands expression, and T cell invasion at day 10–12 post-injection and at end stage. Circulating γδ T cells transiently increased and upregulated Annexin V expression at post-tumor day 10–12 followed by a dramatic decline in γδ T cell count at end stage. T cell receptor repertoire showed no changes in Vγ1, Vγ4, Vγ7 or Vδ1 subsets from controls at post-tumor day 10–12 or at end stage except for an end-stage increase in the Vδ4 population. Approximately 12% of γδ T cells produced IFN-γ. IL-17 and IL-4 producing γδ T cells were not detected. Tumor progression was the same in TCRδ-/- C57BL/6 mice as that observed in WT mice, suggesting that γδ T cells exerted neither a regulatory nor a sustainable cytotoxic effect on the tumor. WT mice that received an intracranial injection of γδ T cells 15m following tumor placement showed evidence of local tumor growth inhibition but this was insufficient to confer a survival advantage over untreated controls. Taken together, our findings suggest that an early nonspecific proliferation of γδ T cells followed by their depletion occurs in mice implanted with syngeneic GL261 gliomas. The mechanism by which γδ T cell expansion occurs remains a subject for further investigation of the mechanisms responsible for this immune response in the setting of high-grade glioma. PMID:25955158

  14. 31 CFR 358.6 - What is the procedure for converting bearer corpora and detached bearer coupons to book-entry?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false What is the procedure for converting bearer corpora and detached bearer coupons to book-entry? 358.6 Section 358.6 Money and Finance: Treasury... § 358.6 What is the procedure for converting bearer corpora and detached bearer coupons to...

  15. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model

    PubMed Central

    Woolf, Eric C.; Curley, Kara L.; Liu, Qingwei; Turner, Gregory H.; Charlton, Julie A.; Preul, Mark C.; Scheck, Adrienne C.

    2015-01-01

    Background The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood. Methods To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma. Results Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4. Conclusions The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas. PMID:26083629

  16. Ultrastructural characterization of the optic pathway in a mouse model of neurofibromatosis-1 optic glioma.

    PubMed

    Kim, K Y; Ju, W K; Hegedus, B; Gutmann, D H; Ellisman, M H

    2010-09-29

    The purpose of this study was to investigate the progression of changes in retinal ganglion cells and optic nerve glia in neurofibromatosis-1 (NF1) genetically-engineered mice with optic glioma. Optic glioma tumors were generated in Nf1+/- mice lacking Nf1 expression in GFAP+ cells (astrocytes). Standard immunohistochemistry methods were employed to identify astrocytes (GFAP, S100beta), proliferating progenitor cells (sox2, nestin), microglia (Iba1), endothelial cells (CD31) and retinal ganglion cell (RGC) axons (Neurofilament 68k) in Nf1+/-, Nf1(GFAP)CKO (wild-type mice with Nf1 loss in glial cells), and Nf1+/-(GFAP)CKO (Nf1+/- mice with Nf1 loss in glial cells) mice. Ultrastructural changes in the optic chiasm and nerve were assessed by electron microscopy (EM). RGC were counted in whole retina preparations using high-resolution, mosaic confocal microscopy following their delineation by retrograde FluoroGold labeling. We found that only Nf1+/-(GFAP)CKO mice exhibited gross pre-chiasmatic optic nerve and chiasm enlargements containing aggregated GFAP+/nestin+ and S100beta+/sox2+ cells (neoplastic glia) as well as increased numbers of blood vessels and microglia. Optic gliomas in Nf1+/-(GFAP)CKO mice contained axon fiber irregularities and multilamellar bodies of degenerated myelin. EM and EM tomographic analyses showed increased glial disorganization, disoriented axonal projections, profiles of degenerating myelin and structural alterations at nodes of Ranvier. Lastly, we found reduced RGC numbers in Nf1+/-(GFAP)CKO mice, supporting a model in which the combination of optic nerve Nf1 heterozygosity and glial cell Nf1 loss results in disrupted axonal-glial relationships, subsequently culminating in the degeneration of optic nerve axons and loss of their parent RGC neurons. PMID:20600672

  17. Magnetic Targeting of Novel Heparinized Iron Oxide Nanoparticles Evaluated in a 9L-glioma mouse model

    PubMed Central

    Zhang, Jian; Shin, Meong Cheol; Yang, Victor C.

    2013-01-01

    Purpose A novel PEGylated and heparinized magnetic iron oxide nano-platform (DNPH) was synthesized for simultaneous magnetic resonance imaging (MRI) and tumor targeting. Methods Starch-coated magnetic iron oxide nanoparticles (“D”) were crosslinked, aminated (DN) and then simultaneously PEGylated and heparinized with different feed ratios of PEG and heparin (DNPH1-4). DNPH products were characterized by Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and superconducting quantum interference device (SQUID). The magentic targeting of DNPH3, with appropriate amounts of conjugated PEG and heparin, in a mouse 9L-glioma subcutaneous tumor model was confirmed by magnetic resonance imaging (MRI)/electron spin resonance (ESR). Results DNPH3 showed long circulating properties in vivo (half-life > 8 h, more than 60-fold longer than that of parent D) and low reticuloendothelial system (RES) recognition in liver and spleen. Protamine, a model cationic protein, was efficiently loaded onto DNPH3 with a maxium loading content of 26.4 μg/mg Fe. Magnetic capture of DNPH3 in tumor site with optimized conditions (I.D. of 12 mg/kg, targeting time of 45 min) was up to 29.42 μg Fe/g tissue (12.26% I.D./g tissue). Conclusion DNPH3 showed the potential to be used as a platform for cationic proteins for simultaneous tumor targeting and imaging. PMID:24065589

  18. Heparan sulfate sulfatase SULF2 regulates PDGFRα signaling and growth in human and mouse malignant glioma

    PubMed Central

    Phillips, Joanna J.; Huillard, Emmanuelle; Robinson, Aaron E.; Ward, Anna; Lum, David H.; Polley, Mei-Yin; Rosen, Steven D.; Rowitch, David H.; Werb, Zena

    2012-01-01

    Glioblastoma (GBM), a uniformly lethal brain cancer, is characterized by diffuse invasion and abnormal activation of multiple receptor tyrosine kinase (RTK) signaling pathways, presenting a major challenge to effective therapy. The activation of many RTK pathways is regulated by extracellular heparan sulfate proteoglycans (HSPG), suggesting these molecules may be effective targets in the tumor microenvironment. In this study, we demonstrated that the extracellular sulfatase, SULF2, an enzyme that regulates multiple HSPG-dependent RTK signaling pathways, was expressed in primary human GBM tumors and cell lines. Knockdown of SULF2 in human GBM cell lines and generation of gliomas from Sulf2–/– tumorigenic neurospheres resulted in decreased growth in vivo in mice. We found a striking SULF2 dependence in activity of PDGFRα, a major signaling pathway in GBM. Ablation of SULF2 resulted in decreased PDGFRα phosphorylation and decreased downstream MAPK signaling activity. Interestingly, in a survey of SULF2 levels in different subtypes of GBM, the proneural subtype, characterized by aberrations in PDGFRα, demonstrated the strongest SULF2 expression. Therefore, in addition to its potential as an upstream target for therapy of GBM, SULF2 may help identify a subset of GBMs that are more dependent on exogenous growth factor–mediated signaling. Our results suggest the bioavailability of growth factors from the microenvironment is a significant contributor to tumor growth in a major subset of human GBM. PMID:22293178

  19. Pulsed and oscillating gradient MRI for assessment of cell size and extracellular space (POMACE) in mouse gliomas.

    PubMed

    Reynaud, Olivier; Winters, Kerryanne Veronica; Hoang, Dung Minh; Wadghiri, Youssef Zaim; Novikov, Dmitry S; Kim, Sungheon Gene

    2016-10-01

    Solid tumor microstructure is related to the aggressiveness of the tumor, interstitial pressure and drug delivery pathways, which are closely associated with treatment response, metastatic spread and prognosis. In this study, we introduce a novel diffusion MRI data analysis framework, pulsed and oscillating gradient MRI for assessment of cell size and extracellular space (POMACE), and demonstrate its feasibility in a mouse tumor model. In vivo and ex vivo POMACE experiments were performed on mice bearing the GL261 murine glioma model (n = 8). Since the complete diffusion time dependence is in general non-analytical, the tumor microstructure was modeled in an appropriate time/frequency regime by impermeable spheres (radius Rcell , intracellular diffusivity Dics ) surrounded by extracellular space (ECS) (approximated by constant apparent diffusivity Decs in volume fraction ECS). POMACE parametric maps (ECS, Rcell , Dics , Decs ) were compared with conventional diffusion-weighted imaging metrics, electron microscopy (EM), alternative ECS determination based on effective medium theory (EMT), and optical microscopy performed on the same samples. It was shown that Decs can be approximated by its long time tortuosity limit in the range [1/(88 Hz)-31 ms]. ECS estimations (44 ± 7% in vivo and 54 ± 11% ex vivo) were in agreement with EMT-based ECS and literature on brain gliomas. Ex vivo, ECS maps correlated well with optical microscopy. Cell sizes (Rcell  = 4.8 ± 1.3 in vivo and 4.3 ± 1.4 µm ex vivo) were consistent with EM measurements (4.7 ± 1.8 µm). In conclusion, Rcell and ECS can be quantified and mapped in vivo and ex vivo in brain tumors using the proposed POMACE method. Our experimental results support the view that POMACE provides a way to interpret the frequency or time dependence of the diffusion coefficient in tumors in terms of objective biophysical parameters of neuronal tissue, which can be used for non

  20. ET-06PRECLINICAL TESTING OF THE HISTONE DEACETYLASE INHIBITOR, PANOBINOSTAT, IN A GENETICALLY ENGINEERED DIFFUSE INTRINSIC PONTINE GLIOMA MOUSE MODEL

    PubMed Central

    Barton, Kelly; Misuraca, Katie; Becher, Oren

    2014-01-01

    Diffuse Intrinsic Pontine Glioma (DIPG) is a type of incurable pediatric brain tumor with a dismal outcome. With overall survival of less than one year, and no therapeutic advancements over the last three decades, gaining a better understanding of how to treat these deadly tumors is crucial. Recent genomic analysis has revealed that nearly 80% of DIPGS harbor a K27M mutation in histone H3.3 (K27M H3.3) or histone H3.1 (K27M H3.1). In an effort to elucidate novel therapeutics to treat DIPG, we examined Panobinostat, a potent pan-histone deacetylase inhibitor (HDACi) currently in clinical trials for a variety of different cancers. HDACi are a promising new class of agents known to have multiple target effects. Panobinostat targets HDACs in Classes I, II and IV and can cause disruption of genes involved in cell cycle control, apoptosis, DNA damage repair, and differentiation. To determine the effect of Panobinostat on DIPG, we utilized cell lines derived from a genetically engineered DIPG mouse model driven by PDGF-B overexpression, p53 loss, and either K27M or WT H3.3. Our results indicate that Panobinostat is highly effective at low nanomolar concentrations (<50nM), decreasing proliferation and viability, and increasing apoptosis in a dose dependent manner. Furthermore, utilizing isogenic lines we found the sensitivity of DIPG cells to Panobinostat to be independent of their H3.3 mutational status and that both K27M H3.3 and WT H3.3 lines were equally susceptible to treatment. In conclusion, murine DIPG cell lines, both with and without the K27M H3.3 mutation, show high sensitivity to Panobinostat in vitro. We are currently investigating its efficacy in vivo with hopes of translation to the clinic as a new therapeutic avenue for DIPG.

  1. Combined molecular MRI and immuno-spin-trapping for in vivo detection of free radicals in orthotopic mouse GL261 gliomas.

    PubMed

    Towner, Rheal A; Smith, Nataliya; Saunders, Debra; De Souza, Patricia Coutinho; Henry, Leah; Lupu, Florea; Silasi-Mansat, Robert; Ehrenshaft, Marilyn; Mason, Ronald P; Gomez-Mejiba, Sandra E; Ramirez, Dario C

    2013-12-01

    Free radicals play a major role in gliomas. By combining immuno-spin-trapping (IST) and molecular magnetic resonance imaging (mMRI), in vivo levels of free radicals were detected within mice bearing orthotopic GL261 gliomas. The nitrone spin trap DMPO (5,5-dimethyl pyrroline N-oxide) was administered prior to injection of an anti-DMPO probe (anti-DMPO antibody covalently bound to a bovine serum albumin (BSA)-Gd (gadolinium)-DTPA (diethylene triamine penta acetic acid)-biotin MRI contrast agent) to trap tumor-associated free radicals. mMRI detected the presence of anti-DMPO adducts by either a significant sustained increase (p<0.001) in MR signal intensity or a significant decrease (p<0.001) in T1 relaxation, measured as %T1 change. In vitro assessment of the anti-DMPO probe indicated a significant decrease (p<0.0001) in T1 relaxation in GL261 cells that were oxidatively stressed with hydrogen peroxide, compared to controls. The biotin moiety of the anti-DMPO probe was targeted with fluorescently-labeled streptavidin to locate the anti-DMPO probe in excised brain tissues. As a negative control a non-specific IgG antibody covalently bound to the albumin-Gd-DTPA-biotin construct was used. DMPO adducts were also confirmed in tumor tissue from animals administered DMPO, compared to non-tumor brain tissue. GL261 gliomas were found to have significantly increased malondialdehyde (MDA) protein adducts (p<0.001) and 3-nitrotyrosine (3-NT) (p<0.05) compared to normal mouse brain tissue, indicating increased oxidized lipids and proteins, respectively. Co-localization of the anti-DMPO probe with either 3-NT or 4-hydroxynonenal was also observed. This is the first report regarding the detection of in vivo levels of free radicals from a glioma model.

  2. 31 CFR 358.4 - Which bearer corpora or detached bearer coupons are eligible for conversion to transferable BECCS...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... bearer coupons are eligible for conversion to transferable BECCS or CUBES securities? 358.4 Section 358.4... for conversion to transferable BECCS or CUBES securities? (a) For a callable corpus to be eligible for conversion to a transferable BECCS security, all associated callable coupons must be submitted with...

  3. 31 CFR 358.4 - Which bearer corpora or detached bearer coupons are eligible for conversion to transferable BECCS...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... bearer coupons are eligible for conversion to transferable BECCS or CUBES securities? 358.4 Section 358.4... for conversion to transferable BECCS or CUBES securities? (a) For a callable corpus to be eligible for conversion to a transferable BECCS security, all associated callable coupons must be submitted with...

  4. 31 CFR 358.5 - Which bearer corpora or detached bearer coupons are eligible for conversion to non-transferable...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... bearer coupons are eligible for conversion to non-transferable BECCS or CUBES securities? 358.5 Section... for conversion to non-transferable BECCS or CUBES securities? If all of the callable coupons...-transferable BECCS security. Any remaining callable coupons submitted with the corpus will be converted...

  5. 31 CFR 358.5 - Which bearer corpora or detached bearer coupons are eligible for conversion to non-transferable...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... bearer coupons are eligible for conversion to non-transferable BECCS or CUBES securities? 358.5 Section... for conversion to non-transferable BECCS or CUBES securities? If all of the callable coupons...-transferable BECCS security. Any remaining callable coupons submitted with the corpus will be converted...

  6. Increased age of transformed mouse neural progenitor/stem cells recapitulates age-dependent clinical features of human glioma malignancy

    PubMed Central

    Mikheev, Andrei M.; Ramakrishna, Rohan; Stoll, Elizabeth A.; Mikheeva, Svetlana A.; Beyer, Richard P.; Plotnik, David A.; Schwartz, Jeffrey L.; Rockhill, Jason K.; Silber, John R.; Born, Donald E.; Kosai, Yoshito; Horner, Philip J.; Rostomily, Robert C.

    2012-01-01

    Increasing age is the most robust predictor of greater malignancy and treatment resistance in human gliomas. However, the adverse association of clinical course with aging is rarely considered in animal glioma models, impeding delineation of the relative importance of organismal versus progenitor cell aging in the genesis of glioma malignancy. To address this limitation, we implanted transformed neural stem/progenitor cells (NSPCs), the presumed cells of glioma origin, from 3 and 18month old mice into 3 and 20-month host animals. Transplantation with progenitors from older animals resulted in significantly shorter (p ≤ 0.0001) median survival in both 3month (37.5 vs 83 days) and 20-month (38 vs 67 days) hosts, indicating that age-dependent changes intrinsic to NSPCs rather than host animal age accounted for greater malignancy. Subsequent analyses revealed that increased invasiveness, genomic instability, resistance to therapeutic agents and tolerance to hypoxic stress accompanied aging in transformed NSPCs. Greater tolerance to hypoxia in older progenitor cells, as evidenced by elevated HIF-1 promoter reporter activity and hypoxia response gene (HRG) expression, mirror the upregulation of HRGs in cohorts of older vs younger glioma patients revealed by analysis of gene expression databases, suggesting that differential response to hypoxic stress may underlie age-dependent differences in invasion, genomic instability and treatment resistance. Our study provides strong evidence that progenitor cell aging is responsible for promoting the hallmarks of age-dependent glioma malignancy and that consideration of progenitor aging will facilitate development of physiologically and clinically relevant animal models of human gliomas. PMID:22958206

  7. Neurofibromatosis-1 heterozygosity increases microglia in a spatially and temporally restricted pattern relevant to mouse optic glioma formation and growth.

    PubMed

    Simmons, Grant W; Pong, Winnie W; Emnett, Ryan J; White, Crystal R; Gianino, Scott M; Rodriguez, Fausto J; Gutmann, David H

    2011-01-01

    Whereas carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression are heavily influenced by the local microenvironment. Previous studies from our laboratory have used Neurofibromatosis-1 (NF1) genetically engineered mice to characterize the role of stromal cells and signals to optic glioma formation and growth. Previously, we have shown that Nf1+/- microglia in the tumor microenvironment are critical cellular determinants of optic glioma proliferation. To define the role of microglia in tumor formation and maintenance further, we used CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times after ganciclovir administration. Ganciclovir-mediated microglia reduction reduced Nf1 optic glioma proliferation during both tumor maintenance and tumor development. We identified the developmental window during which microglia are increased in the Nf1+/- optic nerve and demonstrated that this accumulation reflected delayed microglia dispersion. The increase in microglia in the Nf1+/- optic nerve was associated with reduced expression of the chemokine receptor, CX3CR1, such that reduced Cx3cr1 expression in Cx3cr1-GFP heterozygous knockout mice led to a similar increase in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance of Nf1 optic glioma.

  8. Silver nanoparticles outperform gold nanoparticles in radiosensitizing U251 cells in vitro and in an intracranial mouse model of glioma

    PubMed Central

    Liu, Peidang; Jin, Haizhen; Guo, Zhirui; Ma, Jun; Zhao, Jing; Li, Dongdong; Wu, Hao; Gu, Ning

    2016-01-01

    Radiotherapy performs an important function in the treatment of cancer, but resistance of tumor cells to radiation still remains a serious concern. More research on more effective radiosensitizers is urgently needed to overcome such resistance and thereby improve the treatment outcome. The goal of this study was to evaluate and compare the radiosensitizing efficacies of gold nanoparticles (AuNPs) and silver nanoparticles (AgNPs) on glioma at clinically relevant megavoltage energies. Both AuNPs and AgNPs potentiated the in vitro and in vivo antiglioma effects of radiation. AgNPs showed more powerful radiosensitizing ability than AuNPs at the same mass and molar concentrations, leading to a higher rate of apoptotic cell death. Furthermore, the combination of AgNPs with radiation significantly increased the levels of autophagy as compared with AuNPs plus radiation. These findings suggest the potential application of AgNPs as a highly effective nano-radiosensitizer for the treatment of glioma. PMID:27757033

  9. Pharmacological Doses of Daily Ascorbate Protect Tumors from Radiation Damage after a Single Dose of Radiation in an Intracranial Mouse Glioma Model

    PubMed Central

    Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah V.; Castro, M. Leticia; Field, Cameron S.; Schleich, Nanette; McConnell, Melanie J.; Herst, Patries M.

    2014-01-01

    Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8–45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant. PMID:25566497

  10. A High-Throughput In Vitro Drug Screen in a Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma Identifies BMS-754807 as a Promising Therapeutic Agent

    PubMed Central

    Halvorson, Kyle G.; Barton, Kelly L.; Schroeder, Kristin; Misuraca, Katherine L.; Hoeman, Christine; Chung, Alex; Crabtree, Donna M.; Cordero, Francisco J.; Singh, Raj; Spasojevic, Ivan; Berlow, Noah; Pal, Ranadip; Becher, Oren J.

    2015-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice. PMID:25748921

  11. Visualization of implanted GL261 glioma cells in living mouse brain slices using fluorescent 4-(4-(dimethylamino)-styryl)-N-methylpyridinium iodide (ASP+)

    PubMed Central

    Kucheryavykh, Lilia Y.; Kucheryavykh, Yuriy V.; Rolón-Reyes, Kimberleve; Skatchkov, Serguei N.; Eaton, Misty J.; Cubano, Luis A.; Inyushin, Mikhail

    2013-01-01

    Here we describe a new method of glioma cell visualization in living brain slices that can be used for evaluation of tumor size or visualization of internal tumor structures. Glial cells, as well as glioma cells of glial origin, express high levels of organic cation transporters. We demonstrate that application of a fluorescent substrate for these transporters 4-(4-(dimethylamino)-styryl)-N-methylpyridinium iodide (ASP+) to the incubation medium leads to quick accumulation of fluorescence in glioma cells during early developmental stages and in astrocytes, but not in neurons. Stained brain slices can be immediately investigated using confocal or fluorescence microscopy. Glioma and glial cells can be discriminated from each other due to their different morphology. The method described has an advantage of staining living tissue and is simple to perform. PMID:23570046

  12. Inositol 1,4,5-trisphosphate and diacylglycerol mimic bradykinin effects on mouse neuroblastoma x rat glioma hybrid cells.

    PubMed Central

    Brown, D A; Higashida, H

    1988-01-01

    1. The role of inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol (DAG) as possible mediators of the membrane current responses of NG108-15 neuroblastoma x glioma hybrid cells to bradykinin (BK, Brown & Higashida, 1988b) has been tested using intracellular ionophoresis of InsP3 and external application of phorbol dibutyrate (PDBu) and 1-oleoyl-2-acetylglycerol (OAG). 2. Intracellular ionophoresis of InsP3 into cells clamped at -30 to -50 mV produced (i) a transient outward current, (ii) a transient outward current followed by an inward current, or (iii) an inward current. All currents were accompanied by an increased input conductance. 3. The transient outward current reversed at between -80 and -90 mV. The reversal potential was shifted to more positive potentials on raising extracellular [K+], suggesting that it resulted from an increased K+ conductance. 4. The outward current was inhibited by apamin (0.4 microM) or d-tubocurarine (0.2-0.5 mM); these drugs also inhibit the outward current produced by BK or by intracellular Ca2+ injections (Brown & Higashida, 1988 a, b). The outward current was also slowly reduced in 0 mM [Ca2+] or 0.5 mM [Cd2+] plus 2 mM [Co2+] solution. 5. Ionophoretic injection of inositol 1,3,4-trisphosphate and inositol 1,3,4,5-tetrakisphosphate, guanosine trisphosphate or inorganic phosphate did not evoke an outward current but produced only an inward current with an increased conductance, reversing at between -10 and -20 mV. 6. Bath application of PDBu (10 nM-1 microM) or OAG (1-10 microM) produced an inward current with a fall in input conductance. The inward current was voltage dependent and was accompanied by an inhibition of the time-dependent current relaxations associated with activation or deactivation of the voltage-dependent K+ current, IM. 7. PDBu did not clearly reduce the Ca2+ current or the Ca2+-dependent K+ current recorded in these cells. During superfusion with PDBu, the outward current produced by intracellular

  13. Neurofibromatosis-1 Heterozygosity Increases Microglia in a Spatially- and Temporally-Restricted Pattern Relevant to Mouse Optic Glioma Formation and Growth

    PubMed Central

    Simmons, Grant W.; Pong, Winnie W.; Emnett, Ryan J.; White, Crystal R.; Gianino, Scott M.; Rodriguez, Fausto J.; Gutmann, David H.

    2011-01-01

    While carcinogenesis requires the acquisition of driver mutations in progenitor cells, tumor growth and progression is heavily influenced by the local microenvironment. Previous studies from our laboratory have employed Neurofibromatosis-1 (NF1) genetically engineered mice to characterize the role of stromal cells and signals to optic glioma formation and growth. Previously, we have shown that Nf1+/- microglia in the tumor microenvironment are critical cellular determinants of optic glioma proliferation. To define the role of microglia in tumor formation and maintenance further, we employed CD11b-TK mice, in which resident brain microglia (CD11b+, CD68+, Iba1+, CD45low cells) can be ablated at specific times following ganciclovir (GCV) administration. GCV-mediated microglia reduction reduced Nf1 optic glioma proliferation during both tumor maintenance and tumor development. We identified the developmental window during which microglia are increased in the Nf1+/- optic nerve and demonstrated that this accumulation reflected delayed microglia dispersion. The increase in microglia in the Nf1+/- optic nerve was associated with reduced expression of the chemokine receptor, CX3CR1, such that reduced Cx3cr1 expression in Cx3cr1-GFP heterozygous knockout mice led to a similar increase in optic nerve microglia. These results establish a critical role for microglia in the development and maintenance of Nf1 optic glioma. PMID:21157378

  14. MEF promotes stemness in the pathogenesis of gliomas

    PubMed Central

    Bazzoli, Elena; Pulvirenti, Teodoro; Oberstadt, Moritz C.; Perna, Fabiana; Wee, Boyoung; Schultz, Nikolaus; Huse, Jason T.; Fomchenko, Elena I.; Voza, Francesca; Tabar, Viviane; Brennan, Cameron W.; DeAngelis, Lisa M.; Nimer, Stephen D.; Holland, Eric C.; Squatrito, Massimo

    2013-01-01

    Summary High-grade gliomas are aggressive and uniformly fatal tumors, composed of a heterogeneous population of cells that include many with stem cell-like properties. The acquisition of stem-like traits might contribute to glioma initiation, growth and recurrence. Here we investigated the role of the transcription factor myeloid Elf-1 like factor (MEF, also known as ELF4) in glioma. We found that MEF is highly expressed in both human and mouse GBMs and its absence impairs gliomagenesis in a PDGF-driven glioma mouse model. We show that modulation of MEF levels in both mouse neural stem cells and human glioblastoma cells, has a significant impact on neurosphere formation. Moreover, we identify Sox2 as a direct downstream target of MEF. Taken together, our studies implicate MEF as a previously unrecognized gatekeeper gene in gliomagenesis by promoting stem cell characteristics through Sox2 activation. PMID:23217424

  15. Glioma-associated endothelial cells are chemoresistant to temozolomide.

    PubMed

    Virrey, Jenilyn J; Golden, Encouse B; Sivakumar, Walavan; Wang, Weijun; Pen, Ligaya; Schönthal, Axel H; Hofman, Florence M; Chen, Thomas C

    2009-10-01

    Temozolomide is considered the standard of care and drug of choice for the treatment of initially diagnosed malignant gliomas. Although well tolerated, temozolomide still has limited clinical efficacy. Following drug treatment, patient prognosis still remains poor; tumor recurrence is almost universal. We hypothesized that this lack of effectiveness with temozolomide is because this drug does not target the glioma microenvironment, which is highly vascular in malignant gliomas. To test this hypothesis we analyzed the effects of temozolomide on the tumor vasculature in vitro and in vivo. We found that this drug did not affect the viability or proliferation rate of endothelial cells isolated from human glioma specimens, although temozolomide was highly cytotoxic to the glioma cell lines U87MG and U251. Furthermore, temozolomide did not inhibit the migration of these glioma-associated endothelial cells, a key mechanism responsible for tumor angiogenesis. In in vivo studies, using the intracranial glioma mouse model, temozolomide did not cause a pronounced effect on microvessel density. Our findings show that temozolomide has no apparent effect on the glioma vascular microenvironment. Thus combination therapy with anti-vascular agents may enhance temozolomide effectiveness as glioma therapeutic protocol.

  16. Tumor location, but not H3.3K27M, significantly influences the blood-brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma.

    PubMed

    Subashi, Ergys; Cordero, Francisco J; Halvorson, Kyle G; Qi, Yi; Nouls, John C; Becher, Oren J; Johnson, G Allan

    2016-01-01

    Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood-brain-barrier (BBB). In this work, we use dynamic contrast-enhanced (DCE) MRI to evaluate BBB permeability in a genetic mouse model of pHGG as a function of location (cortex vs. brainstem, n = 8 mice/group) and histone mutation (mutant H3.3K27M vs. wild-type H3.3, n = 8 mice/group). The pHGG models are induced either in the brainstem or the cerebral cortex and are driven by PDGF signaling and p53 loss with either H3.3K27M or wild-type H3.3. T2-weighted MRI was used to determine tumor location/extent followed by 4D DCE-MRI for estimating the rate constant (K (trans) ) for tracer exchange across the barrier. BBB permeability was 67 % higher in cortical pHGGs relative to brainstem pHGGs (t test, p = 0.012) but was not significantly affected by the expression of mutant H3.3K27M versus wild-type H3.3 (t-test, p = 0.78). Although mice became symptomatic at approximately the same time, the mean volume of cortical tumors was 3.6 times higher than the mean volume of brainstem tumors. The difference between the mean volume of gliomas with wild-type and mutant H3.3 was insignificant. Mean K (trans) was significantly correlated to glioma volume. These results present a possible explanation for the poor response of brainstem pHGGs to systemic therapy. Our findings illustrate a potential role played by the microenvironment in shaping tumor growth and BBB permeability. PMID:26511492

  17. Genetic epidemiology of glioma.

    PubMed

    Malmer, B; Iselius, L; Holmberg, E; Collins, A; Henriksson, R; Grönberg, H

    2001-02-01

    The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model chi(2)(3) = 6.13, P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases. PMID:11161412

  18. Genetic epidemiology of glioma.

    PubMed

    Malmer, B; Iselius, L; Holmberg, E; Collins, A; Henriksson, R; Grönberg, H

    2001-02-01

    The present study performed a segregation analysis of a cohort of first-degree relatives (FDR) of glioma patients. The families with two or more gliomas were also expanded to determine if any more gliomas could be detected, and if any other types of cancers were associated. These glioma-prone families (n = 24/432) were extended to include first-, second- and third-degree relatives (n = 807) and a cohort was assembled, the standardized incidence risk for other types of cancer calculated and the pedigrees investigated for a possible mode of inheritance. A segregation analysis of the 2141 FDR in 297 families, performed using the Pointer software, did not clearly reject a multifactorial model chi(2)(3) = 6.13, P< 0.2. However, when letting all parameters be free, the recessive model provided the best fit. In the extended families, no increased risk of other types of cancer was found. This population-based study proposes that familial glioma occurs in about 5% of all glioma cases and that 1% have a possible autosomal dominant inheritance. This first segregation analysis performed in familial glioma must be cautiously interpreted, but an autosomal recessive gene provided the best fit, which could possibly explain 2% of all glioma cases.

  19. Histologic classification of gliomas.

    PubMed

    Perry, Arie; Wesseling, Pieter

    2016-01-01

    Gliomas form a heterogeneous group of tumors of the central nervous system (CNS) and are traditionally classified based on histologic type and malignancy grade. Most gliomas, the diffuse gliomas, show extensive infiltration in the CNS parenchyma. Diffuse gliomas can be further typed as astrocytic, oligodendroglial, or rare mixed oligodendroglial-astrocytic of World Health Organization (WHO) grade II (low grade), III (anaplastic), or IV (glioblastoma). Other gliomas generally have a more circumscribed growth pattern, with pilocytic astrocytomas (WHO grade I) and ependymal tumors (WHO grade I, II, or III) as the most frequent representatives. This chapter provides an overview of the histology of all glial neoplasms listed in the WHO 2016 classification, including the less frequent "nondiffuse" gliomas and mixed neuronal-glial tumors. For multiple decades the histologic diagnosis of these tumors formed a useful basis for assessment of prognosis and therapeutic management. However, it is now fully clear that information on the molecular underpinnings often allows for a more robust classification of (glial) neoplasms. Indeed, in the WHO 2016 classification, histologic and molecular findings are integrated in the definition of several gliomas. As such, this chapter and Chapter 6 are highly interrelated and neither should be considered in isolation. PMID:26948349

  20. Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.

    PubMed

    a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja; Haage, Verena; Euskirchen, Philipp; Harms, Christoph; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

    2016-05-01

    Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context. PMID:27030742

  1. Glioma Stem Cells but Not Bulk Glioma Cells Upregulate IL-6 Secretion in Microglia/Brain Macrophages via Toll-like Receptor 4 Signaling.

    PubMed

    a Dzaye, Omar Dildar; Hu, Feng; Derkow, Katja; Haage, Verena; Euskirchen, Philipp; Harms, Christoph; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A; Kettenmann, Helmut

    2016-05-01

    Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-) GL261 cells. In IL-6(-/-) mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context.

  2. 31 CFR 306.27 - Redemption of bearer securities at maturity, upon prior call, or for advance refunding or...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... the securities. If any such coupons are missing, the full face amount thereof will be deducted from... to provide for adjustments or refunds in the event it should be determined that the missing coupons... other instructions, payment or bearer securities will be made by check drawn to the order of the...

  3. 31 CFR 306.27 - Redemption of bearer securities at maturity, upon prior call, or for advance refunding or...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... the securities. If any such coupons are missing, the full face amount thereof will be deducted from... to provide for adjustments or refunds in the event it should be determined that the missing coupons... other instructions, payment or bearer securities will be made by check drawn to the order of the...

  4. Brainstem Glioma in Adults

    PubMed Central

    Hu, Jethro; Western, Stephen; Kesari, Santosh

    2016-01-01

    Brainstem gliomas are not nearly as common in adults as they are in children. They are likely the final common consequence not of a single disease process but of several. They can be difficult to diagnose, and are challenging to treat. Clinical studies of this diagnosis are few and generally small. Because of these factors, our understanding of the biology of adult brainstem glioma is incomplete. However, the knowledge base is growing and progress is being made. In this article, we review the current state of knowledge for brainstem glioma in adults and identify key areas for which additional information is required. PMID:27556016

  5. Pathophysiology of glioma cyst formation.

    PubMed

    Adn, Mahmoudreza; Saikali, Stephan; Guegan, Yvon; Hamlat, Abderrahmane

    2006-01-01

    Fluid filled cystic cavities are accompaniments of some cerebral gliomas. These tumoural cysts together with peritumoural vasogenic brain oedema add to the morbid effects of the gliomas in terms of mass effect and increased intracranial pressure. Although different mechanisms have been suggested as to the pathogenesis of glioma-associated cysts, it is still unclear why these cysts appear in only a limited number of cerebral gliomas while brain oedema, a probable precursor of glioma cysts, is a usual accompaniment of most gliomas. Here, the authors present a two-hit hypothesis of brain glioma cyst formation. We suggest that after the formation of vasogenic tumoural brain oedema, microvascular phenomena may lead to the formation of microcysts, which might later become confluent and grow to form macroscopic cysts. Progress in the understanding of pathogenesis of cerebral glioma cysts might set targets for treatment of brain edema and glioma cysts.

  6. Immunotherapeutic Approaches for Glioma

    PubMed Central

    Okada, Hideho; Kohanbash, Gary; Zhu, Xinmei; Kastenhuber, Edward R.; Hoji, Aki; Ueda, Ryo; Fujita, Mitsugu

    2009-01-01

    The development of effective immunotherapy strategies for glioma requires adequate understanding of the unique immunological microenvironment in the central nervous system (CNS) and CNS tumors. Although the CNS is often considered to be an immunologically privileged site and poses unique challenges for the delivery of effector cells and molecules, recent advances in technology and discoveries in CNS immunology suggest novel mechanisms that may significantly improve the efficacy of immunotherapy against gliomas. In this review, we first summarize recent advances in the CNS and CNS tumor immunology. We address factors that may promote immune escape of gliomas. We also review advances in passive and active immunotherapy strategies for glioma, with an emphasis on lessons learned from recent early-phase clinical trials. We also discuss novel immunotherapy strategies that have been recently tested in non-CNS tumors and show great potential for application to gliomas. Finally, we discuss how each of these promising strategies can be combined to achieve clinical benefit for patients with gliomas. PMID:19348609

  7. Ubiquitin-specific protease 28 is overexpressed in human glioblastomas and contributes to glioma tumorigenicity by regulating MYC expression

    PubMed Central

    Wang, Zengwu; Song, Qimin; Xue, Jian; Zhao, Yumei

    2015-01-01

    The transcription factor MYC, which is dysregulated in the majority of gliomas, is difficult to target directly. Deubiquitinase ubiquitin-specific protease 28 (USP28) stabilizes oncogenic factors, including MYC. However, the contribution of USP28 in tumorigenesis, particularly in glioma, is unknown. Here, we determined the expression of USP28 and assessed its clinical significance in human glioma. We found that USP28 is overexpressed in human glioma but not in normal brain tissue. The level of USP28 protein expression in human glioma tissues was directly correlated with glioma grade. Meanwhile, the level of USP28 protein expression in human glioblastoma tissues was inversely correlated with patient survival. Enforced USP28 expression promotes SW1783 glioma cell proliferation. Moreover, gliomas that arose from USP28-transfected SW1783 cells displayed tumorigenicity in nude mouse model systems. Inhibition of USP28 expression in glioblastoma U373 cells suppressed anchorage-independent growth in vitro and tumorigenicity in vivo. Furthermore, USP28 regulates the expression of MYC protein, which is essential in USP28-induced cell growth in glioma cells. These results showed that USP28 is overexpressed in human glioblastomas and it contributes to glioma tumorigenicity. Therefore, USP28 could be a new target of therapy for human malignant glioma. PMID:26209720

  8. Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway.

    PubMed

    Rolón-Reyes, Kimberleve; Kucheryavykh, Yuriy V; Cubano, Luis A; Inyushin, Mikhail; Skatchkov, Serguei N; Eaton, Misty J; Harrison, Jeffrey K; Kucheryavykh, Lilia Y

    2015-01-01

    Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells. PMID:26098895

  9. Microglia Activate Migration of Glioma Cells through a Pyk2 Intracellular Pathway

    PubMed Central

    Rolón-Reyes, Kimberleve; Kucheryavykh, Yuriy V.; Cubano, Luis A.; Inyushin, Mikhail; Skatchkov, Serguei N.; Eaton, Misty J.; Harrison, Jeffrey K.; Kucheryavykh, Lilia Y.

    2015-01-01

    Glioblastoma is one of the most aggressive and fatal brain cancers due to the highly invasive nature of glioma cells. Microglia infiltrate most glioma tumors and, therefore, make up an important component of the glioma microenvironment. In the tumor environment, microglia release factors that lead to the degradation of the extracellular matrix and stimulate signaling pathways to promote glioma cell invasion. In the present study, we demonstrated that microglia can promote glioma migration through a mechanism independent of extracellular matrix degradation. Using western blot analysis, we found upregulation of proline rich tyrosine kinase 2 (Pyk2) protein phosphorylated at Tyr579/580 in glioma cells treated with microglia conditioned medium. This upregulation occurred in rodent C6 and GL261 as well as in human glioma cell lines with varying levels of invasiveness (U-87MG, A172, and HS683). siRNA knock-down of Pyk2 protein and pharmacological blockade by the Pyk2/focal-adhesion kinase (FAK) inhibitor PF-562,271 reversed the stimulatory effect of microglia on glioma migration in all cell lines. A lower concentration of PF-562,271 that selectively inhibits FAK, but not Pyk2, did not have any effect on glioma cell migration. Moreover, with the use of the CD11b-HSVTK microglia ablation mouse model we demonstrated that elimination of microglia in the implanted tumors (GL261 glioma cells were used for brain implantation) by the local in-tumor administration of Ganciclovir, significantly reduced the phosphorylation of Pyk2 at Tyr579/580 in implanted tumor cells. Taken together, these data indicate that microglial cells activate glioma cell migration/dispersal through the pro-migratory Pyk2 signaling pathway in glioma cells. PMID:26098895

  10. Molecular classification of gliomas.

    PubMed

    Masui, Kenta; Mischel, Paul S; Reifenberger, Guido

    2016-01-01

    The identification of distinct genetic and epigenetic profiles in different types of gliomas has revealed novel diagnostic, prognostic, and predictive molecular biomarkers for refinement of glioma classification and improved prediction of therapy response and outcome. Therefore, the new (2016) World Health Organization (WHO) classification of tumors of the central nervous system breaks with the traditional principle of diagnosis based on histologic criteria only and incorporates molecular markers. This will involve a multilayered approach combining histologic features and molecular information in an "integrated diagnosis". We review the current state of diagnostic molecular markers for gliomas, focusing on isocitrate dehydrogenase 1 or 2 (IDH1/IDH2) gene mutation, α-thalassemia/mental retardation syndrome X-linked (ATRX) gene mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutation in adult tumors, as well as v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and H3 histone family 3A (H3F3A) aberrations in pediatric gliomas. We also outline prognostic and predictive molecular markers, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and discuss the potential clinical relevance of biologic glioblastoma subtypes defined by integration of multiomics data. Commonly used methods for individual marker detection as well as novel large-scale DNA methylation profiling and next-generation sequencing approaches are discussed. Finally, we illustrate how advances in molecular diagnostics affect novel strategies of targeted therapy, thereby raising new challenges and identifying new leads for personalized treatment of glioma patients. PMID:26948350

  11. Bearer channel control protocol for the dynamic VB5.2 interface in ATM access networks

    NASA Astrophysics Data System (ADS)

    Fragoulopoulos, Stratos K.; Mavrommatis, K. I.; Venieris, Iakovos S.

    1996-12-01

    In the multi-vendor systems, a customer connected to an Access network (AN) must be capable of selecting a specific Service Node (SN) according to the services the SN provides. The multiplicity of technologically varying AN calls for the definition of a standard reference point between the AN and the SN widely known as the VB interface. Two versions are currently offered. The VB5.1 is simpler to implement but is not as flexible as the VB5.2, which supports switched connections. The VB5.2 functionality is closely coupled to the Broadband Bearer Channel Connection Protocol (B-BCCP). The B-BCCP is used for conveying the necessary information for dynamic resource allocation, traffic policing and routing in the AN as well as for information exchange concerning the status of the AN before a new call is established by the SN. By relying on such a protocol for the exchange of information instead of intercepting and interpreting signalling messages in the AN, the architecture of the AN is simplified because the functionality related to processing is not duplicated. In this paper a prominent B- BCCP candidate is defined, called the Service node Access network Interaction Protocol.

  12. A Mismatch between the Perceived Fighting Signal and Fighting Ability Reveals Survival and Physiological Costs for Bearers

    PubMed Central

    González-Santoyo, Isaac; González-Tokman, Daniel M.; Munguía-Steyer, Roberto E.; Córdoba-Aguilar, Alex

    2014-01-01

    Signals of fighting indicate an animal's intention to attack and so they serve to prevent costly aggressive encounters. However, according to theory, a signal that is different in design (i.e. a novel signal) but that fails to inform fighting intentions will result in negative fitness consequences for the bearer. In the present study we used males of the territorial damselfly Hetaerina americana, which have a red wing spot during territory defense that has evolved as a signal of fighting ability. By producing a novel signal (covering the red spot with blue ink) in territory owners, we investigated: a) the behavioral responses by conspecific males; b) survival cost and c) three physiological mediators of impaired survival: muscular fat reserves, muscle mass and immune ability. We predicted that males with the novel signal would be attacked more often by conspecifics as the former would fail to convey fighting ability and intentions adequately. This will result in lower survival and physiological condition for the novel signal bearers. We found that, compared to control males (males whose red spot was not changed), experimental males had reduced survival, were less able to hold a territory, and had a reduced muscle mass. It seems that spot modified males were not able to effectively communicate their territory tenancy, which may explain why they lost their defended sites. Our results provide support for theoretical models that a novel signal that fails to informing fighting ability may lead to a fitness cost for bearers. PMID:24409304

  13. Chlorotoxin-conjugated onconase as a potential anti-glioma drug

    PubMed Central

    WANG, XIAOMIN; GUO, ZHANYUN

    2015-01-01

    Gliomas are rarely curable malignant brain tumors arising from normal glial cells. The scorpion-derived small peptide, chlorotoxin (CTX), can selectively bind malignant gliomas. In the present study, a CTX-conjugated onconase (Onc), a small cytotoxic ribonuclease, was prepared as a potential anti-glioma drug. In this conjugate, recombinant CTX was covalently linked with recombinant Onc by reversible disulfide linkage. The chemically conjugated CTX-Onc showed much higher cytotoxicity to the cultured glioma U251 and SHG-44 cells than the physical mixture of CTX and Onc (CTX + Onc). In the nude mouse models bearing subcutaneous U251 or SHG-44 tumors, the CTX-Onc conjugate also showed improved anti-tumor effects than the CTX + Onc control. These results suggested that the reversible chemical-conjugated CTX promoted the tumor targeting of Onc, and thus the present CTX-Onc conjugate could be further developed as a potential targeted anti-glioma drug. PMID:25663909

  14. A role for intracellular zinc in glioma alteration of neuronal chloride equilibrium

    PubMed Central

    Di Angelantonio, S; Murana, E; Cocco, S; Scala, F; Bertollini, C; Molinari, M G; Lauro, C; Bregestovski, P; Limatola, C; Ragozzino, D

    2014-01-01

    Glioma patients commonly suffer from epileptic seizures. However, the mechanisms of glioma-associated epilepsy are far to be completely understood. Using glioma-neurons co-cultures, we found that tumor cells are able to deeply influence neuronal chloride homeostasis, by depolarizing the reversal potential of γ-aminobutyric acid (GABA)-evoked currents (EGABA). EGABA depolarizing shift is due to zinc-dependent reduction of neuronal KCC2 activity and requires glutamate release from glioma cells. Consistently, intracellular zinc loading rapidly depolarizes EGABA in mouse hippocampal neurons, through the Src/Trk pathway and this effect is promptly reverted upon zinc chelation. This study provides a possible molecular mechanism linking glioma invasion to excitation/inhibition imbalance and epileptic seizures, through the zinc–mediated disruption of neuronal chloride homeostasis. PMID:25356870

  15. KITENIN promotes glioma invasiveness and progression, associated with the induction of EMT and stemness markers

    PubMed Central

    Oh, Se-Jeong; Kim, Ok; Joo, Young-Eun; Bae, Jeong-A; Yoon, Somy; Ryu, Hyang-Hwa; Jung, Shin; Kim, Kyung-Keun; Lee, Jae-Hyuk; Moon, Kyung-Sub

    2015-01-01

    KITENIN (KAI1 COOH-terminal interacting tetraspanin) promotes tumor invasion and metastasis in various cancers. This study assessed the association between KITENIN expression and advanced glioma grade in patients. In vitro assays revealed that KITENIN knockdown inhibited the invasion and migration of glioma cells, whereas KITENIN overexpression promoted their invasion and migration. In orthotopic mouse tumor models, mice transplanted with KITENIN-transfected glioma cells had significantly shorter survival than mice transplanted with mock-transfected cells. Patients with low KITENIN expression showed a significantly longer progression-free survival than patients with high KITENIN expression. KITENIN induced the expression of the epithelial-mesenchymal transition (EMT) markers (N-cadherin, ZEB1, ZEB2, SNAIL and SLUG) as well as the glioma stemness markers (CD133, ALDH1 and EPH-B1). Taken together, these findings showed that high levels of KITENIN increased glioma invasiveness and progression, associated with the up-regulation of EMT and stemness markers. PMID:25605251

  16. MicroRNA-544 inhibits glioma proliferation, invasion and migration but induces cell apoptosis by targeting PARK7

    PubMed Central

    Jin, Shiguang; Dai, Yan; Li, Cheng; Fang, Xiao; Han, Huijing; Wang, Daxin

    2016-01-01

    Glioma is a common type of primary brain tumor. The survival rate in people with malignant gliomas is extremely low associated with the lack of effective treatment. Here, we firstly observed that miR-544 expression is downregulated in glioma tissues and its overexpression in glioma cell line dramatically reduces cell proliferation, migration and invasion. In addition, we found that the tumor growth in nude mouse was as well inhibited by miR-544 overexpressed in glioma cell. Our further investigation showed that the inhibitor role of miR-544 in tumor development was related to the downregulated expression of Park7 gene which has been demonstrated as a functional downstream target of miR-544. Thus, our discovery suggested that miR-544 might used as a therapeutic reagent for the treatment of glioma in the future. PMID:27186306

  17. MicroRNA-544 inhibits glioma proliferation, invasion and migration but induces cell apoptosis by targeting PARK7.

    PubMed

    Jin, Shiguang; Dai, Yan; Li, Cheng; Fang, Xiao; Han, Huijing; Wang, Daxin

    2016-01-01

    Glioma is a common type of primary brain tumor. The survival rate in people with malignant gliomas is extremely low associated with the lack of effective treatment. Here, we firstly observed that miR-544 expression is downregulated in glioma tissues and its overexpression in glioma cell line dramatically reduces cell proliferation, migration and invasion. In addition, we found that the tumor growth in nude mouse was as well inhibited by miR-544 overexpressed in glioma cell. Our further investigation showed that the inhibitor role of miR-544 in tumor development was related to the downregulated expression of Park7 gene which has been demonstrated as a functional downstream target of miR-544. Thus, our discovery suggested that miR-544 might used as a therapeutic reagent for the treatment of glioma in the future.

  18. A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas

    ClinicalTrials.gov

    2016-07-08

    Pilomyxoid Astrocytoma; Pilocytic Astrocytoma; Glioma, Astrocytic; Optic Nerve Glioma; Pleomorphic Xanthoastrocytoma; Glioblastoma Multiforme; Anaplastic Astrocytoma; Gliosarcoma; Diffuse Intrinsic Pontine Glioma; DIPG; Low-grade Glioma; Brainstem Glioma

  19. Combination Therapy for Gliomas Using Temozolomide and Interferon-Beta Secreting Human Bone Marrow Derived Mesenchymal Stem Cells

    PubMed Central

    Park, Jae-Hyun; Ryu, Chung Heon; Kim, Mi Jin

    2015-01-01

    Objective Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-β) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-β on gliomas. Methods We engineered human MSCs to secret mouse IFN-β (MSC-IFN-β) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-β treatment. Results In vitro, the combination of MSC-IFN-β and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-β and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. Conclusion These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-β and TMZ could be considered as a new option for the treatment of malignant gliomas. PMID:26113958

  20. Suprasellar chordoid glioma.

    PubMed

    Ricoy, J R; Lobato, R D; Báez, B; Cabello, A; Martínez, M A; Rodríguez, G

    2000-06-01

    Brat et al. (J Neuropathol Exp Neurol 57:288-290, 1998) reported eight cases of a new clinico-pathological entity, which occurs mainly in the third ventricle of middle-aged females, which they described as chordoid glioma of the third ventricle. We report a new case of a 41-year-old woman with a suprasellar chordoid glioma with histological, immunohistochemical and ultrastructural studies. We discuss the differential diagnosis between chordoma, chordoid meningioma, germinoma and pituitary adenoma. Histologically, the tumour showed cords and lobules of isomorphic epithelioid cells in a vacuolated matrix with prominent multifocal lymphoplasmacytic infiltrates in which some histiocytes and isolated Touton-type giant cells were seen; cells were immunoreactive for glial fibrillary acidic protein but negative for epithelial membrane antigen. Ultrastructural examination revealed abundant intermediate filament but no desmosomes, microvilli nor cilia were seen.

  1. Circulating glioma biomarkers

    PubMed Central

    Kros, Johan M.; Mustafa, Dana M.; Dekker, Lennard J.M.; Sillevis Smitt, Peter A.E.; Luider, Theo M.; Zheng, Ping-Pin

    2015-01-01

    Validated biomarkers for patients suffering from gliomas are urgently needed for standardizing measurements of the effects of treatment in daily clinical practice and trials. Circulating body fluids offer easily accessible sources for such markers. This review highlights various categories of tumor-associated circulating biomarkers identified in blood and cerebrospinal fluid of glioma patients, including circulating tumor cells, exosomes, nucleic acids, proteins, and oncometabolites. The validation and potential clinical utility of these biomarkers is briefly discussed. Although many candidate circulating protein biomarkers were reported, none of these have reached the required validation to be introduced for clinical practice. Recent developments in tracing circulating tumor cells and their derivatives as exosomes and circulating nuclear acids may become more successful in providing useful biomarkers. It is to be expected that current technical developments will contribute to the finding and validation of circulating biomarkers. PMID:25253418

  2. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

    PubMed

    Solga, Anne C; Pong, Winnie W; Kim, Keun-Young; Cimino, Patrick J; Toonen, Joseph A; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L; Ly, Amy; Ellisman, Mark H; Mardis, Elaine R; Gutmann, David H

    2015-10-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  3. Imaging hypoxia in gliomas

    PubMed Central

    Mendichovszky, I; Jackson, A

    2011-01-01

    Hypoxia plays a central role in tumour development, angiogenesis, growth and resistance to treatment. Owing to constant developments in medical imaging technology, significant advances have been made towards in vitro and in vivo imaging of hypoxia in a variety of tumours, including gliomas of the central nervous system. The aim of this article is to review the literature on imaging approaches currently available for measuring hypoxia in human gliomas and provide an insight into recent advances and future directions in this field. After a brief overview of hypoxia and its importance in gliomas, several methods of measuring hypoxia will be presented. These range from invasive monitoring by Eppendorf polarographic O2 microelectrodes, positron electron tomography (PET) tracers based on 2-nitroimidazole compounds [18F-labelled fluoro-misonidazole (18F-MISO) or 1-(2-[(18)F]fluoro-1-[hydroxymethyl]ethoxy)methyl-2-nitroimidazole (FRP-170)], 64Cu-ATSM Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) or 99mTc- and 68Ga-labelled metronidazole (MN) agents to advanced MRI methods, such as blood oxygenation level dependent (BOLD) MRI, oxygen-enhanced MRI, diffusion-weighted MRI (DWI-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and 1H-magnetic resonance spectroscopy. PMID:22433825

  4. Jumonji AT-rich interactive domain 1B overexpression is associated with the development and progression of glioma

    PubMed Central

    FANG, LIPING; ZHAO, JIUHAN; WANG, DAN; ZHU, LIYU; WANG, JIAN; JIANG, KUI

    2016-01-01

    Previous studies have suggested that jumonji AT-rich interactive domain 1B (JARID1B) plays an important role in the genesis of some types of cancer, and it is therefore considered to be an important drug target protein. Although the expression of JARID1B has been researched in some types of cancer, little is known about JARID1B expression in glioma and its function in the tumorigenesis of gliomas. In the present study, we examined the expression of JARID1B in glioma. In addition, RT-PCR, western blot analysis and immunohistochemical analysis were performed using glioma tissue samples and the results revealed that JARID1B expression increased according to the histological grade of glioma. However, in the normal brain tissue samples JARID1B expression was barely detected. Kaplan-Meier analysis revealed that higher JARID1B expression in patients with glioma was associated with a poorer prognosis. The overexpression of JARID1B stimulated the proliferation and migration of glioma cells as well as sphere formation, whereas suppressing the expression of JARID1B produced opposite effects. The overexpression of JARID1B increased the tumorigenicity of glioma cells in vivo in a nude mouse xenograft model of glioma. Moreover, the activation of phosphorylated (p-)Smad2 contributes to JARID1B-induced oncogenic activities. These findings suggest that JARID1B is involved in the pathogenesis of glioma, and that the downregulation of JARID1B in glioma cells may be a therapeutic target for the treatment of patients with glioma. PMID:27246838

  5. Two Unique Glioma Subtypes Revealed.

    PubMed

    Poh, Alissa

    2016-04-01

    A comprehensive analysis of 1,122 diffuse glioma samples from The Cancer Genome Atlas has revealed two new subtypes of this common brain cancer, with molecular and clinical features that diverge from the norm. The study findings also support the use of DNA methylation profiles to improve glioma classification and treatment.

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

    PubMed Central

    2011-01-01

    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 agents that efficiently

  7. Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma.

    PubMed

    Breunig, Joshua J; Levy, Rachelle; Antonuk, C Danielle; Molina, Jessica; Dutra-Clarke, Marina; Park, Hannah; Akhtar, Aslam Abbasi; Kim, Gi Bum; Hu, Xin; Bannykh, Serguei I; Verhaak, Roel G W; Danielpour, Moise

    2015-07-14

    As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.

  8. Sleeping Beauty mouse models identify candidate genes involved in gliomagenesis.

    PubMed

    Vyazunova, Irina; Maklakova, Vilena I; Berman, Samuel; De, Ishani; Steffen, Megan D; Hong, Won; Lincoln, Hayley; Morrissy, A Sorana; Taylor, Michael D; Akagi, Keiko; Brennan, Cameron W; Rodriguez, Fausto J; Collier, Lara S

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma.

  9. Intracellular glycine receptor function facilitates glioma formation in vivo.

    PubMed

    Förstera, Benjamin; a Dzaye, Omar Dildar; Winkelmann, Aline; Semtner, Marcus; Benedetti, Bruno; Markovic, Darko S; Synowitz, Michael; Wend, Peter; Fähling, Michael; Junier, Marie-Pierre; Glass, Rainer; Kettenmann, Helmut; Meier, Jochen C

    2014-09-01

    The neuronal function of Cys-loop neurotransmitter receptors is established; however, their role in non-neuronal cells is poorly defined. As brain tumors are enriched in the neurotransmitter glycine, we studied the expression and function of glycine receptors (GlyRs) in glioma cells. Human brain tumor biopsies selectively expressed the GlyR α1 and α3 subunits, which have nuclear localization signals (NLSs). The mouse glioma cell line GL261 expressed GlyR α1, and knockdown of GlyR α1 protein expression impaired the self-renewal capacity and tumorigenicity of GL261 glioma cells, as shown by a neurosphere assay and GL261 cell inoculation in vivo, respectively. We furthermore showed that the pronounced tumorigenic effect of GlyR α1 relies on a new intracellular signaling function that depends on the NLS region in the large cytosolic loop and impacts on GL261 glioma cell gene regulation. Stable expression of GlyR α1 and α3 loops rescued the self-renewal capacity of GlyR α1 knockdown cells, which demonstrates their functional equivalence. The new intracellular signaling function identified here goes beyond the well-established role of GlyRs as neuronal ligand-gated ion channels and defines NLS-containing GlyRs as new potential targets for brain tumor therapies.

  10. Chlorotoxin labeled magnetic nanovectors for targeted gene delivery to glioma.

    PubMed

    Kievit, Forrest M; Veiseh, Omid; Fang, Chen; Bhattarai, Narayan; Lee, Donghoon; Ellenbogen, Richard G; Zhang, Miqin

    2010-08-24

    Glioma accounts for 80% of brain tumors and currently remains one of the most lethal forms of cancers. Gene therapy could potentially improve the dismal prognosis of patients with glioma, but this treatment modality has not yet reached the bedside from the laboratory due to the lack of safe and effective gene delivery vehicles. In this study we investigate targeted gene delivery to C6 glioma cells in a xenograft mouse model using chlorotoxin (CTX) labeled nanoparticles. The developed nanovector consists of an iron oxide nanoparticle core, coated with a copolymer of chitosan, polyethylene glycol (PEG), and polyethylenimine (PEI). Green fluorescent protein (GFP) encoding DNA was bound to these nanoparticles, and CTX was then attached using a short PEG linker. Nanoparticles without CTX were also prepared as a control. Mice bearing C6 xenograft tumors were injected intravenously with the DNA-bound nanoparticles. Nanoparticle accumulation in the tumor site was monitored using magnetic resonance imaging and analyzed by histology, and GFP gene expression was monitored through Xenogen IVIS fluorescence imaging and confocal fluorescence microscopy. Interestingly, the CTX did not affect the accumulation of nanoparticles at the tumor site but specifically enhanced their uptake into cancer cells as evidenced by higher gene expression. These results indicate that this targeted gene delivery system may potentially improve treatment outcome of gene therapy for glioma and other deadly cancers.

  11. Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas

    PubMed Central

    Wakimoto, Hiroaki; Tanaka, Shota; Curry, William T.; Loebel, Franziska; Zhao, Dan; Tateishi, Kensuke; Chen, Juxiang; Klofas, Lindsay K.; Lelic, Nina; Kim, James C.; Dias-Santagata, Dora; Ellisen, Leif W.; Borger, Darrell R.; Fendt, Sarah-Maria; Heiden, Matthew G. Vander; Batchelor, Tracy T.; Iafrate, A. John; Cahill, Daniel P.; Chi, Andrew S.

    2014-01-01

    PURPOSE Isocitrate dehydrogenase (IDH) gene mutations occur in low-grade and high-grade gliomas. We sought to identify the genetic basis of malignant phenotype heterogeneity in IDH-mutant gliomas. METHODS We prospectively implanted tumor specimens from 20 consecutive IDH1-mutant glioma resections into mouse brains and genotyped all resection specimens using a CLIA-certified molecular panel. Gliomas with cancer driver mutations were tested for sensitivity to targeted inhibitors in vitro. Associations between genomic alterations and outcomes were analyzed in patients. RESULTS By 10 months, 8 of 20 IDH1-mutant gliomas developed intracerebral xenografts. All xenografts maintained mutant IDH1 and high levels of 2-hydroxyglutarate on serial transplantation. All xenograft-producing gliomas harbored “lineage-defining” mutations in CIC (oligodendroglioma) or TP53 (astrocytoma), and 6 of 8 additionally had activating mutations in PIK3CA or amplification of PDGFRA, MET or N-MYC. Only IDH1 and CIC/TP53 mutations were detected in non-xenograft-forming gliomas (P=.0007). Targeted inhibition of the additional alterations decreased proliferation in vitro. Moreover, we detected alterations in known cancer driver genes in 13.4% of IDH-mutant glioma patients, including PIK3CA, KRAS, AKT or PTEN mutation or PDGFRA, MET or N-MYC amplification. IDH/CIC mutant tumors were associated with PIK3CA/KRAS mutations while IDH/TP53 tumors correlated with PDGFRA/MET amplification. Presence of driver alterations at progression was associated with shorter subsequent progression-free survival (median 9.0 vs. 36.1 months, P=.0011). CONCLUSION A subset of IDH-mutant gliomas with mutations in driver oncogenes has a more malignant phenotype in patients. Identification of these alterations may provide an opportunity for use of targeted therapies in these patients. PMID:24714777

  12. KCa3.1 channel inhibition sensitizes malignant gliomas to temozolomide treatment

    PubMed Central

    D'Alessandro, Giuseppina; Grimaldi, Alfonso; Chece, Giuseppina; Porzia, Alessandra; Esposito, Vincenzo; Santoro, Antonio; Salvati, Maurizio; Mainiero, Fabrizio; Ragozzino, Davide; Angelantonio, Silvia Di; Wulff, Heike; Catalano, Myriam; Limatola, Cristina

    2016-01-01

    Malignant gliomas are among the most frequent and aggressive cerebral tumors, characterized by high proliferative and invasive indexes. Standard therapy for patients, after surgery and radiotherapy, consists of temozolomide (TMZ), a methylating agent that blocks tumor cell proliferation. Currently, there are no therapies aimed at reducing tumor cell invasion. Ion channels are candidate molecular targets involved in glioma cell migration and infiltration into the brain parenchyma. In this paper we demonstrate that: i) blockade of the calcium-activated potassium channel KCa3.1 with TRAM-34 has co-adjuvant effects with TMZ, reducing GL261 glioma cell migration, invasion and colony forming activity, increasing apoptosis, and forcing cells to pass the G2/M cell cycle phase, likely through cdc2 de-phosphorylation; ii) KCa3.1 silencing potentiates the inhibitory effect of TMZ on glioma cell viability; iii) the combination of TMZ/TRAM-34 attenuates the toxic effects of glioma conditioned medium on neuronal cultures, through a microglia dependent mechanism since the effect is abolished by clodronate-induced microglia killing; iv) TMZ/TRAM-34 co-treatment increases the number of apoptotic tumor cells, and the mean survival time in a syngeneic mouse glioma model (C57BL6 mice implanted with GL261 cells); v) TMZ/TRAM-34 co-treatment reduces cell viability of GBM cells and cancer stem cells (CSC) freshly isolated from patients. Taken together, these data suggest a new therapeutic approach for malignant glioma, targeting both glioma cell proliferating and migration, and demonstrate that TMZ/TRAM-34 co-treatment affects both glioma cells and infiltrating microglia, resulting in an overall reduction of tumor cell progression. PMID:27096953

  13. Development of a Sox2 reporter system modeling cellular heterogeneity in glioma

    PubMed Central

    Stoltz, Kevin; Sinyuk, Maksim; Hale, James S.; Wu, Qiulian; Otvos, Balint; Walker, Kiera; Vasanji, Amit; Rich, Jeremy N.; Hjelmeland, Anita B.; Lathia, Justin D.

    2015-01-01

    Background Malignant gliomas are complex systems containing a number of factors that drive tumor initiation and progression, including genetic aberrations that lead to extensive cellular heterogeneity within the neoplastic compartment. Mouse models recapitulate these genetic aberrations, but readily observable heterogeneity remains challenging. Methods To interrogate cellular heterogeneity in mouse glioma models, we utilized a replication-competent avian sarcoma-leukosis virus long terminal repeat with splice acceptor/tumor virus A (RCAS-tva) system to generate spontaneous mouse gliomas that contained a Sox2-enhanced green fluorescent protein (EGFP) reporter. Glial fibrillary acidic protein-tva mice were crossed with Sox2–EGFP mice, and tumors were initiated that contained a subpopulation of Sox2–EGFP-high cells enriched for tumor-initiating cell properties such as self-renewal, multilineage differentiation potential, and perivascular localization. Results Following implantation into recipient mice, Sox2–EGFP-high cells generated tumors containing Sox2–EGFP-high and Sox2–EGFP-low cells. Kinomic analysis of Sox2–EGFP-high cells revealed activation of known glioma signaling pathways that are strongly correlated with patient survival including platelet-derived growth factor receptor beta, phosphoinositide-3 kinase, and vascular endothelial growth factor. Our functional analysis identified active feline sarcoma (Fes) signaling in Sox2–EGFP-high cells. Fes negatively correlated with glioma patient survival and was coexpressed with Sox2-positive cells in glioma xenografts and primary patient-derived tissue. Conclusions Our RCAS-tva/Sox2-EGFP model will empower closer examination of cellular heterogeneity and will be useful for identifying novel glioma pathways as well as testing preclinical treatment efficacy. PMID:25416826

  14. Complications of glioma surgery.

    PubMed

    Jackson, Christina; Westphal, Manfred; Quiñones-Hinojosa, Alfredo

    2016-01-01

    Even with current advances in adjunctive therapies, including radiation, chemotherapy, and various clinical trials of gene therapy and immunotherapy, surgical resection remains one of the most effective treatment for intra-axial gliomas. Survival in these patients has been shown to be related to the extent of resection. In some cases, it can provide cures of long-term remission; in others, it can provide disease control when combined with the above adjunctive treatments. However, surgical resection carries its own risks and complications. These complications can be broadly divided into neurologic, regional, and systemic, including direct cortical and vascular injury, surgical wound complications, and postsurgical medical complications. Certain patient characteristics, including Karnofsky performance status score (KPS) and pathology of the tumor, have been shown to have an impact on the risk of postsurgical complications. Advancement in preoperative and intraoperative adjunct technology such as cortical mapping and navigation has improved the surgeon's ability to safely and maximally resect the tumors. It is therefore important to understand the perioperative complications after craniotomy and tumor resection and factors affecting morbidity and mortality in order for surgeons to optimally select and counsel patients who will benefit the most from surgical resection. This chapter will focus on the complications associated with craniotomy for intrinsic glioma and ways of avoiding these events.

  15. Chromosome abnormalities in glioma

    SciTech Connect

    Li, Y.S.; Ramsay, D.A.; Fan, Y.S.

    1994-09-01

    Cytogenetic studies were performed in 25 patients with gliomas. An interesting finding was a seemingly identical abnormality, an extra band on the tip of the short arm of chromosome 1, add(1)(p36), in two cases. The abnormality was present in all cells from a patient with a glioblastoma and in 27% of the tumor cells from a patient with a recurrent irradiated anaplastic astrocytoma; in the latter case, 7 unrelated abnormal clones were identified except 4 of those clones shared a common change, -Y. Three similar cases have been described previously. In a patient with pleomorphic astrocytoma, the band 1q42 in both homologues of chromosome 1 was involved in two different rearrangements. A review of the literature revealed that deletion of the long arm of chromosome 1 including 1q42 often occurs in glioma. This may indicate a possible tumor suppressor gene in this region. Cytogenetic follow-up studies were carried out in two patients and emergence of unrelated clones were noted in both. A total of 124 clonal breakpoints were identified in the 25 patients. The breakpoints which occurred three times or more were: 1p36, 1p22, 1q21, 1q25, 3q21, 7q32, 8q22, 9q22, 16q22, and 22q13.

  16. Surgical approaches for the gliomas.

    PubMed

    Watts, Colin; Sanai, Nader

    2016-01-01

    Neurosurgical intervention remains the first step in effective glioma management. Mounting evidence suggests that cytoreduction for low- and high-grade gliomas is associated with a survival benefit. Beyond conventional neurosurgical principles, an array of techniques have been refined in recent years to maximize the effect of the neurosurgical oncologist and facilitate the impact of subsequent adjuvant therapy. With intraoperative mapping techniques, aggressive microsurgical resection can be safely pursued even when tumors occupy essential functional pathways. Other adjunct techniques, such as intraoperative magnetic resonance imaging, intraoperative ultrasonography, and fluorescence-guided surgery, can be valuable tools to safely reduce the tumor burden of low- and high-grade gliomas. Taken together, this collection of surgical strategies has pushed glioma extent of resection towards the level of cellular resolution.

  17. Surgery for gliomas.

    PubMed

    Tate, Matthew C

    2015-01-01

    Surgical resection, with the goal of maximal tumor removal, is now standard of care for the overwhelming majority of newly diagnosed gliomas. In order to achieve this goal while minimizing the risk of postoperative neurologic deficits, intraoperative brain mapping remains the gold standard. Recent advances in technical aspects of preoperative and intraoperative brain mapping, as well as our understanding of the functional anatomy of the human brain with respect to language, movement, sensation, and cognition, particularly at the subcortical level, have improved our ability to safely perform aggressive resective surgeries in eloquent areas. In this chapter, the functional anatomy of the human brain relevant to intrinsic tumor resection is reviewed. In addition, general principles governing surgical management of patients are highlighted, with a particular emphasis on awake brain mapping.

  18. General Information about Childhood Brain Stem Glioma

    MedlinePlus

    ... Brain Stem Glioma Treatment (PDQ®)–Patient Version General Information About Childhood Brain Stem Glioma Go to Health ... the PDQ Pediatric Treatment Editorial Board . Clinical Trial Information A clinical trial is a study to answer ...

  19. ABCG1 maintains high-grade glioma survival in vitro and in vivo

    PubMed Central

    Chen, Yi-Hsien; Cimino, Patrick J.; Luo, Jingqin; Dahiya, Sonika; Gutmann, David H.

    2016-01-01

    The overall survival for adults with malignant glioma (glioblastoma) remains poor despite advances in radiation and chemotherapy. One of the mechanisms by which cancer cells develop relative resistance to treatment is through de-regulation of endoplasmic reticulum (ER) homeostasis. We have recently shown that ABCG1, an ATP-binding cassette transporter, maintains ER homeostasis and suppresses ER stress-induced apoptosis in low-grade glioma. Herein, we demonstrate that ABCG1 expression is increased in human adult glioblastoma, where it correlates with poor survival in individuals with the mesenchymal subtype. Leveraging a mouse model of mesenchymal glioblastoma (NPcis), shRNA-mediated Abcg1 knockdown (KD) increased CHOP ER stress protein expression and resulted in greater NPcis glioma cell death in vitro. Moreover, Abcg1 KD reduced NPcis glioma growth and increased mouse survival in vivo. Collectively, these results demonstrate that ABCG1 is critical for malignant glioma cell survival, and might serve as a future therapeutic target for these deadly brain cancers. PMID:26981778

  20. Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells

    PubMed Central

    Baker, Gregory J.; Castro, Maria G.; Lowenstein, Pedro R.

    2016-01-01

    Our laboratory has recently demonstrated that natural killer (NK) cells are capable of eradicating orthotopically implanted mouse GL26 and rat CNS-1 malignant gliomas soon after intracranial engraftment if the cancer cells are rendered deficient in their expression of the β-galactoside-binding lectin galectin-1 (gal-1). More recent work now shows that a population of Gr-1+/CD11b+ myeloid cells is critical to this effect. To better understand the mechanisms by which NK and myeloid cells cooperate to confer gal-1-deficient tumor rejection we have developed a comprehensive protocol for the isolation and analysis of glioma-infiltrating peripheral blood mononuclear cells (PBMC). The method is demonstrated here by comparing PBMC infiltration into the tumor microenvironment of gal-1-expressing GL26 gliomas with those rendered gal-1-deficient via shRNA knockdown. The protocol begins with a description of how to culture and prepare GL26 cells for inoculation into the syngeneic C57BL/6J mouse brain. It then explains the steps involved in the isolation and flow cytometric analysis of glioma-infiltrating PBMCs from the early brain tumor microenvironment. The method is adaptable to a number of in vivo experimental designs in which temporal data on immune infiltration into the brain is required. The method is sensitive and highly reproducible, as glioma-infiltrating PBMCs can be isolated from intracranial tumors as soon as 24 hr post-tumor engraftment with similar cell counts observed from time point matched tumors throughout independent experiments. A single experimentalist can perform the method from brain harvesting to flow cytometric analysis of glioma-infiltrating PBMCs in roughly 4–6 hr depending on the number of samples to be analyzed. Alternative glioma models and/or cell-specific detection antibodies may also be used at the experimentalists’ discretion to assess the infiltration of several other immune cell types of interest without the need for alterations to the

  1. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1

    PubMed Central

    Solga, Anne C.; Pong, Winnie W.; Kim, Keun-Young; Cimino, Patrick J.; Toonen, Joseph A.; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L.; Ly, Amy; Ellisman, Mark H.; Mardis, Elaine R.; Gutmann, David H.

    2015-01-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  2. Rehabilitation of patients with glioma.

    PubMed

    Vargo, Mary; Henriksson, Roger; Salander, Pär

    2016-01-01

    Disabling sequelae occur in a majority of patients diagnosed with brain tumor, including glioma, such as cognitive deficits, weakness, and visual perceptual changes. Often, multiple impairments are present concurrently. Healthcare staff must be aware of the "biographic disruption" the patient with glioma has experienced. While prognostic considerations factor into rehabilitation goals and expectations, regardless of prognosis the treatment team must offer cohesive support, facilitating hope, function, and quality of life. Awareness of family and caregiver concerns plays an important role in the overall care. Inpatient rehabilitation, especially after surgical resection, has been shown to result in functional improvement and homegoing rates on a par with individuals with other neurologic conditions, such as stroke or traumatic brain injury. Community integration comprises a significant element of life satisfaction, as has been shown in childhood glioma survivors. Employment is often affected by the glioma diagnosis, but may be ameliorated, when appropriate, by addressing modifiable factors such as depression, fatigue, or sleep disturbance, or by workplace accommodations. Further research is needed into many facets of rehabilitation in the setting of glioma, including establishing better care models for consistently identifying and addressing functional limitations in this population, measuring outcomes of various levels of rehabilitation care, identifying optimal physical activity strategies, delineating the long-term effects of rehabilitation interventions, and exploring impact of rehabilitation interventions on caregiver burden. The effective elements of cognitive rehabilitation, including transition of cognitive strategies to everyday living, need to be better defined. PMID:26948361

  3. EGFR immunolabeling pattern may discriminate low-grade gliomas from gliosis.

    PubMed

    Burel-Vandenbos, Fanny; Benchetrit, Maxime; Miquel, Catherine; Fontaine, Denys; Auvergne, Romane; Lebrun-Frenay, Christine; Cardot-Leccia, Nathalie; Michiels, Jean-François; Paquis-Flucklinger, Veronique; Virolle, Thierry

    2011-04-01

    Overexpression of epidermal growth factor receptor (EGFR) is common in gliomas. Gliomas are infiltrating tumors in which neoplastic glial cells can be intermingled with reactive glial cells, particularly in diffuse low-grade gliomas. As overexpression of EGFR has also been described in gliosis, it can be difficult to evaluate EGFR immunolabeling in diffuse low-grade gliomas because of this cell mix. We compared EGFR immunolabeling between gliosis and low-grade gliomas in order to identify distinctive criteria. We studied EGFR expression in 28 cases of gliosis and 39 diffuse low-grade gliomas (23 astrocytomas and 16 oligodendrogliomas). EGFR immunohistochemistry staining was performed on paraffin-embedded sections with a mouse monoclonal antibody (clone 2-18C9; Dako). Co-expression of EGFR with Olig2, Mib-1, and p53 was assessed in seven cases of low-grade gliomas using double immunolabeling. Then, EGFR immunostaining was blindly tested on 22 small specimens of indeterminate glial lesions provided by a reference neuropathological center. Two pathologists of our local center were asked to classify the lesions into diffuse low-grade glioma or gliosis according to the pattern of EGFR expression. Weak expression of EGFR was commonly detected in gliosis (23/28 cases). Strongly-stained cells were absent. Positive cells had reactive glial cell morphology. EGFR expression in gliomas was characterized by constant strongly-stained cells (39/39 cases). All strongly-stained cells had a high nucleus-to-cytoplasm ratio, with minimal to moderate nuclear atypia. Most of the strongly EGFR-positive cells were Olig2-positive. All the cases displayed cells co-expressing EGFR and Mib-1. In three p53-positive tumors, many p53-positive cells were strongly EGFR-positive. On the basis of EGFR expression, 14 out of the 22 indeterminate cases were classified as gliomas and eight as gliosis by both pathologists. Concordance with the initial diagnosis established by the reference center and

  4. Immunotherapy for malignant glioma.

    PubMed

    Suryadevara, Carter M; Verla, Terence; Sanchez-Perez, Luis; Reap, Elizabeth A; Choi, Bryan D; Fecci, Peter E; Sampson, John H

    2015-01-01

    Malignant gliomas (MG) are the most common type of primary malignant brain tumor. Most patients diagnosed with glioblastoma (GBM), the most common and malignant glial tumor, die within 12-15 months. Moreover, conventional treatment, which includes surgery followed by radiation and chemotherapy, can be highly toxic by causing nonspecific damage to healthy brain and other tissues. The shortcomings of standard-of-care have thus created a stimulus for the development of novel therapies that can target central nervous system (CNS)-based tumors specifically and efficiently, while minimizing off-target collateral damage to normal brain. Immunotherapy represents an investigational avenue with the promise of meeting this need, already having demonstrated its potential against B-cell malignancy and solid tumors in clinical trials. T-cell engineering with tumor-specific chimeric antigen receptors (CARs) is one proven approach that aims to redirect autologous patient T-cells to sites of tumor. This platform has evolved dramatically over the past two decades to include an improved construct design, and these modern CARs have only recently been translated into the clinic for brain tumors. We review here emerging immunotherapeutic platforms for the treatment of MG, focusing on the development and application of a CAR-based strategy against GBM.

  5. Period2 downregulation inhibits glioma cell apoptosis by activating the MDM2-TP53 pathway

    PubMed Central

    Hechun, Xia; Jun, Wang; Lijian, Zhang; Dede, Ma; Wenbin, Liu; Lei, Yin

    2016-01-01

    The Period2 (Per2) gene is an essential component of the mammalian circadian clock and is strongly linked to glioma occurrence and its response to radiotherapy. Here, we examined the role of Per2 in the response to X-ray-induced DNA damage in U343 glioma cells and in a mouse cancer model. Following low dose X-ray irradiation, we observed that lowering Per2 expression using RNAi reduces DNA damage and cell death in U343 cells and glioma tissue. Additionally, Per2 was associated with increased TP53 activity and was involved in the DNA damage during TP53-mediated apoptosis. These findings suggest that Per2, a core circadian gene, is not only a tumor suppressor gene but can also be regarded as an upstream regulator of TP53. It thus appears that Per2 is an important inhibitor of tumor growth that acts by increasing TP53 expression, DNA damage repair, and apoptosis. PMID:27036047

  6. 4'-Acetoamido-4-hydroxychalcone, a chalcone derivative, inhibits glioma growth and invasion through regulation of the tropomyosin 1 gene

    SciTech Connect

    Ku, Bo Mi; Ryu, Hyung Won; Lee, Yeon Kyung; Ryu, Jinhyun; Jeong, Joo Yeon; Choi, Jungil; Cho, Hee Jun; Park, Ki Hun; Kang, Sang Soo

    2010-11-19

    Research highlights: {yields} 4'-Acetoamido-4-hydroxychalcone (AHC) has anti-cancer property for glioma. {yields} 4'-Acetoamido-4-hydroxychalcone (AHC) increased tropomyosin expreesion through activattion of PKA signaling. {yields} 4'-Acetoamido-4-hydroxychalcone (AHC) inhibits glioma cell migration and invasion. {yields} In vivo administration of 4'-acetoamido-4-hydroxychalcone (AHC) reduced tumor growth. -- Abstract: Chalcones are precursors of flavonoids and have been shown to have anti-cancer activity. Here, we identify the synthetic chalcone derivative 4'-acetoamido-4-hydroxychalcone (AHC) as a potential therapeutic agent for the treatment of glioma. Treatment with AHC reduced glioma cell invasion, migration, and colony formation in a concentration-dependent manner. In addition, AHC inhibited vascular endothelial growth factor-induced migration, invasion, and tube formation in HUVECs. To determine the mechanism underlying the inhibitory effect of AHC on glioma cell invasion and migration, we investigated the effect of AHC on the gene expression change and found that AHC affects actin dynamics in U87MG glioma cells. In actin cytoskeleton regulating system, AHC increased tropomyosin expression and stress fiber formation, probably through activation of PKA. Suppression of tropomyosin expression by siRNA or treatment with the PKA inhibitor H89 reduced the inhibitory effects of AHC on glioma cell invasion and migration. In vivo experiments also showed that AHC inhibited tumor growth in a xenograft mouse tumor model. Together, these data suggest that the synthetic chalcone derivative AHC has potent anti-cancer activity through inhibition of glioma proliferation, invasion, and angiogenesis and is therefore a potential chemotherapeutic candidate for the treatment of glioma.

  7. Erythropoietin Augments Survival of Glioma Cells After Radiation and Temozolomide

    SciTech Connect

    Hassouna, Imam; Sperling, Swetlana; Kim, Ella; Schulz-Schaeffer, Walter; Rave-Fraenk, Margret; Hasselblatt, Martin; Jelkmann, Wolfgang; Giese, Alf; Ehrenreich, Hannelore

    2008-11-01

    Purpose: Despite beneficial effects of irradiation/chemotherapy on survival of glioblastoma (GBM) patients, collateral damage to intact neural tissue leads to 'radiochemobrain' and reduced quality of life in survivors. For prophylactic neuroprotection, erythropoietin (EPO) is a promising candidate, provided that concerns regarding potential tumor promoting effects are alleviated. Methods and Materials: Human GBM-derived cell lines U87, G44, G112, and the gliosarcoma-derived line G28 were treated with EPO, with and without combinations of irradiation or temozolomide (TMZ). Responsiveness of glioma cells to EPO was measured by cell migration from spheroids, cell proliferation, and clonogenic survival. Implantation of U87 cells into brains of nude mice, followed 5 days later by EPO treatment (5,000 U/kg intraperitoneal every other day for 2 weeks) should reveal effects of EPO on tumor growth in vivo. Reverse transcriptase-polymerase chain reaction was performed for EPOR, HIF-1{alpha}, and epidermal growth factor receptor (EGFR)vIII in cell lines and 22 human GBM specimens. Results: EPO did not modulate basal glioma cell migration and stimulated proliferation in only one of four cell lines. Importantly, EPO did not enhance tumor growth in mouse brains. Preincubation of glioma cells with EPO for 3 h, followed by irradiation and TMZ for another 24 h, resulted in protection against chemoradiation-induced cytotoxicity in three cell lines. Conversely, EPO induced a dose-dependent decrease in survival of G28 gliosarcoma cells. In GBM specimens, expression of HIF-1{alpha} correlated positively with expression of EPOR and EGFRvIII. EPOR and EGFRvIII expression did not correlate. Conclusions: EPO is unlikely to appreciably influence basal glioma growth. However, concomitant use of EPO with irradiation/chemotherapy in GBM patients is not advisable.

  8. Postirradiation cerebellar glioma. Case report

    SciTech Connect

    Raffel, C.; Edwards, M.S.; Davis, R.L.; Ablin, A.R.

    1985-02-01

    A 13-year-old girl developed an anaplastic astrocytoma of the cerebellum 7 years after irradiation of the central nervous system and prophylactic chemotherapy for acute lymphocytic leukemia. The fact that the astrocytoma was anaplastic and infiltrative was unusual for astroglial tumors at this site. It is proposed that this is a radiation-induced glioma.

  9. Recent surgical management of gliomas.

    PubMed

    Sanai, Nader; Berger, Mitchel S

    2012-01-01

    Refinement of neurosurgical technique has enabled safer operations with more aggressive outcomes. One cornerstone of modern-day practice is the utilization of intraoperative stimulation mapping. In addition to identifying critical motor pathways, this technique can be adapted to reliable identify language pathways, as well. Given the individual variability of cortical language localization, such awake language mapping is essential to minimize language deficits following tumor resection. Our experience suggests that cortical language mapping is a safe and efficient adjunct to optimize tumor resection while preserving essential language sites, even in the setting of negative mapping data. However, the value of maximizing glioma resections remains surprisingly unclear, as there is no general consensus in the literature regarding the efficacy of extent of glioma resection in improving patient outcome. While the importance of resection in obtaining tissue diagnosis and to alleviate symptoms is clear, a lack of Class I evidence prevents similar certainty in assessing the influence of extent of resection. Beyond an analysis of modern intraoperative mapping techniques, we examine every major clinical publication since 1990 on the role of extent of resection in glioma outcome. The mounting evidence suggests that, despite persistent limitations in the quality of available studies, a more extensive surgical resection is associated with longer life expectancy for both low-grade and high-grade gliomas.

  10. Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells

    PubMed Central

    Kim, Ella L.; Wüstenberg, Robin; Rübsam, Anne; Schmitz-Salue, Christoph; Warnecke, Gabriele; Bücker, Eva-Maria; Pettkus, Nadine; Speidel, Daniel; Rohde, Veit; Schulz-Schaeffer, Walter; Deppert, Wolfgang; Giese, Alf

    2010-01-01

    Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy. PMID:20308316

  11. Multicentric glioma with unusual clinical presentation.

    PubMed

    Zamponi, N; Rychlicki, F; Ducati, A; Regnicolo, L; Salvolini, U; Ricciuti, R A

    2001-01-01

    Multiple glioma is a well-recognized but uncommon entity. They are grouped in two categories: multifocal and multicentric gliomas. Multifocal gliomas grow through dissemination along an established route, spreading through commissural pathways, CSF channels, or the blood or by local extension through satellite formation; at the opposite end of the spectrum, multicentric gliomas are widely separated lesions whose simultaneous presence cannot be attributed to any of the above pathways. Reports in the literature refer to single cases or small series of multicentric gliomas, almost always in adult patients, their occurrence in children being even less frequent. We report the case of a 12-year-old boy with multicentric glioma, atypical acute clinical onset and fast growth of three other tumors in 8 months, and then discuss the problems of diagnosis and therapy.

  12. Epigenetic modification of miR-141 regulates SKA2 by an endogenous ‘sponge’ HOTAIR in glioma

    PubMed Central

    Wang, Chao; Zong, Gang; Wang, Hong-Liang; Zhao, Bing

    2016-01-01

    Aberrant expression of miR-141 has recently implicated in the occurrence and development of various types of malignant tumors. However whether the involvement of miR-141 in the pathogenesis of glioma remains unknown. Here, we showed that miR-141 was markedly downregulated in glioma tissues and cell lines compared with normal brain tissues, and its expression correlated with the pathological grading. Enforced expression of miR-141 in glioma cells significantly inhibited cell proliferation, migration and invasion, whereas knockdown of miR-141 exerted opposite effect. Mechanistic investigations revealed that HOTAIR might act as an endogenous ‘sponge’ of miR-141, thereby regulating the derepression of SKA2. Further, we explored the molecular mechanism by which miR-141 expression was regulated, and found that the miR-141 promoter was hypermethylated and that promoter methylation of miR-141 was mediated by DNMT1 in glioma cells. Finally, both overexpression of miR-141 and knockdown of HOTAIR in a mouse model of human glioma resulted in significant reduction of tumor growth in vivo. Collectively, these results suggest that epigenetic modification of miR-141 and the interaction of ceRNA regulatory network will provide a new approach for therapeutics against glioma. PMID:27121316

  13. Pediatric Low-Grade Gliomas

    PubMed Central

    Sievert, Angela J.; Fisher, Michael J.

    2010-01-01

    Pediatric low-grade gliomas encompass a heterogeneous set of tumors of different histologies. Cerebellar pilocytic astrocytomas occur most frequently followed by supratentorial diffuse fibrillary astrocytomas. Recent research has implicated activation of the RAS/RAF/MEK pathway in tumorigenesis of these tumors. Surgery is the mainstay of therapy. Overall survival rates for patients whose tumors are completely resected are 90% or greater, 10 years from diagnosis. Conversely, most optic pathway/hypothalamic, deep midline, and brain stem gliomas have minimal potential for resection; these tumors can be difficult to treat and deserve special attention. Combination chemotherapy is currently recommended as front-line adjuvant treatment for progressive or recurrent tumors. Second-line radiotherapy can also improve overall survival but is associated with more frequent and significant neurocognitive, endocrine, and other long-term toxicities. PMID:19841428

  14. Bearers of Hope

    ERIC Educational Resources Information Center

    Landsman, Julie

    2006-01-01

    Landsman explores the qualities that enable teachers to effectively work with students who are homeless or live in extreme poverty. The most effective strategy seems to be maintaining high expectations. Successful teachers "cut deals" with students, finding ways to connect school work to students' life concerns and helping them successfully to…

  15. GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo.

    PubMed

    Zhou, Xiang; Shen, Fazheng; Ma, Pengju; Hui, Hongyan; Pei, Sujuan; Chen, Ming; Wang, Zhongwei; Zhou, Wenke; Jin, Baozhe

    2015-10-01

    Glioma is a type of primary malignant tumor of the central nervous system in humans. At present, standard treatment involves surgical resection, followed by radiation therapy and chemotherapy. However, the prognosis is poor and the long‑term survival rate remains low. An improved understanding of the molecular basis for glioma tumorigenesis is in urgently required. The pro‑survival effect of the insulin‑like growth factor (IGF) signaling pathway has been implicated in progression of the glioma disease state. GSK1838705A is a novel, small molecule kinase inhibitor of IGF‑IR, which inhibits IGF signal transduction and downstream target activation. Its anti-proliferative activity has been demonstrated in various tumor cell lines. The present study investigated the potential use of GSK1838705A for the treatment of glioma. Human U87MG glioma cells were used to examine the inhibitory activity of GSK1838705A in cell proliferation, migration and apoptosis. The antitumor activity of GSK1838705A was assessed in a xenograft mouse model. GSK1838705A inhibited the growth and induced the apoptosis of the U87MG glioma cells in a dose‑dependent manner. The GSK1838705A‑treated cells exhibited reduced migratory activity in response to chemoattractants. The present study further demonstrated the antitumor activity of GSK1838705A in vivo. The administration of GSK1838705A significantly inhibited the growth of glioma tumors by inducing the apoptosis of tumor cells. These results suggested that targeting IGF signaling with GSK1838705A may be a promising therapeutic strategy for the treatment of patients with glioma. PMID:26238593

  16. GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo

    PubMed Central

    ZHOU, XIANG; SHEN, FAZHENG; MA, PENGJU; HUI, HONGYAN; PEI, SUJUAN; CHEN, MING; WANG, ZHONGWEI; ZHOU, WENKE; JIN, BAOZHE

    2015-01-01

    Glioma is a type of primary malignant tumor of the central nervous system in humans. At present, standard treatment involves surgical resection, followed by radiation therapy and chemotherapy. However, the prognosis is poor and the long-term survival rate remains low. An improved understanding of the molecular basis for glioma tumorigenesis is in urgently required. The pro-survival effect of the insulin-like growth factor (IGF) signaling pathway has been implicated in progression of the glioma disease state. GSK1838705A is a novel, small molecule kinase inhibitor of IGF-IR, which inhibits IGF signal transduction and downstream target activation. Its anti-proliferative activity has been demonstrated in various tumor cell lines. The present study investigated the potential use of GSK1838705A for the treatment of glioma. Human U87MG glioma cells were used to examine the inhibitory activity of GSK1838705A in cell proliferation, migration and apoptosis. The antitumor activity of GSK1838705A was assessed in a xenograft mouse model. GSK1838705A inhibited the growth and induced the apoptosis of the U87MG glioma cells in a dose-dependent manner. The GSK1838705A-treated cells exhibited reduced migratory activity in response to chemoattractants. The present study further demonstrated the antitumor activity of GSK1838705A in vivo. The administration of GSK1838705A significantly inhibited the growth of glioma tumors by inducing the apoptosis of tumor cells. These results suggested that targeting IGF signaling with GSK1838705A may be a promising therapeutic strategy for the treatment of patients with glioma. PMID:26238593

  17. Intraarterial Infusion Of Erbitux and Bevacizumab For Relapsed/Refractory Intracranial Glioma In Patients Under 22

    ClinicalTrials.gov

    2016-03-16

    Glioblastoma Multiforme; Fibrillary Astrocytoma of Brain; Glioma of Brainstem; Anaplastic Astrocytoma; Pilomyxoid Astrocytoma; Mixed Oligodendroglioma-Astrocytoma; Brain Stem Glioma; Diffuse Intrinsic Pontine Glioma

  18. The Potential of Tetrandrine against Gliomas.

    PubMed

    Chen, Yun; Tseng, Sheng-Hong

    2010-09-01

    Patients with malignant gliomas have poor prognoses, and the majority of the patients have local tumor recurrence after various treatments including surgery, radiotherapy, and chemotherapy. Thus it is mandatory to develop better therapies for treatment of these malignant brain tumors. Tetrandrine, a bisbenzylisoquinoline alkaloid, has antitumor effects against some cancers. Tetrandrine affects the cell cycle, production of reactive oxygen species, mitogen-activated protein kinase activity, and reverses multidrug resistance in various cancer cells. Since tetrandrine is a highly lipid-soluble and hydrophobic molecule with a low molecular weight, it may cross the blood brain barrier; thus, it could be used for the treatment of gliomas. Tetrandrine inhibits the large-conductance, calcium-activated potassium (BK) channels and the expression of BK channel has a positive correlation with tumor malignancy grade in human gliomas. Furthermore, tetrandrine also exerts cytotoxic effects, and induces apoptosis and radiosensitization in glioma cells by elimination of radiation-induced cell cycle perturbation. It also has anti-angiogenesis effects in gliomas, and exerts an antitumor effect on subcutaneous and intracerebral gliomas. Tetrandrine is a radiosensitizer and also a multidrug resistance reversing agent. Tetrandrine can probably be combined with radiotherapy or other chemotherapeutic agents to treat gliomas. Nonetheless, it is important to determine the balance between the safety and efficacy of tetrandrine in patients with malignant gliomas before any clinical application.

  19. Unique biology of gliomas: challenges and opportunities

    PubMed Central

    Watkins, Stacey; Sontheimer, Harald

    2013-01-01

    Gliomas are terrifying primary brain tumors for which patient outlook remains bleak. Recent research provides novel insights into the unique biology of gliomas. For example, these tumors exhibit an unexpected pluripotency that enables them to grow their own vasculature. They have an unusual ability to navigate tortuous extracellular pathways as they invade, and they use neurotransmitters to inflict damage and create room for growth. Here, we review studies that illustrate the importance of considering interactions of gliomas with their native brain environment. Such studies suggest that gliomas constitute a neurodegenerative disease caused by the malignant growth of brain support cells. The chosen examples illustrate how targeted research into the biology of gliomas is yielding new and much needed therapeutic approaches to this challenging nervous system disease. PMID:22683220

  20. Associations of High-Grade Glioma With Glioma Risk Alleles and Histories of Allergy and Smoking

    PubMed Central

    Lachance, Daniel H.; Yang, Ping; Johnson, Derek R.; Decker, Paul A.; Kollmeyer, Thomas M.; McCoy, Lucie S.; Rice, Terri; Xiao, Yuanyuan; Ali-Osman, Francis; Wang, Frances; Stoddard, Shawn M.; Sprau, Debra J.; Kosel, Matthew L.; Wiencke, John K.; Wiemels, Joseph L.; Patoka, Joseph S.; Davis, Faith; McCarthy, Bridget; Rynearson, Amanda L.; Worra, Joel B.; Fridley, Brooke L.; O’Neill, Brian Patrick; Buckner, Jan C.; Il’yasova, Dora; Jenkins, Robert B.; Wrensch, Margaret R.

    2011-01-01

    Glioma risk has consistently been inversely associated with allergy history but not with smoking history despite putative biologic plausibility. Data from 855 high-grade glioma cases and 1,160 controls from 4 geographic regions of the United States during 1997–2008 were analyzed for interactions between allergy and smoking histories and inherited variants in 5 established glioma risk regions: 5p15.3 (TERT), 8q24.21 (CCDC26/MLZE), 9p21.3 (CDKN2B), 11q23.3 (PHLDB1/DDX6), and 20q13.3 (RTEL1). The inverse relation between allergy and glioma was stronger among those who did not (odds ratioallergy-glioma = 0.40, 95% confidence interval: 0.28, 0.58) versus those who did (odds ratioallergy-glioma = 0.76, 95% confidence interval: 0.59, 0.97; Pinteraction = 0.02) carry the 9p21.3 risk allele. However, the inverse association with allergy was stronger among those who carried (odds ratioallergy-glioma = 0.44, 95% confidence interval: 0.29, 0.68) versus those who did not carry (odds ratioallergy-glioma = 0.68, 95% confidence interval: 0.54, 0.86) the 20q13.3 glioma risk allele, but this interaction was not statistically significant (P = 0.14). No relation was observed between glioma risk and smoking (odds ratio = 0.92, 95% confidence interval: 0.77, 1.10; P = 0.37), and there were no interactions for glioma risk of smoking history with any of the risk alleles. The authors’ observations are consistent with a recent report that the inherited glioma risk variants in chromosome regions 9p21.3 and 20q13.3 may modify the inverse association of allergy and glioma. PMID:21742680

  1. Convection-enhanced delivery: targeted toxin treatment of malignant glioma.

    PubMed

    Hall, Walter A; Sherr, Gregory T

    2006-04-15

    Historically, malignant gliomas are perhaps the most difficult intracranial neoplasms to treat. Surgery, radiation therapy, and traditional chemotherapy have not been able to significantly alter the course of this disease. By definition, these tumors are located in the protected space of the cranial vault, where the blood-brain barrier prevents most therapies from gaining access. Because of the difficulty in treating this disease, new, innovative treatments and alternative delivery techniques for those therapies are needed. Targeted toxins are fusion proteins that represent a novel medical treatment for these cancers that is under development. However, the efficacy of these agents is dependent on the method of delivery to the tumor. The administration of targeted toxins requires image-guided placement of catheters, either within the tumor or into the adjacent infiltrated brain, and positive pressure infusion. The term that has been applied to this microinfusion technique is convection-enhanced delivery (CED). This infusion method was first attempted via direct intratumoral infusion in nude mouse flank tumor models of human malignant glioma. After significant development of this delivery technique in animal models, the successful demonstration of in vivo efficacy of targeted toxins in Phase I and II clinical trials was reported. Currently, ongoing targeted toxin trials are being conducted at academic health centers to define the best clinical practice for CED. This work involves refining the details of delivery such as infusion rate, duration of treatment, and drug dosing. The early results of CED of targeted toxins supports their continued investigation, as few other treatment modalities have produced durable results in the fight against gliomas.

  2. Incidence of gliomas by anatomic location.

    PubMed

    Larjavaara, Suvi; Mäntylä, Riitta; Salminen, Tiina; Haapasalo, Hannu; Raitanen, Jani; Jääskeläinen, Juha; Auvinen, Anssi

    2007-07-01

    The anatomic location of a glioma influences prognosis and treatment options. The aim of our study was to describe the distribution of gliomas in different anatomic areas of the brain. A representative population-based sample of 331 adults with glioma was used for preliminary analyses. The anatomic locations for 89 patients from a single center were analyzed in more detail from radiologic imaging and recorded on a three-dimensional 1 x 1 x 1-cm grid. The age-standardized incidence rate of gliomas was 4.7 per 100,000 person-years. The most frequent subtypes were glioblastoma (47%) and grade II-III astrocytoma (23%), followed by oligodendroglioma and mixed glioma. The gliomas were located in the frontal lobe in 40% of the cases, temporal in 29%, parietal in 14%, and occipital lobe in 3%, with 14% in the deeper structures. The difference in distribution between lobes remained after adjustment for their tissue volume: the tumor:volume ratio was 4.5 for frontal, 4.8 for temporal, and 2.3 for parietal relative to the occipital lobe. The area with the densest occurrence was the anterior subcortical brain. Statistically significant spatial clustering was found in the three-dimensional analysis. No differences in location were found among glioblastoma, diffuse astrocytoma, and oligodendroglioma. Our results demonstrate considerable heterogeneity in the anatomic distribution of gliomas within the brain.

  3. Gallic acid suppresses cell viability, proliferation, invasion and angiogenesis in human glioma cells

    PubMed Central

    Lu, Yong; Jiang, Feng; Jiang, Hao; Wu, Kalina; Zheng, Xuguang; Cai, Yizhong; Katakowski, Mark; Chopp, Michael; To, Shing-Shun Tony

    2010-01-01

    Gallic acid, an organic acid, also known as 3,4,5-trihydroxybenzoic acid, is cytotoxic against certain cancer cells, without harming normal cells. The objective of this study is to evaluate whether gallic acid can inhibit glioma cell viability, proliferation, invasion and reduce glioma cell mediated angiogenesis. Treatment of U87 and U251n glioma cells with gallic acid inhibited cell viability in a dose- and time-dependent manner. BrdU and tube formation assays indicated that gallic acid significantly decreased glioma cell proliferation and tube formation in mouse brain endothelial cells, respectively. In addition, gallic acid decreased U87 cell invasion in vitro. Western blot analysis showed that expression of ADAM17, p-Akt and p-Erk was suppressed by gallic acid in both U87 and U251n cell lines. These data suggest that suppression of ADAM17 and downregulation of PI3K/Akt and Ras/MAPK signaling pathways may contribute to gallic acid-induced decrease of invasiveness. Gallic acid may be a valuable candidate for treatment of brain tumor. PMID:20553913

  4. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression.

    PubMed

    Turner, Kristen M; Sun, Youting; Ji, Ping; Granberg, Kirsi J; Bernard, Brady; Hu, Limei; Cogdell, David E; Zhou, Xinhui; Yli-Harja, Olli; Nykter, Matti; Shmulevich, Ilya; Yung, W K Alfred; Fuller, Gregory N; Zhang, Wei

    2015-03-17

    Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

  5. Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression

    PubMed Central

    Turner, Kristen M.; Sun, Youting; Ji, Ping; Granberg, Kirsi J.; Bernard, Brady; Hu, Limei; Cogdell, David E.; Zhou, Xinhui; Yli-Harja, Olli; Nykter, Matti; Shmulevich, Ilya; Yung, W. K. Alfred; Fuller, Gregory N.; Zhang, Wei

    2015-01-01

    Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor. PMID:25737557

  6. Disruption of astrocyte-vascular coupling and the blood-brain barrier by invading glioma cells

    PubMed Central

    Watkins, Stacey; Robel, Stefanie; Kimbrough, Ian F.; Robert, Stephanie M.; Ellis-Davies, Graham; Sontheimer, Harald

    2014-01-01

    Astrocytic endfeet cover the entire cerebral vasculature and serve as exchange sites for ions, metabolites, and energy substrates from the blood to the brain. They maintain endothelial tight junctions that form the blood-brain barrier (BBB) and release vasoactive molecules that regulate vascular tone. Malignant gliomas are highly invasive tumors that use the perivascular space for invasion and co-opt existing vessels as satellite tumors form. Here we use a clinically relevant mouse model of glioma and find that glioma cells, as they populate the perivascular space of pre-existing vessels, displace astrocytic endfeet from endothelial or vascular smooth muscle cells. This causes a focal breach in the BBB. Furthermore, astrocyte-mediated gliovascular coupling is lost, and glioma cells seize control over regulation of vascular tone through Ca2+-dependent release of K+. These findings have important clinical implications regarding blood flow in the tumor-associated brain and the ability to locally deliver chemotherapeutic drugs in disease. PMID:24943270

  7. Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Misuraca, Katherine L.; Cordero, Francisco J.; Becher, Oren J.

    2015-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of 6 and 8. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years, however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab and to potentially treat them in the clinic. This review will detail the initial strides toward modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of in vitro cell and in vivo xenograft models derived directly from autopsy material of DIPG patients or from human embryonic stem cells. Finally, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients. PMID:26258075

  8. Glioma Stem Cell-Targeted Dendritic Cells as a Tumor Vaccine Against Malignant Glioma

    PubMed Central

    Ji, Baowei; Liu, Baohui; Wu, Liquan; Tian, Daofeng; Guo, Zhentao; Yi, Wei

    2013-01-01

    Purpose Cancer stem cells have recently been thought to be closely related to tumor development and reoccurrence. It may be a promising way to cure malignant glioma by using glioma stem cell-targeted dendritic cells as a tumor vaccine. In this study, we explored whether pulsing dendritic cells with antigens of glioma stem cells was a potent way to induce specific cytotoxic T lymphocytes and anti-tumor immunity. Materials and Methods Cancer stem cells were cultured from glioma cell line U251. Lysate of glioma stem cells was obtained by the repeated freezing and thawing method. Dendritic cells (DCs) were induced and cultured from the murine bone marrow cells, the biological characteristics were detected by electron microscope and flow cytometry. The DC vaccine was obtained by mixing DCs with lysate of glioma stem cells. The DC vaccine was charactirizated through the mixed lymphocyte responses and cell killing experiment in vitro. Level of interferon-γ (IFN-γ) in the supernatant was checked by ELISA. Results After stimulation of lysate of glioma stem cell, expression of surface molecules of DC was up-regulated, including CD80, CD86, CD11C and MHC-II. DCs pulsed with lysate of glioma stem cells were more effective than the control group in stimulating original glioma cells-specific cytotoxic T lymphocytes responses, killing glioma cells and boosting the secretion of IFN-γ in vitro. Conclusion The results demonstrated DCs loaded with antigens derived from glioma stem cells can effectively stimulate naive T cells to form specific cytotoxic T cells, kill glioma cells cultured in vitro. PMID:23225804

  9. [Neuropathology and molecular pathology of gliomas].

    PubMed

    Janzer, Robert-Charles

    2009-07-15

    Gliomas are the most frequent primary brain tumours. The WHO classification is essentially based on histological and immunohistochemical criteria. More recently multiple cytogenetic and molecular alterations associated with initiation and progression have been shown and the genetic profiles of tumour entities have been incorporated in the WHO classifiacation. Molecular testing of the MGMT promotor methylation in glioblastoma, predictive for the response to combined radio-/chimiothérapie, and the LOH 1p/19q in oligodendroglial tumours, as prognostic factor supplements the histopathological diagnosis. In the near futur array-based profiling techniques will contribute to a refinement of glioma classification and identify targets for more individualized glioma therapies.

  10. Development of Resistance to EGFR-Targeted Therapy in Malignant Glioma Can Occur through EGFR-Dependent and -Independent Mechanisms.

    PubMed

    Klingler, Stefan; Guo, Baofeng; Yao, Jun; Yan, Haiyan; Zhang, Ling; Vaseva, Angelina V; Chen, Sida; Canoll, Peter; Horner, James W; Wang, Y Alan; Paik, Ji-Hye; Ying, Haoqiang; Zheng, Hongwu

    2015-05-15

    Epidermal growth factor receptor (EGFR) is highly amplified, mutated, and overexpressed in human malignant gliomas. Despite its prevalence and growth-promoting functions, therapeutic strategies to inhibit EGFR kinase activity have not been translated into profound beneficial effects in glioma clinical trials. To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Using combined genetic and pharmacologic interventions, we revealed that EGFR*-driven gliomas were insensitive to EGFR tyrosine kinase inhibitors, although they could efficiently inhibit EGFR* autophosphorylation in vitro and in vivo. This is in contrast with the genetic suppression of EGFR* induction that led to significant tumor regression and prolonged animal survival. However, despite their initial response to genetic EGFR* extinction, all tumors would relapse and propagate independent of EGFR*. We further showed that EGFR*-independent tumor cells existed prior to treatment and were responsible for relapse following genetic EGFR* suppression. And, the addition of a PI3K/mTOR inhibitor could significantly delay relapse and prolong animal survival. Our findings shed mechanistic insight into EGFR drug resistance in glioma and provide a platform to test therapies targeting aberrant EGFR signaling in this setting.

  11. Differential expression of myc, max and RB1 genes in human gliomas and glioma cell lines.

    PubMed Central

    Hirvonen, H. E.; Salonen, R.; Sandberg, M. M.; Vuorio, E.; Västrik, I.; Kotilainen, E.; Kalimo, H.

    1994-01-01

    Deregulated expression of myc proto-oncogenes is implicated in several human neoplasias. We analysed the expression of c-myc, N-myc, L-myc, max and RB1 mRNAs in a panel of human gliomas and glioma cell lines and compared the findings with normal neural cells. The max and RB1 genes were included in the study because their protein products can interact with the Myc proteins, being thus putative modulators of Myc activity. Several gliomas contained c/L-myc mRNAs at levels higher than those in fetal brain, L-myc predominantly in grade II/III and c-myc in grade III gliomas. High-level N-myc expression was detected. In one small-cell glioblastoma and lower levels in five other gliomas. In contrast, glioma cell lines totally lacked N/L-myc expression. The in situ hybridisations revealed mutually exclusive topographic distribution of myc and glial fibrillary acidic protein (GFAP) mRNAs, and a lack of correlation between myc expression and proliferative activity, max and RB1 mRNAs were detected in most tumours and cell lines. The glioma cells displayed interesting alternative splicing patterns of max mRNAs encoding Max proteins which either suppress (Max) or augment (delta Max) the transforming activity of Myc. We conclude that (1) glioma cells in vivo may coexpress several myc genes, thus resembling fetal neural cells; but (2) cultured glioma cells expression only c-myc; (3) myc, max and RB1 are regulated independently in glioma cells; and (4) alternative processing of max mRNA in some glioma cells results in delta Max encoding mRNAs not seen in normal fetal brain. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:8286200

  12. The Art of Intraoperative Glioma Identification

    PubMed Central

    Zhang, Zoe Z.; Shields, Lisa B. E.; Sun, David A.; Zhang, Yi Ping; Hunt, Matthew A.; Shields, Christopher B.

    2015-01-01

    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. PMID:26284196

  13. Improving vaccine efficacy against malignant glioma.

    PubMed

    Ladomersky, Erik; Genet, Matthew; Zhai, Lijie; Gritsina, Galina; Lauing, Kristen L; Lulla, Rishi R; Fangusaro, Jason; Lenzen, Alicia; Kumthekar, Priya; Raizer, Jeffrey J; Binder, David C; James, C David; Wainwright, Derek A

    2016-08-01

    The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored. We conclude by proposing new strategies that are built on current vaccine technologies and improved upon with novel combinatorial approaches. PMID:27622066

  14. Treatment Options for Childhood Brain Stem Glioma

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain stem gliomas may cause ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  15. Stages of Childhood Brain Stem Glioma

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain stem gliomas may cause ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  16. Targeted Radiolabeled Compounds in Glioma Therapy.

    PubMed

    Cordier, Dominik; Krolicki, Leszek; Morgenstern, Alfred; Merlo, Adrian

    2016-05-01

    Malignant gliomas of World Health Organization (WHO) grades II-IV represent the largest entity within the group of intrinsic brain tumors and are graded according to their pathophysiological features with survival times between more than 10 years (WHO II) and only several months (WHO IV). Gliomas arise from astrocytic or oligodendrocytic precursor cells and exhibit an infiltrative growth pattern lacking a clearly identifiable tumor border. The development of effective treatment strategies of the invasive tumor cell front represents the main challenge in glioma therapy. The therapeutic standard consists of surgical resection and, depending on the extent of resection and WHO grade, adjuvant external beam radiotherapy or systemic chemotherapy. Within the last decades, there has been no major improvement of the prognosis of patients with glioma. The consistent overexpression of neurokinin type 1 receptors in gliomas WHO grades II-IV has been used to develop a therapeutic substance P-based targeting system. A substance P-analogue conjugated to the DOTA or DOTAGA chelator has been labeled with different alpha-particle or beta-particle emitting radionuclides for targeted glioma therapy. The radiopharmaceutical has been locally injected into the tumors or the resection cavity. In several clinical studies, the methodology has been examined in adjuvant and neoadjuvant clinical settings. Although no large controlled series have so far been generated, the results of radiolabeled substance P-based targeted glioma therapy compare favorably with standard therapy. Recently, labeling with the alpha particle emitting Bi-213 has been found to be promising due to the high linear energy transfer and the very short tissue range of 0.08 mm. Further development needs to focus on the improvement of the stability of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within the prognostically critical

  17. Targeted Radiolabeled Compounds in Glioma Therapy.

    PubMed

    Cordier, Dominik; Krolicki, Leszek; Morgenstern, Alfred; Merlo, Adrian

    2016-05-01

    Malignant gliomas of World Health Organization (WHO) grades II-IV represent the largest entity within the group of intrinsic brain tumors and are graded according to their pathophysiological features with survival times between more than 10 years (WHO II) and only several months (WHO IV). Gliomas arise from astrocytic or oligodendrocytic precursor cells and exhibit an infiltrative growth pattern lacking a clearly identifiable tumor border. The development of effective treatment strategies of the invasive tumor cell front represents the main challenge in glioma therapy. The therapeutic standard consists of surgical resection and, depending on the extent of resection and WHO grade, adjuvant external beam radiotherapy or systemic chemotherapy. Within the last decades, there has been no major improvement of the prognosis of patients with glioma. The consistent overexpression of neurokinin type 1 receptors in gliomas WHO grades II-IV has been used to develop a therapeutic substance P-based targeting system. A substance P-analogue conjugated to the DOTA or DOTAGA chelator has been labeled with different alpha-particle or beta-particle emitting radionuclides for targeted glioma therapy. The radiopharmaceutical has been locally injected into the tumors or the resection cavity. In several clinical studies, the methodology has been examined in adjuvant and neoadjuvant clinical settings. Although no large controlled series have so far been generated, the results of radiolabeled substance P-based targeted glioma therapy compare favorably with standard therapy. Recently, labeling with the alpha particle emitting Bi-213 has been found to be promising due to the high linear energy transfer and the very short tissue range of 0.08 mm. Further development needs to focus on the improvement of the stability of the compound and the application by dedicated catheter systems to improve the intratumoral distribution of the radiopharmaceutical within the prognostically critical

  18. Rapid Intraoperative Molecular Characterization of Glioma

    PubMed Central

    Shankar, Ganesh M.; Francis, Joshua M.; Rinne, Mikael L.; Ramkissoon, Shakti H.; Huang, Franklin W.; Venteicher, Andrew S.; Akama-Garren, Elliot H.; Kang, Yun Jee; Lelic, Nina; Kim, James C.; Brown, Loreal E.; Charbonneau, Sarah K.; Golby, Alexandra J.; Pedamallu, Chandra Sekhar; Hoang, Mai P.; Sullivan, Ryan J.; Cherniack, Andrew D.; Garraway, Levi A.; Stemmer-Rachamimov, Anat; Reardon, David A.; Wen, Patrick Y.; Brastianos, Priscilla K.; Curry, William T.; Barker, Fred G.; Hahn, William C.; Nahed, Brian V.; Ligon, Keith L.; Louis, David N.; Cahill, Daniel P.; Meyerson, Matthew

    2016-01-01

    IMPORTANCE Conclusive intraoperative pathologic confirmation of diffuse infiltrative glioma guides the decision to pursue definitive neurosurgical resection. Establishing the intraoperative diagnosis by histologic analysis can be difficult in low-cellularity infiltrative gliomas. Therefore, we developed a rapid and sensitive genotyping assay to detect somatic single-nucleotide variants in the telomerase reverse transcriptase (TERT) promoter and isocitrate dehydrogenase 1 (IDH1). OBSERVATIONS This assay was applied to tissue samples from 190 patients with diffuse gliomas, including archived fixed and frozen specimens and tissue obtained intraoperatively. Results demonstrated 96% sensitivity (95% CI, 90%–99%) and 100% specificity (95% CI, 95%–100%) for World Health Organization grades II and III gliomas. In a series of live cases, glioma-defining mutations could be identified within 60 minutes, which could facilitate the diagnosis in an intraoperative timeframe. CONCLUSIONS AND RELEVANCE The genotyping method described herein can establish the diagnosis of low-cellularity tumors like glioma and could be adapted to the point-of-care diagnosis of other lesions that are similarly defined by highly recurrent somatic mutations. PMID:26181761

  19. Potential Application of Temozolomide in Mesenchymal Stem Cell-Based TRAIL Gene Therapy Against Malignant Glioma

    PubMed Central

    Kim, Seong Muk; Woo, Ji Sun; Jeong, Chang Hyun; Ryu, Chung Heon; Jang, Jae-Deog

    2014-01-01

    Because the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively kills tumor cells, it is one of the most promising candidates for cancer treatment. TRAIL-secreting human mesenchymal stem cells (MSC-TRAIL) provide targeted and prolonged delivery of TRAIL in glioma therapy. However, acquired resistance to TRAIL of glioma cells is a major problem to be overcome. We showed a potential therapy that used MSC-TRAIL combined with the chemotherapeutic agent temozolomide (TMZ). The antitumor effects of the combination with MSC-TRAIL and TMZ on human glioma cells were determined by using an in vitro coculture system and an in vivo experimental xenografted mouse model. Intracellular signaling events that are responsible for the TMZ-mediated sensitization to TRAIL-induced apoptosis were also evaluated. Treatment of either TRAIL-sensitive or -resistant human glioma cells with TMZ and MSC-TRAIL resulted in a significant enhancement of apoptosis compared with the administration of each agent alone. We demonstrated that TMZ effectively increased the sensitivity to TRAIL-induced apoptosis via extracellular signal-regulated kinase-mediated upregulation of the death receptor 5 and downregulation of antiapoptotic proteins, such as X-linked inhibitor of apoptosis protein and cellular FLICE-inhibitory protein. Subsequently, this combined treatment resulted in a substantial increase in caspase activation. Furthermore, in vivo survival experiments and bioluminescence imaging analyses showed that treatment using MSC-TRAIL combined with TMZ had greater therapeutic efficacy than did single-agent treatments. These results suggest that the combination of clinically relevant TMZ and MSC-TRAIL is a potential therapeutic strategy for improving the treatment of malignant gliomas. PMID:24436439

  20. Tumour-specific triple-regulated oncolytic herpes virus to target glioma

    PubMed Central

    Delwar, Zahid M.; Liu, Guoyu; Kuo, Yvonne; Lee, Cleo; Bu, Luke; Rennie, Paul S.; Jia, William W.

    2016-01-01

    Oncolytic herpes simplex virus type 1 (oHSV-1) therapy is an emerging treatment modality that selectively destroys cancer. Here we report use of a glioma specific HSV-1 amplicon virus (SU4-124 HSV-1) to selectively target tumour cells. To achieve transcriptional regulation of the SU4-124 HSV-1 virus, the promoter for the essential HSV-1 gene ICP4 was replaced with a tumour specific survivin promoter. Translational regulation was achieved by incorporating 5 copies of microRNA 124 target sequences into the 3′UTR of the ICP4 gene. Additionally, a 5′UTR of rat fibroblast growth factor -2 was added in front of the viral ICP4 gene open reading frame. Our results confirmed enhanced expression of survivin and eIF4E in different glioma cells and increased micro-RNA124 expression in normal human and mouse brain tissue. SU4-124 HSV-1 had an increased ICP4 expression and virus replication in different glioma cells compared to normal neuronal cells. SU4-124 HSV-1 exerted a strong antitumour effect against a panel of glioma cell lines. Intracranial injection of SU4-124 HSV-1 did not reveal any sign of toxicity on day 15 after the injection. Moreover, a significantly enhanced antitumour effect with the intratumourally injected SU4-124 HSV-1 virus was demonstrated in mice bearing human glioma U87 tumours, whereas viral DNA was almost undetectable in normal organs. Our study indicates that incorporation of multiple cancer-specific regulators in an HSV-1 system significantly enhances both cancer specificity and oncolytic activity. PMID:27070093

  1. Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells

    PubMed Central

    Li, Xue-tao; Tang, Wei; Jiang, Ying; Wang, Xiao-min; Wang, Yan-hong; Cheng, Lan; Meng, Xian-sheng

    2016-01-01

    Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood–brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

  2. Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells.

    PubMed

    Li, Xue-Tao; Tang, Wei; Jiang, Ying; Wang, Xiao-Min; Wang, Yan-Hong; Cheng, Lan; Meng, Xian-Sheng

    2016-04-26

    Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood-brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma. PMID:27029055

  3. Vaccine Therapies in Malignant Glioma

    PubMed Central

    Oh, Taemin; Sayegh, Eli T.; Fakurnejad, Shayan; Oyon, Daniel; Lamano, Jonathan Balquiedra; DiDomenico, Joseph David; Bloch, Orin; Parsa, Andrew T.

    2015-01-01

    Glioblastoma is a grade IV astrocytoma that is widely accepted in clinical neurosurgery as being an extremely lethal diagnosis. Long-term survival rates remain dismal and, even when tumors undergo gross resection with confirmation of total removal on neuroimaging, they invariably recur with even greater virulence. Standard therapeutic modalities as well as more contemporary treatments have largely resulted in disappointing improvements. However, the therapeutic potential of vaccine immunotherapy for malignant glioma should not be underestimated. In contrast to many of the available treatments, vaccine immunotherapy is unique because it offers the means of delivering treatment that is highly specific to both the patient and the tumor. Peptide, heat-shock proteins, and dendritic cell vaccines collectively encapsulate the majority of research efforts involving vaccine-based treatment modalities. In this review, important recent findings for these vaccine types are discussed in the context of ongoing clinical trials. Broad challenges to immunotherapy are also considered. PMID:25431096

  4. Sleeping Beauty Mouse Models Identify Candidate Genes Involved in Gliomagenesis

    PubMed Central

    Vyazunova, Irina; Maklakova, Vilena I.; Berman, Samuel; De, Ishani; Steffen, Megan D.; Hong, Won; Lincoln, Hayley; Morrissy, A. Sorana; Taylor, Michael D.; Akagi, Keiko; Brennan, Cameron W.; Rodriguez, Fausto J.; Collier, Lara S.

    2014-01-01

    Genomic studies of human high-grade gliomas have discovered known and candidate tumor drivers. Studies in both cell culture and mouse models have complemented these approaches and have identified additional genes and processes important for gliomagenesis. Previously, we found that mobilization of Sleeping Beauty transposons in mice ubiquitously throughout the body from the Rosa26 locus led to gliomagenesis with low penetrance. Here we report the characterization of mice in which transposons are mobilized in the Glial Fibrillary Acidic Protein (GFAP) compartment. Glioma formation in these mice did not occur on an otherwise wild-type genetic background, but rare gliomas were observed when mobilization occurred in a p19Arf heterozygous background. Through cloning insertions from additional gliomas generated by transposon mobilization in the Rosa26 compartment, several candidate glioma genes were identified. Comparisons to genetic, epigenetic and mRNA expression data from human gliomas implicates several of these genes as tumor suppressor genes and oncogenes in human glioblastoma. PMID:25423036

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

    NASA Astrophysics Data System (ADS)

    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.

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

    PubMed Central

    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

    2016-01-01

    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. PMID:27625116

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

    PubMed

    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

    2016-01-01

    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. PMID:27625116

  8. Microglial action in glioma: a boon turns bane.

    PubMed

    Ghosh, Anirban; Chaudhuri, Swapna

    2010-06-15

    Microglia has the potential to shape the neuroimmune defense with vast array of functional attributes. The cells prime infiltrated lymphocytes to retain their effector functions, play crucial role in controlling microenvironmental milieu and significantly participate in glioma. Reports demonstrate microglial accumulation in glioma and predict their assistance in glioma growth and spreading. Clarification of the 'double-edged' appearance of microglia is necessary to unfold its role in glioma biology. In this article the interpretation of microglial activities has been attempted to reveal their actual function in glioma. Contrary to the trendy acceptance of its glioma promoting infamy, accumulated evidences make an effort to view the state of affairs in favor of the cell. Critical scrutiny indicates that microglial immune assaults are intended to demolish the neoplastic cells in brain. But the weaponry of microglia has been tactically utilized by glioma in their favor as the survival strategy. Hence the defender appears as enemy in advanced glioma. PMID:20338195

  9. LuIII parvovirus selectively and efficiently targets, replicates in, and kills human glioma cells.

    PubMed

    Paglino, Justin C; Ozduman, Koray; van den Pol, Anthony N

    2012-07-01

    Because productive infection by parvoviruses requires cell division and is enhanced by oncogenic transformation, some parvoviruses may have potential utility in killing cancer cells. To identify the parvovirus(es) with the optimal oncolytic effect against human glioblastomas, we screened 12 parvoviruses at a high multiplicity of infection (MOI). MVMi, MVMc, MVM-G17, tumor virus X (TVX), canine parvovirus (CPV), porcine parvovirus (PPV), rat parvovirus 1A (RPV1A), and H-3 were relatively ineffective. The four viruses with the greatest oncolytic activity, LuIII, H-1, MVMp, and MVM-G52, were tested for the ability, at a low MOI, to progressively infect the culture over time, causing cell death at a rate higher than that of cell proliferation. LuIII alone was effective in all five human glioblastomas tested. H-1 progressively infected only two of five; MVMp and MVM-G52 were ineffective in all five. To investigate the underlying mechanism of LuIII's phenotype, we used recombinant parvoviruses with the LuIII capsid replacing the MVMp capsid or with molecular alteration of the P4 promoter. The LuIII capsid enhanced efficient replication and oncolysis in MO59J gliomas cells; other gliomas tested required the entire LuIII genome to exhibit enhanced infection. LuIII selectively infected glioma cells over normal glial cells in vitro. In mouse models, human glioblastoma xenografts were selectively infected by LuIII when administered intratumorally; LuIII reduced tumor growth by 75%. LuIII also had the capacity to selectively infect subcutaneous or intracranial gliomas after intravenous inoculation. Intravenous or intracranial LuIII caused no adverse effects. Intracranial LuIII caused no infection of mature mouse neurons or glia in vivo but showed a modest infection of developing neurons.

  10. Immunoglobulin genes implicated in glioma risk.

    PubMed

    Pandey, Janardan P; Kaur, Navtej; Costa, Sandra; Amorim, Julia; Nabico, Rui; Linhares, Paulo; Vaz, Rui; Viana-Pereira, Marta; Reis, Rui M

    2014-01-01

    Both genetic and environmental factors are thought to be causal in gliomagenesis. Several genes have been implicated in glioma development, but the putative role of a major immunity-related gene complex member, immunoglobulin heavy chain γ (IGHG) has not been evaluated. Prior observations that IGHG-encoded γ marker (GM) allotypes exhibit differential sensitivity to an immunoevasion strategy of cytomegalovirus, a pathogen implicated as a promoter of gliomagenesis, has lead us to hypothesize that these determinants are risk factors for glioma. To test this hypothesis, we genotyped the IGHG locus comprising the GM alleles, specifically GM alleles 3 and 17, of 120 glioma patients and 133 controls via TaqMan® genotyping assay. To assess the associations between GM genotypes and the risk of glioma, we applied an unconditional multivariate logistic regression analysis adjusted for potential confounding variables. In comparison to subjects who were homozygous for the GM 17 allele, the GM 3 homozygotes were over twice as likely, and the GM 3/17 heterozygotes were over three times as likely, to develop glioma. Similar results were achieved when analyzed by combining the data corresponding to alleles GM 3 and GM 3/17 in a dominant model. The GM 3/17 genotype and the combination of GM 3 and GM 3/17 were found to be further associated with over 3 times increased risk for high-grade astrocytoma (grades III-IV). Allele frequency analyses also showed an increased risk for gliomas and high-grade astrocytoma in association with GM 3. Our findings support the premise that the GM 3 allele may present risk for the development of glioma, possibly by modulating immunity to cytomegalovirus.

  11. Phenotypic Transition as a Survival Strategy of Glioma

    PubMed Central

    ICHIKAWA, Tomotsugu; OTANI, Yoshihiro; KUROZUMI, Kazuhiko; DATE, Isao

    2016-01-01

    Malignant glioma is characterized by rapid proliferation, invasion into surrounding central nervous system tissues, and aberrant vascularization. There is increasing evidence that shows gliomas are more complex than previously thought, as each tumor comprises considerable intratumoral heterogeneity with mixtures of genetically and phenotypically distinct subclones. Heterogeneity within and across tumors is recognized as a critical factor that limits therapeutic progress for malignant glioma. Recent genotyping and expression profiling of gliomas has allowed for the creation of classification schemes that assign tumors to subtypes based on similarity to defined expression signatures. Also, malignant gliomas frequently shift their biological features upon recurrence and progression. The ability of glioma cells to resist adverse conditions such as hypoxia and metabolic stress is necessary for sustained tumor growth and strongly influences tumor behaviors. In general, glioma cells are in one of two phenotypic categories: higher proliferative activity with angiogenesis, or higher migratory activity with attenuated proliferative ability. Further, they switch phenotypic categories depending on the situation. To date, a multidimensional approach has been employed to clarify the mechanisms of phenotypic shift of glioma. Various molecular and signaling pathways are involved in phenotypic shifts of glioma, possibly with crosstalk between them. In this review, we discuss molecular and phenotypic heterogeneity of glioma cells and mechanisms of phenotypic shifts in regard to the glioma proliferation, angiogenesis, and invasion. A better understanding of the molecular mechanisms that underlie phenotypic shifts of glioma may provide new insights into targeted therapeutic strategies. PMID:27169497

  12. Glioma-Associated Oncogene Homolog1 (Gli1)-Aquaporin1 pathway promotes glioma cell metastasis

    PubMed Central

    Liao, Zheng-qiang; Ye, Ming; Yu, Pei-gen; Xiao, Chun; Lin, Feng-yun

    2016-01-01

    Glioma-Associated Oncogene Homolog1 (Gli1) is known to be activated in malignant glioma; however, its downstream pathway has not been fully explained. The aim of this study was to explore the role of Gli1-Aquaporin1 (AQP1) signal pathway in glioma cell survival. Our data suggests that both Gli1 and AQP1 are upregulated in glioma tissues, as in comparison to in normal tissues. These up-regulation phenomena were also observed in glioma U251 and U87 cells. It was demonstrated that Gli1 positively regulated the AQP1 expression. By luciferase reporter gene and ChIP assay, we observed that this modulation process was realized by combination of Gli1 with AQP1 promotor. In addition, knock down of Gli1 by siRNA interference reduced the viability of glioma cells as well as suppressed cell metastasis. Also, the inhibitory effects of cell survival by silenced Gli1 were abrogated by AQP1 overexpression. In summary, glioma cell survival is a regulatory process and can be mediated by Gli1-AQP1 pathway. [BMB Reports 2016; 49(7): 394-399] PMID:27157540

  13. [Chemotherapy of chiasmal gliomas in children].

    PubMed

    Helcl, F

    1995-04-01

    Chiasmal gliomas are rare tumors occurring predominantly in childhood. Their optimal treatment is still controversial. In the past only neurosurgeons (performing partial or subtotal removal of the tumor, biopsy or shunting procedure in hydrocephalus) and radiotherapeutists participated in their treatment. In the middle of the eighties there was only a single article dealing with chemotherapy of these tumors (Rosenstock, 1985). Since that time there was an increased number of articles about harmful effects of radiotherapy on the developing child's brain. Neurosurgeons are aware that they will not solve this problem alone. During the past 7 years we have observed gradual retreat from radiotherapy and an inclination to combined chemotherapy of the chiasmal gliomas in children. The author has been engaged in the research of this clinical entity for more than 10 years and he offers to readers a summary of the contemporary knowledge about chemotherapy of chiasmal gliomas in children. Despite the fact that there is lacking experience with long-term survivors after chemotherapy, which is extremely important especially in this disease, the preliminary short-term results of combined chemotherapy of chiasmal gliomas in children are promising. Rapid development of chemistry and pharmacology in the last few years is promising for the discovery of further, more effective anti-tumor drugs. Their new combinations could improve present non-satisfactory results of treatment of chiasmal gliomas in children. (Ref. 25.)

  14. Management of Elderly Patients With Gliomas

    PubMed Central

    Gállego Pérez-Larraya, Jaime

    2014-01-01

    The current progressive aging of the population is resulting in a continuous increase in the incidence of gliomas in elderly people, especially the most frequent subtype, glioblastoma (GBM). This sociohealth shift, known as the “silver tsunami,” has prompted the neuro-oncology community to investigate the role of specific antitumor treatments, such as surgery, radiotherapy, chemotherapy, and other targeted therapies, for these traditionally undertreated patients. Advanced age, a widely recognized poor prognostic factor in both low-grade glioma (LGG) and high-grade glioma patients, should no longer be the sole reason for excluding such older patients from receiving etiologic treatments. Far from it, results from recent prospective trials conducted on elderly patients with GBM demonstrate that active management of these patients can have a positive impact on survival without impairing either cognition or quality of life. Although prospective studies specifically addressing the management of grade 2 and 3 gliomas are lacking and thus needed, the aforementioned tendency toward acknowledging a therapeutic benefit for GBM patients might also apply to the treatment of patients with LGG and anaplastic gliomas. In order to optimize such etiologic treatment in conjunction with symptomatic management, neuro-oncology multidisciplinary boards must individually consider important features such as resectability of the tumor, functional and cognitive status, associated comorbidities, and social support. PMID:25342314

  15. Genetic characterization of adult infratentorial gliomas.

    PubMed

    Miwa, Tomoru; Hirose, Yuichi; Sasaki, Hikaru; Ikeda, Eiji; Yoshida, Kazunari; Kawase, Takeshi

    2009-02-01

    Adult infratentorial gliomas are rare and have not been well studied. We therefore conducted genetic analysis of those tumors to see if there was any characteristic that could be relevant in clinical management and understanding of tumorigenesis. Nineteen adult infratentorial gliomas were analyzed for chromosomal aberration by comparative genomic hybridization, and for expression of p53 and epidermal growth factor receptor (EGFR) by immunohistochemistry. The most frequent chromosomal aberration was the gain of 7p, and five of the seven cerebellar or fourth ventricle malignant gliomas had that aberration. However, the gain of 7q, the characteristic abnormality of supratentorial astrocytomas commonly associated with the gaining of 7p, was observed only in 1 of 11 adult infratentorial astrocytic tumors. Combined losses of 1p and 19q, the genetic hallmark of oligodendroglioma, were not observed. Results of immunohistochemistry of p53 and EGFR were comparable to those reported in supratentorial gliomas. Our findings might suggest the presence of distinct tumorigenic pathway in adult infratentorial gliomas.

  16. Dendritic Cell Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma

    PubMed Central

    Dey, Mahua; Chang, Alan L.; Miska, Jason; Wainwright, Derek A.; Ahmed, Atique U.; Balyasnikova, Irina V.; Pytel, Peter; Han, Yu; Tobias, Alex; Zhang, Lingjiao; Qiao, Jian; Lesniak, Maciej S.

    2015-01-01

    Dendritic cells (DC) are professional antigen presenting cells (APC) that are traditionally divided into two distinct subsets: myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amount of IFN-α. Apart from IFN-α production, pDCs can also process antigen and induce T-cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T-cells (Treg) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective anti-glioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naïve mice can be effectively activated and loaded with SIINFEKL antigen in vitro. Upon intra-dermal injection in the hind leg, a fraction of both types of DCs migrate to the brain and lymph nodes.. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generated a robust Th1 type immune response, characterized by high frequency of CD4+Tbet+ T-cells and CD8+Siinfekel+ T-cells. This robust anti-tumor T-cell response resulted in tumor eradication and long-term survival in 60% of the animals (p<0.001). PMID:26026061

  17. Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.

    PubMed

    Misuraca, Katherine L; Barton, Kelly L; Chung, Alexander; Diaz, Alexander K; Conway, Simon J; Corcoran, David L; Baker, Suzanne J; Becher, Oren J

    2014-01-01

    High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis. PMID:25330836

  18. Bionanotechnology and the Future of Glioma

    PubMed Central

    Chiarelli, Peter A.; Kievit, Forrest M.; Zhang, Miqin; Ellenbogen, Richard G.

    2015-01-01

    Designer nanoscaled materials have the potential to revolutionize diagnosis and treatment for glioma. This review summarizes current progress in nanoparticle-based therapies for glioma treatment including targeting, drug delivery, gene delivery, and direct tumor ablation. Preclinical and current human clinical trials are discussed. Although progress in the field has been significant over the past decade, many successful strategies demonstrated in the laboratory have yet to be implemented in human clinical trials. Looking forward, we provide examples of combined treatment strategies, which harness the potential for nanoparticles to interact with their biochemical environment, and simultaneously with externally applied photons or magnetic fields. We present our notion of the “ideal” nanoparticle for glioma, a concept that may soon be realized. PMID:25722933

  19. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas.

    PubMed

    Paugh, Barbara S; Zhu, Xiaoyan; Qu, Chunxu; Endersby, Raelene; Diaz, Alexander K; Zhang, Junyuan; Bax, Dorine A; Carvalho, Diana; Reis, Rui M; Onar-Thomas, Arzu; Broniscer, Alberto; Wetmore, Cynthia; Zhang, Jinghui; Jones, Chris; Ellison, David W; Baker, Suzanne J

    2013-10-15

    The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic-activating mutations were identified in 14.4% (13 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures of these murine HGGs reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG. PMID:23970477

  20. Glial Progenitors as Targets for Transformation in Glioma

    PubMed Central

    Ilkanizadeh, Shirin; Lau, Jasmine; Huang, Miller; Foster, Daniel J.; Wong, Robyn; Frantz, Aaron; Wang, Susan; Weiss, William A.; Persson, Anders I.

    2014-01-01

    Glioma is the most common primary malignant brain tumor and arises throughout the central nervous system (CNS). Recent focus on stem-like glioma cells has implicated neural stem cells (NSCs), a minor precursor population restricted to germinal zones, as a potential source of gliomas. In this review, we will focus on the relationship between oligodendrocyte progenitor cells (OPCs), the largest population of cycling glial progenitors in the postnatal brain, and gliomas. Recent studies suggest that OPCs can give rise to gliomas. Furthermore, signaling pathways often associated with NSCs also play key roles during OPC lineage development. Recent advances suggesting that gliomas can undergo a switch from progenitor- to stem-like phenotype after therapy, implicating that an OPC-origin is more likely than previously recognized. Future in-depth studies of OPC biology may shed light on the etiology of OPC-derived gliomas and reveal new therapeutic avenues. PMID:24889528

  1. [Surgical treatment of chiasmal gliomas in children].

    PubMed

    Helcl, F

    1997-03-01

    Chiasmal gliomas are rare brain tumors occurring especially in children. Their proper treatment is still controversial and consists of surgery, radiotherapy and chemotherapy. Surgical removal of these tumors can usually be only partial or subtotal and radiotherapy frequently follows. There are supporters of surgical approach, as well as its enemies. The author has been engaged in problems of optimal treatment of this entity for more than 10 years. He is offering a review of knowledge from the literature concerning surgical treatment of this disease in children. The great majority of articles in the literature are dealing with retrospective analysis of relatively small series of patients usually treated in single neurosurgical department and the surgical treatment is enclosed like a part of combined therapy. Articles dealing only with surgical treatment of chiasmal gliomas are few and reviews determining the contemporary role of surgery of this entity are also lacking. This was the main impulse for writing this compilation. The short history of surgical therapy is reviewed. Some new trends of this therapy are also mentioned (microsurgery, Cavitron Ultrasonic Surgical Aspirator and peroperative use of visual evoked potentials). Up to date criteria for surgical treatment of chiasmal gliomas in children are given-exploration of chiasmal region and performing a biopsy in all cases, radical surgery only in extrinsic gliomas of the chiasmal region and conservative surgical approach to intrinsic chiasmal gliomas. It is emphasized that the significance of obstructive hydrocephalus in this entity has not been fully estimated till now, as well as the role of shunting procedures. Surgical treatment remains, nevertheless, an important armamentarium in the management of chiasmal gliomas in children. (Ref. 20.)

  2. Radical resection for the treatment of glioma.

    PubMed

    Laws, E R

    1995-01-01

    The surgical management of gliomas of the brain continues to be an area for investigation and of some controversy. Many of the questions can be answered by careful clinical investigation, using modern techniques of epidemiology and carefully controlled prospective studies. Until these studies are available, a strong case can be made for the treatment of many gliomas of the brain with radical surgical resection. In some cases this strategy can provide cures or long-term remissions, and in others it can provide disease control when combined with adjunctive measures, such as radiation therapy.

  3. Using bioluminescence imaging in glioma research.

    PubMed

    Luwor, Rodney B; Stylli, Stanley S; Kaye, Andrew H

    2015-05-01

    Glioblastoma multiforme (GBM) is the most common malignant brain tumour and has the worst prognosis. Over the last decade, the use of bioluminescence imaging technology has rapidly become widespread to further understand the mechanisms that drive GBM development and progression. Pre-clinical evaluation and optimisation of therapeutic efficacy in GBM research has also utilised this simple non-invasive technology. Here we summarise recent advances made in glioma biology and therapeutic intervention using bioluminescence imaging. This review also describes the current knowledge regarding the use of luciferase-based reporters in examining the role of specific cancer signalling cascades that promote glioma progression.

  4. [Guidelines for the radiotherapy of gliomas].

    PubMed

    Feuvret, L; Antoni, D; Biau, J; Truc, G; Noël, G; Mazeron, J-J

    2016-09-01

    Gliomas are the most frequent primary brain tumours. Treating these tumours is difficult because of the proximity of organs at risk, infiltrating nature, and radioresistance. Clinical prognostic factors such as age, Karnofsky performance status, tumour location, and treatments such as surgery, radiation therapy, and chemotherapy have long been recognized in the management of patients with gliomas. Molecular biomarkers are increasingly evolving as additional factors that facilitate diagnosis and therapeutic decision-making. These practice guidelines aim at helping in choosing the best treatment, in particular radiation therapy.

  5. In vivo MRI detection of gliomas by chlorotoxin-conjugated superparamagnetic nanoprobes.

    PubMed

    Sun, Conroy; Veiseh, Omid; Gunn, Jonathan; Fang, Chen; Hansen, Stacey; Lee, Donghoon; Sze, Raymond; Ellenbogen, Richard G; Olson, Jim; Zhang, Miqin

    2008-03-01

    Converging advances in the development of nanoparticle-based imaging probes and improved understanding of the molecular biology of brain tumors offer the potential to provide physicians with new tools for the diagnosis and treatment of these deadly diseases. However, the effectiveness of promising nanoparticle technologies is currently limited by insufficient accumulation of these contrast agents within tumors. Here a biocompatible nanoprobe composed of a poly(ethylene glycol) (PEG) coated iron oxide nanoparticle that is capable of specifically targeting glioma tumors via the surface-bound targeting peptide, chlorotoxin (CTX), is presented. The preferential accumulation of the nanoprobe within gliomas and subsequent magnetic resonance imaging (MRI) contrast enhancement are demonstrated in vitro in 9L cells and in vivo in tumors of a xenograft mouse model. TEM imaging reveals that the nanoprobes are internalized into the cytoplasm of 9L cells and histological analysis of selected tissues indicates that there are no acute toxic effects of these nanoprobes. High targeting specificity and benign biological response establish this nanoprobe as a potential platform to aid in the diagnosis and treatment of gliomas and other tumors of neuroectodermal origin.

  6. Revealing the potential pathogenesis of glioma by utilizing a glioma associated protein-protein interaction network.

    PubMed

    Pan, Weiran; Li, Gang; Yang, Xiaoxiao; Miao, Jinming

    2015-04-01

    This study aims to explore the potential mechanism of glioma through bioinformatic approaches. The gene expression profile (GSE4290) of glioma tumor and non-tumor samples was downloaded from Gene Expression Omnibus database. A total of 180 samples were available, including 23 non-tumor and 157 tumor samples. Then the raw data were preprocessed using robust multiarray analysis, and 8,890 differentially expressed genes (DEGs) were identified by using t-test (false discovery rate < 0.0005). Furthermore, 16 known glioma related genes were abstracted from Genetic Association Database. After mapping 8,890 DEGs and 16 known glioma related genes to Human Protein Reference Database, a glioma associated protein-protein interaction network (GAPN) was constructed. In addition, 51 sub-networks in GAPN were screened out through Molecular Complex Detection (score ≥ 1), and sub-network 1 was found to have the closest interaction (score = 3). What' more, for the top 10 sub-networks, Gene Ontology (GO) enrichment analysis (p value < 0.05) was performed, and DEGs involved in sub-network 1 and 2, such as BRMS1L and CCNA1, were predicted to regulate cell growth, cell cycle, and DNA replication via interacting with known glioma related genes. Finally, the overlaps of DEGs and human essential, housekeeping, tissue-specific genes were calculated (p value = 1.0, 1.0, and 0.00014, respectively) and visualized by Venn Diagram package in R. About 61% of human tissue-specific genes were DEGs as well. This research shed new light on the pathogenesis of glioma based on DEGs and GAPN, and our findings might provide potential targets for clinical glioma treatment.

  7. Lymphoid Cell-Glioma Cell Interaction Enhances Cell Coat Production by Human Gliomas: Novel Suppressor Mechanism

    NASA Astrophysics Data System (ADS)

    Dick, Steven J.; Macchi, Beatrice; Papazoglou, Savvas; Oldfield, Edward H.; Kornblith, Paul L.; Smith, Barry H.; Gately, Maurice K.

    1983-05-01

    Certain human glioma lines produce mucopolysaccharide coats that impair the generation of cytolytic lymphocytes in response to these lines in vitro. Coat production is substantially enhanced by the interaction of glioma cells with a macromolecular factor released by human peripheral blood mononuclear cells in culture. This interaction thus constitutes an unusual mechanism by which inflammatory cells may nonspecifically suppress the cellular immune response to at least one class of solid tumors in humans.

  8. [Classification of nucleotide sequences over their frequency dictionaries reveals a relation between the structure of sequences and taxonomy of their bearers].

    PubMed

    Gorban', A N; Popova, T G; Sadovskiĭ, M G

    2003-01-01

    Classification of 16S RNA sequences over their frequency dictionaries, both real ones, and transformed ones was studied. Two entities were considered to be close each other from the point of view of their structure, if their frequency dictionaries were close, in Eucledian metric. A transformation procedure of a frequency dictionary has been implemented that reveals the peculiarities of information structure of a nucleotide sequence. A comparative study of two classification developed over the real frequency dictionary vs. that one developed over the transformed frequency dictionary was carried out. The strong correlation is revealed between the classification and the taxonomy of 16S RNA bearer. For the classes isolated, the information valuable words were identified. These words are the main factors of a difference between the classes. The frequency dictionaries containing the words of the length 3 exhibit the best correlation between a class and a genus. A genus, as a rule, is included into the same class, and the exclusion are sporadic. A development of hierarchy classification over the transformed frequency dictionaries separated one or two taxonomy groups, as each stage of classification. The unexpectedly frequent, or contrary, unexpectedly rare occurred of words (of the length 3) in entities under consideration make the structure difference between the classes of the nucleotide sequences.

  9. Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

    PubMed Central

    Reis, Marco; Czupalla, Cathrin J.; Ziegler, Nicole; Devraj, Kavi; Zinke, Jenny; Seidel, Sascha; Heck, Rosario; Thom, Sonja; Macas, Jadranka; Bockamp, Ernesto; Fruttiger, Marcus; Taketo, Makoto M.; Dimmeler, Stefanie; Plate, Karl H.

    2012-01-01

    Endothelial Wnt/β-catenin signaling is necessary for angiogenesis of the central nervous system and blood–brain barrier (BBB) differentiation, but its relevance for glioma vascularization is unknown. In this study, we show that doxycycline-dependent Wnt1 expression in subcutaneous and intracranial mouse glioma models induced endothelial Wnt/β-catenin signaling and led to diminished tumor growth, reduced vascular density, and normalized vessels with increased mural cell attachment. These findings were corroborated in GL261 glioma cells intracranially transplanted in mice expressing dominant-active β-catenin specifically in the endothelium. Enforced endothelial β-catenin signaling restored BBB characteristics, whereas inhibition by Dkk1 (Dickkopf-1) had opposing effects. By overactivating the Wnt pathway, we induced the Wnt/β-catenin–Dll4/Notch signaling cascade in tumor endothelia, blocking an angiogenic and favoring a quiescent vascular phenotype, indicated by induction of stalk cell genes. We show that β-catenin transcriptional activity directly regulated endothelial expression of platelet-derived growth factor B (PDGF-B), leading to mural cell recruitment thereby contributing to vascular quiescence and barrier function. We propose that reinforced Wnt/β-catenin signaling leads to inhibition of angiogenesis with normalized and less permeable vessels, which might prove to be a valuable therapeutic target for antiangiogenic and edema glioma therapy. PMID:22908324

  10. Photodynamic therapy of supratentorial gliomas

    NASA Astrophysics Data System (ADS)

    Muller, Paul J.; Wilson, Brian C.

    1997-05-01

    We are reporting the results form intraoperative intracavitary PDT treatment in 56 patients with recurrent supratentorial gliomas who had failed previous surgery and radiotherapy. These patients received 2mg/kg Photofin iv. 12-36 hours prior to surgical resection of their tumor or tumor cyst drainage. The median survival times in weeks for glioblastoma (GBM), malignant astrocytoma (MA), malignant mixed astrocytoma-oligodendroglioma and ependymoma were 30, 40, >56 and >174 weeks, respectively. Eight patients with recurrent GBM who received >60 J/cm2 had a median survival of 58 weeks and 24 patients who received <60 J/cm2 survived 29 weeks. The survival of patients with recurrent glioblastoma who undergo surgical treatment alone is only 20 weeks. We are also reporting the results of PDT treatment in 20 patients with newly diagnosed MA or GBM treated with intracavitary Photofin-PDT at the time of their initial craniotomy. The median survival of the whole cohort was 44 weeks with a 1 and 2 year survival of 40 percent and 15 percent, respectively. The median survival of patients with GBM was 37 weeks with a 1 and 2 year actuarial survival of 35 percent and 0 percent, respectively. The median survival of patients with MA as 48 weeks with a 1 and 2 year actuarial survival of 44 percent and 33 percent, respectively. Six patients with a Karnofsky score of >70 who received a light dose of >1260J had a median survival of 92 weeks with a 1 and 2 year survival of 83 percent and 33 percent, respectively. The mortality rate in our total series of 93 PDT treatments or brain tumor is 3 percent. The combined serious mortality-morbidity rate is 8 percent.

  11. Enhancement of Glioma Radiotherapy and Chemotherapy Response With Targeted Antibody Therapy Against Death Receptor 5

    SciTech Connect

    Fiveash, John B. Gillespie, G. Yancey; Oliver, Patsy G.; Zhou Tong; Belenky, Michael L.; Buchsbaum, Donald J.

    2008-06-01

    Purpose: TRA-8 is an agonistic mouse monoclonal antibody that binds to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5, which induces apoptosis in cancer cells through a caspase-8-dependent mechanism. We investigated the ability of TRA-8 to augment the radiotherapy (RT) and chemotherapy response of human glioma cells in vitro and in vivo. Methods and Materials: The in vitro cytotoxicity of TRA-8 and temozolomide (Tmz) or RT was examined using adenosine triphosphate-dependent viability and clonogenic survival assays with five glioma cell lines. Death receptor 5 expression was determined by flow cytometry. In vivo studies included subcutaneous and intracranial xenograft models testing various combination treatments, including RT, Tmz, and TRA-8. Results: TRA-8, combined with Tmz or RT, produced enhanced cytotoxicity against five glioma cell lines compared with the use of the individual agents alone. Death receptor 5 upregulation occurred in response to RT. Complete tumor regression in the subcutaneous experiments was the most common in animals that received combination therapy with TRA-8/Tmz/RT. TRA-8 enhanced tumor growth delay in combination with RT or Tmz. TRA-8 alone had limited activity against intracranial tumors. In contrast, the median survival of mice treated with TRA-8/Tmz/RT was significantly greater than the control or TRA-8-alone-treated mice. The median survival of the mice treated with TRA-8/Tmz/RT or chemoradiotherapy only was significantly greater than the control or TRA-8-treated mice. A trend toward improved survival was observed between TRA-8/Tmz/RT-treated and Tmz/RT-treated mice. Conclusions: These preliminary findings support the hypothesis that TRA-8 will augment the RT and chemotherapy response in gliomas. A humanized version of TRA-8 is being evaluated in a Phase II clinical trial.

  12. IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas

    PubMed Central

    Moore, Lynette M.; Holmes, Kristen M.; Smith, Sarah M.; Wu, Ying; Tchougounova, Elena; Uhrbom, Lene; Sawaya, Raymond; Bruner, Janet M.; Fuller, Gregory N.; Zhang, Wei

    2009-01-01

    The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-β (PDGFB). Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16INK4a and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16INK4a is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas. PMID:19805356

  13. Robotics in the neurosurgical treatment of glioma

    PubMed Central

    Sutherland, Garnette R.; Maddahi, Yaser; Gan, Liu Shi; Lama, Sanju; Zareinia, Kourosh

    2015-01-01

    Background: The treatment of glioma remains a significant challenge with high recurrence rates, morbidity, and mortality. Merging image guided robotic technology with microsurgery adds a new dimension as they relate to surgical ergonomics, patient safety, precision, and accuracy. Methods: An image-guided robot, called neuroArm, has been integrated into the neurosurgical operating room, and used to augment the surgical treatment of glioma in 18 patients. A case study illustrates the specialized technical features of a teleoperated robotic system that could well enhance the performance of surgery. Furthermore, unique positional and force information of the bipolar forceps during surgery were recorded and analyzed. Results: The workspace of the bipolar forceps in this robot-assisted glioma resection was found to be 25 × 50 × 50 mm. Maximum values of the force components were 1.37, 1.84, and 2.01 N along x, y, and z axes, respectively. The maximum total force was 2.45 N. The results indicate that the majority of the applied forces were less than 0.6 N. Conclusion: Robotic surgical systems can potentially increase safety and performance of surgical operation via novel features such as virtual fixtures, augmented force feedback, and haptic high-force warning system. The case study using neuroArm robot to resect a glioma, for the first time, showed the positional information of surgeon's hand movement and tool-tissue interaction forces. PMID:25722932

  14. Glioma virus therapies between bench and bedside.

    PubMed

    Kaufmann, Johanna K; Chiocca, E Antonio

    2014-03-01

    Despite extensive research, current glioma therapies are still unsatisfactory, and novel approaches are pressingly needed. In recent years, both nonreplicative viral vectors and replicating oncolytic viruses have been developed for brain cancer treatment, and the mechanistic background of their cytotoxicity has been unveiled. A growing number of clinical trials have convincingly established viral therapies to be safe in glioma patients, and maximum tolerated doses have generally not been reached. However, evidence for therapeutic benefit has been limited: new generations of therapeutic vectors need to be developed in order to target not only tumor cells but also the complex surrounding microenvironment. Such therapies could also direct long-lasting immune responses toward the tumor while reducing early antiviral reactions. Furthermore, viral delivery methods are to be improved and viral spread within the tumor will have to be enhanced. Here, we will review the outcome of completed glioma virus therapy trials as well as highlight the ongoing clinical activities. On this basis, we will give an overview of the numerous strategies to enhance therapeutic efficacy of new-generation viruses and novel treatment regimens. Finally, we will conclude with approaches that may be crucial to the development of successful glioma therapies in the future. PMID:24470549

  15. Economics of Malignant Gliomas: A Critical Review

    PubMed Central

    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

    Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. PMID:25466707

  16. A dual functional fluorescent probe for glioma imaging mediated by blood-brain barrier penetration and glioma cell targeting.

    PubMed

    Ma, Hongwei; Gao, Zhiyong; Yu, Panfeng; Shen, Shun; Liu, Yongmei; Xu, Bainan

    2014-06-20

    Glioma is a huge threat for human being because it was hard to be completely removed owing to both the infiltrating growth of glioma cells and integrity of blood brain barrier. Thus effectively imaging the glioma cells may pave a way for surgical removing of glioma. In this study, a fluorescent probe, Cy3, was anchored onto the terminal of AS1411, a glioma cell targeting aptamer, and then TGN, a BBB targeting peptide, was conjugated with Cy3-AS1411 through a PEG linker. The production, named AsT, was characterized by gel electrophoresis, (1)H NMR and FTIR. In vitro cellular uptake and glioma spheroid uptake demonstrated the AsT could not only be uptaken by both glioma and endothelial cells, but also penetrate through endothelial cell monolayer and uptake by glioma spheroids. In vivo, AsT could effectively target to glioma with high intensity. In conclusion, AsT could be used as an effective glioma imaging probe. PMID:24802402

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

    SciTech Connect

    Dai, Bin; Hu, Zhiqiang; Huang, Hui; Zhu, Guangtong; Xiao, Zhiyong; Wan, Weiqing; Zhang, Peng; Jia, Wang; Zhang, Liwei

    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.

  18. Expression and clinical significance of microRNA-326 in human glioma miR-326 expression in glioma.

    PubMed

    Wang, Shuai; Lu, Shengkui; Geng, Shaomei; Ma, Shucheng; Liang, Zhaohui; Jiao, Baohua

    2013-03-01

    As a suppressor of Hedgehog signaling pathway, microRNA-326 (miR-326) has been demonstrated to control the development of cerebellar neuronal progenitor and tumor cells. More recently, it has been reported that miR-326 was down-regulated in glioblastoma tissues and might regulate the metabolic activity of glioma and glioma stem cells, suggesting the involvement of miR-326 in tumorigenesis and progression of gliomas. However, the role of miR-326 in human glioma has not been clearly understood. Therefore, the aim of this study was to investigate the clinical significance of miR-326 expression in human glioma. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis was used to characterize the expression patterns of miR-326 in 108 glioma and 20 normal brain tissues. The associations of miR-326 expression with clinicopathological factors and prognosis of glioma patients were also statistically analyzed. The expression levels of miR-326 in glioma tissues were significantly lower than those in normal brain tissues (P < 0.001). Additionally, the decreased miR-326 expression in glioma was significantly associated with advanced pathological grade (P = 0.01) and low Karnofsky performance score (KPS, P = 0.03). Moreover, Kaplan-Meier survival and Cox regression analyses showed that low expression of miR-326 (P = 0.01) and advanced pathological grade (P = 0.02) were independent factors predicting poor prognosis for gliomas. Furthermore, subgroup analyses showed that miR-326 expression was significantly associated with poor overall survival in glioma patients with high pathological grades (for grade III-IV: P < 0.001). Down-regulation of miR-326 may have potential value for predicting clinical outcomes in glioma patients with high pathological grades, suggesting that miR-326 is an important candidate tumor suppressor, and its down-regulated expression may contribute to glioma progression.

  19. Selective migration of neuralized embryonic stem cells to stem cell factor and media conditioned by glioma cell lines

    PubMed Central

    Serfozo, Peter; Schlarman, Maggie S; Pierret, Chris; Maria, Bernard L; Kirk, Mark D

    2006-01-01

    Background Pluripotent mouse embryonic stem (ES) cells can be induced in vitro to become neural progenitors. Upon transplantation, neural progenitors migrate toward areas of damage and inflammation in the CNS. We tested whether undifferentiated and neuralized mouse ES cells migrate toward media conditioned by glioma cell lines (C6, U87 & N1321) or Stem Cell Factor (SCF). Results Cell migration assays revealed selective migration by neuralized ES cells to conditioned media as well as to synthetic SCF. Migration of undifferentiated ES cells was extensive, but not significantly different from that of controls (Unconditioned Medium). RT-PCR analysis revealed that all the three tumor cell lines tested synthesized SCF and that both undifferentiated and neuralized ES cells expressed c-kit, the receptor for SCF. Conclusion Our results demonstrate that undifferentiated ES cells are highly mobile and that neural progenitors derived from ES cells are selectively attracted toward factors produced by gliomas. Given that the glioma cell lines synthesize SCF, SCF may be one of several factors that contribute to the selective migration observed. PMID:16436212

  20. Veliparib, Radiation Therapy, and Temozolomide in Treating Younger Patients With Newly Diagnosed Diffuse Pontine Gliomas

    ClinicalTrials.gov

    2016-10-05

    Childhood Mixed Glioma; Untreated Childhood Anaplastic Astrocytoma; Untreated Childhood Brain Stem Glioma; Untreated Childhood Fibrillary Astrocytoma; Untreated Childhood Giant Cell Glioblastoma; Untreated Childhood Glioblastoma; Untreated Childhood Gliosarcoma

  1. Slit2/Robo1 signaling in glioma migration and invasion.

    PubMed

    Xu, Yun; Li, Wen-Liang; Fu, Li; Gu, Feng; Ma, Yong-Jie

    2010-12-01

    Slit2/Robo1 is a conserved ligand-receptor system, which greatly affects the distribution, migration, axon guidance and branching of neuron cells. Slit2 and its transmembrane receptor Robo1 have different distribution patterns in gliomas. The expression of Slit2 is at very low levels in pilocytic astrocytoma, fibrillary astrocytoma and glioblastoma, while Robo1 is highly expressed in different grades of gliomas at both mRNA and protein levels. Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Although the specific mechanisms of tumor-suppressive effect of Slit2/Robo1 have not been elucidated, it has been proved that Slit2/Robo1 signaling inhibits glioma cell migration and invasion by inactivation of Cdc42-GTP. With the research development on the molecular mechanisms of Slit2/Robo1 signaling in glioma invasion and migration, Slit2/Robo1 signaling may become a potential target for glioma prevention and treatment.

  2. Terahertz reflectometry imaging for low and high grade gliomas

    PubMed Central

    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

  3. A mathematical model of pre-diagnostic glioma growth

    PubMed Central

    Sturrock, Marc; Hao, Wenrui; Schwartzbaum, Judith; Rempala, Grzegorz A.

    2015-01-01

    Due to their location, the malignant gliomas of the brain in humans are very difficult to treat in advanced stages. Blood-based biomarkers for glioma are needed for more accurate evaluation of treatment response as well as early diagnosis. However, biomarker research in primary brain tumors is challenging given their relative rarity and genetic diversity. It is further complicated by variations in the permeability of the blood brain barrier that affects the amount of marker released into the bloodstream. Inspired by recent temporal data indicating a possible decrease in serum glucose levels in patients with gliomas yet to be diagnosed, we present an ordinary differential equation model to capture early stage glioma growth. The model contains glioma-glucose-immune interactions and poses a potential mechanism by which this glucose drop can be explained. We present numerical simulations, parameter sensitivity analysis, linear stability analysis and a numerical experiment whereby we show how a dormant glioma can become malignant. PMID:26073722

  4. BMPs as Therapeutic Targets and Biomarkers in Astrocytic Glioma

    PubMed Central

    González-Gómez, Pilar; Anselmo, Nilson Praia; Mira, Helena

    2014-01-01

    Astrocytic glioma is the most common brain tumor. The glioma initiating cell (GIC) fraction of the tumor is considered as highly chemoresistant, suggesting that GICs are responsible for glioma relapse. A potential treatment for glioma is to induce differentiation of GICs to a more benign and/or druggable cell type. Given BMPs are among the most potent inducers of GIC differentiation, they have been considered as noncytotoxic therapeutic compounds that may be of use to prevent growth and recurrence of glioma. We herein summarize advances made in the understanding of the role of BMP signaling in astrocytic glioma, with a particular emphasis on the effects exerted on GICs. We discuss the prognostic value of BMP signaling components and the implications of BMPs in the differentiation of GICs and in their sensitization to alkylating drugs and oncolytic therapy/chemotherapy. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer. PMID:24877113

  5. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.

    PubMed

    Feng, Jie; Hao, Shuyu; Pan, Changcun; Wang, Yu; Wu, Zhen; Zhang, Junting; Yan, Hai; Zhang, Liwei; Wan, Hong

    2015-11-01

    Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets.

  6. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults.

    PubMed

    Feng, Jie; Hao, Shuyu; Pan, Changcun; Wang, Yu; Wu, Zhen; Zhang, Junting; Yan, Hai; Zhang, Liwei; Wan, Hong

    2015-11-01

    Brainstem and thalamic gliomas are rare, and they are poorly understood in adults. Genetic aberrations that occur in these tumors are still unknown. In this study, we investigated whether thalamic gliomas have different genetic aberrations and clinical outcomes compared with brainstem gliomas in adults. Forty-three glioma samples were selected, including 28 brainstem and 15 thalamic gliomas. The frequency of the K27M mutation in adult midline gliomas was 58.1%. High-grade gliomas in the thalamus were statistically significantly more numerous than brainstem gliomas. Patients with K27M mutant brainstem gliomas had a significantly shorter overall survival than patients with wild-type tumors (P = .020) by Cox regression after adjustment for other independent risk factors. However, there was no statistical tendency toward a poorer overall survival in thalamic gliomas containing the K27M mutation compared with wild-type tumors. The presence of the K27M mutation significantly corresponded with mutations in TP53 in thalamic gliomas. Interestingly, the K27M mutation was mutually exclusive with mutations in IDH1, which was detected only in brainstem gliomas. The microarray data identified 86 differentially expressed genes between brainstem and thalamic gliomas with the K27M mutation. The cyclin-dependent kinase 6 (CDK6) gene, which plays an important role in cancer pathways, was found to be differentially expressed between brainstem and thalamic gliomas with K27M mutations. Although the K27M mutation was frequently observed in adult brainstem and thalamic gliomas, this mutation tended to be associated with a poorer prognosis in brainstem gliomas but not in thalamic gliomas. Brainstem gliomas may present different genetic aberrations from thalamic gliomas. These differences may provide guidance for therapeutic decisions for the treatment of adult brainstem and thalamic gliomas, which may have different molecular targets. PMID:26297251

  7. Functional analysis of a novel glioma antigen, EFTUD1

    PubMed Central

    Saito, Katsuya; Iizuka, Yukihiko; Ohta, Shigeki; Takahashi, Satoshi; Nakamura, Kenta; Saya, Hideyuki; Yoshida, Kazunari; Kawakami, Yutaka; Toda, Masahiro

    2014-01-01

    Background A cDNA library made from 2 glioma cell lines, U87MG and T98G, was screened by serological identification of antigens by recombinant cDNA expression (SEREX) using serum from a glioblastoma patient. Elongation factor Tu GTP binding domain containing protein 1 (EFTUD1), which is required for ribosome biogenesis, was identified. A cancer microarray database showed overexpression of EFTUD1 in gliomas, suggesting that EFTUD1 is a candidate molecular target for gliomas. Methods EFTUD1 expression in glioma cell lines and glioma tissue was assessed by Western blot, quantitative PCR, and immunohistochemistry. The effect on ribosome biogenesis, cell growth, cell cycle, and induction of apoptosis and autophagy in glioma cells during the downregulation of EFTUD1 was investigated. To reveal the role of autophagy, the autophagy-blocker, chloroquine (CQ), was used in glioma cells downregulating EFTUD1. The effect of combining CQ with EFTUD1 inhibition in glioma cells was analyzed. Results EFTUD1 expression in glioma cell lines and tissue was higher than in normal brain tissue. Downregulating EFTUD1 induced G1 cell-cycle arrest and apoptosis, leading to reduced glioma cell proliferation. The mechanism underlying this antitumor effect was impaired ribosome biogenesis via EFTUD1 inhibition. Additionally, protective autophagy was induced by glioma cells as an adaptive response to EFTUD1 inhibition. The antitumor effect induced by the combined treatment was significantly higher than that of either EFTUD1 inhibition or CQ alone. Conclusion These results suggest that EFTUD1 represents a novel therapeutic target and that the combination of EFTUD1 inhibition with autophagy blockade may be effective in the treatment of gliomas. PMID:25015090

  8. Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma.

    PubMed

    Dey, Mahua; Chang, Alan L; Miska, Jason; Wainwright, Derek A; Ahmed, Atique U; Balyasnikova, Irina V; Pytel, Peter; Han, Yu; Tobias, Alex; Zhang, Lingjiao; Qiao, Jian; Lesniak, Maciej S

    2015-07-01

    Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naive mice can be effectively activated and loaded with SIINFEKL Ag in vitro. Upon intradermal injection in the hindleg, a fraction of both types of DCs migrate to the brain and lymph nodes. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generate a robust Th1 type immune response, characterized by high frequency of CD4(+)T-bet(+) T cells and CD8(+)SIINFEKEL(+) T cells. This robust antitumor T cell response results in tumor eradication and long-term survival in 60% of the animals (p < 0.001). PMID:26026061

  9. Dendritic Cell-Based Vaccines that Utilize Myeloid Rather than Plasmacytoid Cells Offer a Superior Survival Advantage in Malignant Glioma.

    PubMed

    Dey, Mahua; Chang, Alan L; Miska, Jason; Wainwright, Derek A; Ahmed, Atique U; Balyasnikova, Irina V; Pytel, Peter; Han, Yu; Tobias, Alex; Zhang, Lingjiao; Qiao, Jian; Lesniak, Maciej S

    2015-07-01

    Dendritic cells (DCs) are professional APCs that are traditionally divided into two distinct subsets, myeloid DC (mDCs) and plasmacytoid DC (pDCs). pDCs are known for their ability to secrete large amounts of IFN-α. Apart from IFN-α production, pDCs can also process Ag and induce T cell immunity or tolerance. In several solid tumors, pDCs have been shown to play a critical role in promoting tumor immunosuppression. We investigated the role of pDCs in the process of glioma progression in the syngeneic murine model of glioma. We show that glioma-infiltrating pDCs are the major APC in glioma and are deficient in IFN-α secretion (p < 0.05). pDC depletion leads to increased survival of the mice bearing intracranial tumor by decreasing the number of regulatory T cells (Tregs) and by decreasing the suppressive capabilities of Tregs. We subsequently compared the ability of mDCs and pDCs to generate effective antiglioma immunity in a GL261-OVA mouse model of glioma. Our data suggest that mature pDCs and mDCs isolated from naive mice can be effectively activated and loaded with SIINFEKL Ag in vitro. Upon intradermal injection in the hindleg, a fraction of both types of DCs migrate to the brain and lymph nodes. Compared to mice vaccinated with pDC or control mice, mice vaccinated with mDCs generate a robust Th1 type immune response, characterized by high frequency of CD4(+)T-bet(+) T cells and CD8(+)SIINFEKEL(+) T cells. This robust antitumor T cell response results in tumor eradication and long-term survival in 60% of the animals (p < 0.001).

  10. In Vivo Measurement of Glioma-Induced Vascular Permeability

    PubMed Central

    Lee, Jisook; Baird, Andrew; Eliceiri, Brian P.

    2014-01-01

    The normal blood–brain barrier (BBB) consists of tight interendothelial cell junctions and adjacent astrocyte end feet separated by a basal lamina surrounding the endothelium. The interactions between the different cell types of BBB are disrupted in distinct patterns in the microenvironment of glioma. Malignant gliomas infiltrate the surrounding normal brain parenchyma; a process associated with vascular permeability (VP) and breakdown of the BBB. Herein, we describe methods to quantitatively measure glioma-induced vascular permeability, utilizing an orthotopic xenograft model of glioma. PMID:21874468

  11. Chlorotoxin-conjugated nanoparticles as potential glioma-targeted drugs.

    PubMed

    Fu, Yuejun; An, Na; Li, Ke; Zheng, Yali; Liang, Aihua

    2012-05-01

    Development of glioma-specific nanoparticles has been an area of intense research over the past several years. Iron oxide, multifunctional superparamagnetic, and NaYF(4):Yb,rare-earth upconversion nanoparticles, conjugated with chlorotoxin (CTX, a key toxin in scorpion venom which has been shown to bind specifically to glioma cell surface as a specific chloride channel and matrix metalloproteinase-2 blocker), exhibit high affinity for glioma and direct tumor visualization. We review the latest improvements of CTX-modified nanoparticle platforms which might enable development of more effective therapeutic agents in clinical treatment of glioma.

  12. Sunitinib in Treating Patients With Recurrent Malignant Gliomas

    ClinicalTrials.gov

    2016-01-29

    Adult Anaplastic Astrocytoma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma

  13. Malignant gliomas: old and new systemic treatment approaches

    PubMed Central

    Mesti, Tanja

    2016-01-01

    Abstract Background Malignant (high-grade) gliomas are rapidly progressive brain tumours with very high morbidity and mortality. Until recently, treatment options for patients with malignant gliomas were limited and mainly the same for all subtypes of malignant gliomas. The treatment included surgery and radiotherapy. Chemotherapy used as an adjuvant treatment or at recurrence had a marginal role. Conclusions Nowadays, the treatment of malignant gliomas requires a multidisciplinary approach. The treatment includes surgery, radiotherapy and chemotherapy. The chosen approach is more complex and individually adjusted. By that, the effect on the survival and quality of life is notable higher. PMID:27247544

  14. Identify paraffin-embedded brain glioma using terahertz pulsed spectroscopy

    NASA Astrophysics Data System (ADS)

    Li, Ze-ren; Meng, Kun; Chen, Tu-nan; Chen, Tao; Zhu, Li-guo; Liu, Qiao; Li, Zhao; Li, Fei; Zhong, Sen-cheng; Feng, Hua; Zhao, Jian-heng

    2015-01-01

    The refractive indices, absorption coefficients and complex dielectric constants spectra of paraffin-embedded brain glioma and normal brain tissues have been measured by a terahertz time domain spectroscopy (THz-TDS) system in the range of 0.2 - 2.0 THz. The spectral differences between glioma and normal brain tissues were obtained. Our results indicate that, compared with normal tissue, glioma had higher refractive index, absorption coefficient, and dielectric constant. Based on these results, the suitable frequency components for different methods of glioma imaging (intensity imaging, coherent imaging and terahertz pulsed imaging) are analyzed.

  15. Combined efficacy of cediranib and quinacrine in glioma is enhanced by hypoxia and causally linked to autophagic vacuole accumulation.

    PubMed

    Lobo, Merryl R; Wang, Xiaoyan; Gillespie, G Yancey; Woltjer, Randall L; Pike, Martin M

    2014-01-01

    We have previously reported that the in vivo anti-glioma efficacy of the anti-angiogenic receptor tyrosine kinase inhibitor cediranib is substantially enhanced via combination with the late-stage autophagy inhibitor quinacrine. The current study investigates the role of hypoxia and autophagy in combined cediranib/quinacrine efficacy. EF5 immunostaining revealed a prevalence of hypoxia in mouse intracranial 4C8 glioma, consistent with high-grade glioma. MTS cell viability assays using 4C8 glioma cells revealed that hypoxia potentiated the efficacy of combined cediranib/quinacrine: cell viability reductions induced by 1 µM cediranib +2.5 µM quinacrine were 78±7% (hypoxia) vs. 31±3% (normoxia), p<0.05. Apoptosis was markedly increased for cediranib/quinacrine/hypoxia versus all other groups. Autophagic vacuole biomarker LC3-II increased robustly in response to cediranib, quinacrine, or hypoxia. Combined cediranib/quinacrine increased LC3-II further, with the largest increases occurring with combined cediranib/quinacrine/hypoxia. Early stage autophagy inhibitor 3-MA prevented LC3-II accumulation with combined cediranib/quinacrine/hypoxia and substantially attenuated the associated reduction in cell viability. Combined efficacy of cediranib with bafilomycin A1, another late-stage autophagy inhibitor, was additive but lacked substantial potentiation by hypoxia. Substantially lower LC3-II accumulation was observed with bafilomycin A1 in comparison to quinacrine. Cediranib and quinacrine each strongly inhibited Akt phosphoryation, while bafilomycin A1 had no effect. Our results provide compelling evidence that autophagic vacuole accumulation plays a causal role in the anti-glioma cytotoxic efficacy of combined cediranib/quinacrine. Such accumulation is likely related to stimulation of autophagosome induction by hypoxia, which is prevalent in the glioma tumor microenvironment, as well as Akt signaling inhibition from both cediranib and quinacrine. Quinacrine's unique

  16. Bevacizumab and Irinotecan in Treating Young Patients With Recurrent, Progressive, or Refractory Glioma, Medulloblastoma, Ependymoma, or Low Grade Glioma

    ClinicalTrials.gov

    2016-07-14

    Childhood Cerebral Anaplastic Astrocytoma; Childhood Oligodendroglioma; Childhood Spinal Cord Neoplasm; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma

  17. Tumor initiating cells in malignant gliomas

    PubMed Central

    Hadjipanayis, Costas G.; Van Meir, Erwin G.

    2009-01-01

    A rare subpopulation of cells within malignant gliomas, which shares canonical properties with neural stem cells (NSCs), may be integral to glial tumor development and perpetuation. These cells, also known as tumor initiating cells (TICs), have the ability to self-renew, develop into any cell in the overall tumor population (multipotency), and proliferate. A defining property of TICs is their ability to initiate new tumors in immunocompromised mice with high efficiency. Mounting evidence suggests that TICs originate from the transformation of NSCs and their progenitors. New findings show that TICs may be more resistant to chemotherapy and radiation than the bulk of tumor cells, thereby permitting recurrent tumor formation and accounting for the failure of conventional therapies. The development of new therapeutic strategies selectively targeting TICs while sparing NSCs may provide for more effective treatment of malignant gliomas. PMID:19189072

  18. Glioma Stem Cells: Signaling, Microenvironment, and Therapy

    PubMed Central

    Liebelt, Brandon D.; Shingu, Takashi; Zhou, Xin; Ren, Jiangong; Shin, Seul A.; Hu, Jian

    2016-01-01

    Glioblastoma remains the most common and devastating primary brain tumor despite maximal therapy with surgery, chemotherapy, and radiation. The glioma stem cell (GSC) subpopulation has been identified in glioblastoma and likely plays a key role in resistance of these tumors to conventional therapies as well as recurrent disease. GSCs are capable of self-renewal and differentiation; glioblastoma-derived GSCs are capable of de novo tumor formation when implanted in xenograft models. Further, GSCs possess unique surface markers, modulate characteristic signaling pathways to promote tumorigenesis, and play key roles in glioma vascular formation. These features, in addition to microenvironmental factors, present possible targets for specifically directing therapy against the GSC population within glioblastoma. In this review, the authors summarize the current knowledge of GSC biology and function and the role of GSCs in new vascular formation within glioblastoma and discuss potential therapeutic approaches to target GSCs. PMID:26880988

  19. Treatment of malignant gliomas: a new approach.

    PubMed

    Paccapelo, A; Piana, C; Rychlicki, F; Recchioni, M A; Salvolini, U; Ducati, A; Bonsignori, M

    1998-01-01

    The aim of this study is to describe the authors' experience with intra-arterial ACNU chemotherapy of malignant gliomas. The prognosis of cerebral malignant gliomas remains poor, whatever traditional therapy is applied. ACNU is a well tolerated nitrosourea with a strong antimitotic effect on neurogenic cells both in vitro and in vivo; this drug has enhanced efficacy when used at high concentrations, particularly as an intraarterial infusion. Seventy-six patients have been studied to date, 68 of whom are evaluable; these patients were treated by intra-arterial infusion of ACNU (100 mg/m2) every 6 weeks, with a mean of 2.5 courses per patient. The objective response (OR) was 28% and analysis of pretreatment factors revealed that survival was influenced by histological grade, other types of therapy applied, and age. In general IAC is well tolerated and the response and survival appear to be better than with systemic chemotherapy.

  20. PDGF and PDGF receptors in glioma

    PubMed Central

    Nazarenko, Inga; Hede, Sanna-Maria; He, Xiaobing; Hedrén, Anna; Thompson, James; Lindström, Mikael S.

    2012-01-01

    The family of platelet-derived growth factors (PDGFs) plays a number of critical roles in normal embryonic development, cellular differentiation, and response to tissue damage. Not surprisingly, as it is a multi-faceted regulatory system, numerous pathological conditions are associated with aberrant activity of the PDGFs and their receptors. As we and others have shown, human gliomas, especially glioblastoma, express all PDGF ligands and both the two cell surface receptors, PDGFR-α and -β. The cellular distribution of these proteins in tumors indicates that glial tumor cells are stimulated via PDGF/PDGFR-α autocrine and paracrine loops, while tumor vessels are stimulated via the PDGFR-β. Here we summarize the initial discoveries on the role of PDGF and PDGF receptors in gliomas and provide a brief overview of what is known in this field. PMID:22509804

  1. Overview of current immunotherapeutic strategies for glioma

    PubMed Central

    Calinescu, Anda-Alexandra; Kamran, Neha; Baker, Gregory; Mineharu, Yohei; Lowenstein, Pedro Ricardo; Castro, Maria Graciela

    2015-01-01

    In the last decade, numerous studies of immunotherapy for malignant glioma (glioblastoma multiforme) have brought new knowledge and new hope for improving the prognosis of this incurable disease. Some clinical trials have reached Phase III, following positive outcomes in Phase I and II, with respect to safety and immunological end points. Results are encouraging especially when considering the promise of sustained efficacy by inducing antitumor immunological memory. Progress in understanding the mechanisms of tumor-induced immune suppression led to the development of drugs targeting immunosuppressive checkpoints, which are used in active clinical trials for glioblastoma multiforme. Insights related to the heterogeneity of the disease bring new challenges for the management of glioma and underscore a likely cause of therapeutic failure. An emerging therapeutic strategy is represented by a combinatorial, personalized approach, including the standard of care: surgery, radiation, chemotherapy with added active immunotherapy and multiagent targeting of immunosuppressive checkpoints. PMID:26598957

  2. AT1 receptor is present in glioma cells; its blockage reduces the growth of rat glioma

    PubMed Central

    Rivera, E; Arrieta, O; Guevara, P; Duarte-Rojo, A; Sotelo, J

    2001-01-01

    Malignancy of neoplasms is partly dependent on angiogenesis. Angiotensin II mediates angiogenesis and transcription of growth-related factors through stimulation of the AT1 receptor (AT1R). Losartan, a drug used mostly for treatment of hypertension, binds strongly to this receptor. We found the presence of AT1 receptor on C6 glioma cells and studied the effect of Losartan on the growth and angiogenesis of C6 rat glioma; Losartan in dose of 80 mg/kg induced 79% reduction of tumoural volume with a significant decrease of vascular density, mitotic index and cell proliferation. Our results demonstrate the conspicuous presence of AT1R in malignant glial cells and a favourable therapeutic response in experimental glioma by selective blockage of the AT1 receptor. © 2001 Cancer Research Campaign  http://www.bjcancer.com PMID:11720480

  3. Low-grade gliomas in adults.

    PubMed

    Sanai, Nader; Chang, Susan; Berger, Mitchel S

    2011-11-01

    In recent years, advances in the understanding of low-grade glioma (LGG) biology have driven new paradigms in molecular markers, diagnostic imaging, operative techniques and technologies, and adjuvant therapies. Taken together, these developments are collectively pushing the envelope toward improved quality of life and survival. In this article, the authors evaluate the recent literature to synthesize a comprehensive review of LGGs in the modern neurosurgical era.

  4. Raman spectroscopy of gliomas: an exploratory study

    NASA Astrophysics Data System (ADS)

    Shenoy, Mahesh; Hole, Arti R.; Shridhar, E.; Moiyadi, Aliasgar V.; Krishna, C. Murali

    2014-03-01

    Gliomas are extremely infiltrative type of brain cancers, the borders of which are difficult to locate. Gliomas largely consist of tumors of astrocytic or oligodendroglial lineage. Usually stereotactic surgery is performed to obtain tumor tissue sample. Complete excision of these tumors with preservation of uninvolved normal areas is important during brain tumor surgeries. The present study was undertaken to explore feasibility of classifying abnormal and normal glioma tissues with Raman spectroscopy (RS). RS is a nondestructive vibrational spectroscopic technique, which provides information about molecular composition, molecular structures and molecular interactions in tissue. Postoperated 33 (20-abnormal and 13-normal) gliomas tissue samples of different grades were collected under clinical supervision. Five micron section from tissue sample was used for confirmatory histopathological diagnosis while the remaining tissue was placed on CaF2 window and spectra were acquired using a fiberoptic-probe-coupled HE-785 Raman-spectrometer. Spectral acquisition parameters were laser power-80mW, integration-20s and averaged over 3 accumulations. Spectra were pre-processed and subjected to unsupervised Principal-Component Analysis (PCA) to identify trends of classification. Supervised PC-LDA (Principal-Component-Linear-Discriminant Analysis) was used to develop standard-models using spectra of 12 normal and abnormal specimens each. Leave-one-out crossvalidation yielded classification-efficiency of 90% and 80% for normal and abnormal conditions, respectively. Evaluation with an independent-test data-set comprising of 135 spectra of 9 samples provided sensitivity of 100% and specificity of 70%. Findings of this preliminary study may pave way for objective tumor margin assessment during brain surgery.

  5. [Mnesic disorders caused by left temporal gliomas].

    PubMed

    Verlut, C; Sylvestre, G; Curtit, E; Baron, M-H; Medeiros De Bustos, E; Moulin, T; Magnin, E

    2015-04-01

    Episodic memory disorders are frequent in patients with temporal lesion. Verbal or visuo-spatial memory disorders depend on the location and the lateralization of the lesion. These disorders are well described in temporal epilepsy but rarely in population with cerebral tumor and especially not specifically focus on temporal glioma. The purpose of this study was to describe neuropsychological examination in patient with temporal glioma in the database of the regional memory centre of Besançon. Four patients were identified (all right-handed and with a left temporal glioma). Verbal episodic memory impairment and auditory-verbal short-term memory impairment were observed. One patient had also visual memory disorders. Therefore, further investigations showed an associated Alzheimer's disease. This finding modified the clinical management of this patient. Extensive neuropsychological assessment should be systematic initially to seek an associated pathology, especially in elderly patients, if the cognitive profile is unusual, during the follow-up to better understand cognitive evolution and the effect of therapies on cognition.

  6. Choline Derivate-Modified Doxorubicin Loaded Micelle for Glioma Therapy.

    PubMed

    Li, Jianfeng; Yang, Huiying; Zhang, Yujie; Jiang, Xutao; Guo, Yubo; An, Sai; Ma, Haojun; He, Xi; Jiang, Chen

    2015-09-30

    Ligand-mediated polymeric micelles have enormous potential for improving the efficacy of glioma therapy. Linear-dendritic drug-polymer conjugates composed of doxorubicin (DOX) and polyethylene glycol (PEG) were synthesized with or without modification of choline derivate (CD). The resulting MeO-PEG-DOX8 and CD-PEG-DOX8 could self-assemble into polymeric micelles with a nanosized diameter around 30 nm and a high drug loading content up to 40.6 and 32.3%, respectively. The optimized formulation 20% CD-PEG-DOX8 micelles had superior cellular uptake and antitumor activity against MeO-PEG-DOX8 micelles. The subcellular distribution using confocal study revealed that 20% CD-PEG-DOX8 micelles preferentially accumulated in the mitochondria. Pharmacokinetic study showed area under the plasma concentration-time curve (AUC0-t) and Cmax for 20% CD-PEG-DOX8 micelles and DOX solution were 1336.58 ± 179.43 mg/L·h, 96.35 ± 3.32 mg/L and 1.40 ± 0.19 mg/L·h, 1.15 ± 0.25 mg/L, respectively. Biodistribution study showed the DOX concentration of 20% CD-PEG-DOX8 micelles treated group at 48 h was 2.37-fold higher than that of MeO-PEG-DOX8 micelles treated group at 48 h and was 24 fold-higher than that of DOX solution treated group at 24 h. CD-PEG-DOX8 micelles (20%) were well tolerated with reduced cardiotoxicity, as evaluated in the body weight change and HE staining studies, while they induced most significant antitumor activity with longest media survival time in an orthotopic mouse model of U87-luci glioblastoma model as displayed in the bioluminescence imaging and survival curve studies. Our findings consequently indicated that 20% CD-PEG-DOX8 micelles are promising drug delivery system for glioma chemotherapy. PMID:26356793

  7. The molecular profile of microglia under the influence of glioma

    PubMed Central

    Li, Wei; Graeber, Manuel B.

    2012-01-01

    Microglia, which contribute substantially to the tumor mass of glioblastoma, have been shown to play an important role in glioma growth and invasion. While a large number of experimental studies on functional attributes of microglia in glioma provide evidence for their tumor-supporting roles, there also exist hints in support of their anti-tumor properties. Microglial activities during glioma progression seem multifaceted. They have been attributed to the receptors expressed on the microglia surface, to glioma-derived molecules that have an effect on microglia, and to the molecules released by microglia in response to their environment under glioma control, which can have autocrine effects. In this paper, the microglia and glioma literature is reviewed. We provide a synopsis of the molecular profile of microglia under the influence of glioma in order to help establish a rational basis for their potential therapeutic use. The ability of microglia precursors to cross the blood–brain barrier makes them an attractive target for the development of novel cell-based treatments of malignant glioma. PMID:22573310

  8. Vasculogenic mimicry: a novel target for glioma therapy.

    PubMed

    Chen, Yin-Sheng; Chen, Zhong-Ping

    2014-02-01

    Anti-angiogenic therapy has shown promising but insufficient efficacy on gliomas. Recent studies suggest that vasculogenic mimicry (VM), or the formation of non-endothelial, tumor-cell-lined microvascular channels, occurs in aggressive tumors, including gliomas. There is also evidence of a physiological connection between the endothelial-lined vasculature and VM channels. Tumor cells, by virtue of their high plasticity, can form vessel-like structures themselves, which may function as blood supply networks. Our previous study on gliomas showed that microvessel density was comparably less in VM-positive tumors than in VM-negative tumors. Thus, VM may act as a complement to ensure tumor blood supply, especially in regions with less microvessel density. Patients with VM-positive gliomas survived a shorter period of time than did patients with VM-negative gliomas. Although the detailed molecular mechanisms for VM are not fully understood, glioma stem cells might play a key role, since they are involved in tumor tissue remodeling and contribute to neovascularization via transdifferentiation. In the future, successful treatment of gliomas should involve targeting both VM and angiogenesis. In this review, we summarize the progress and challenges of VM in gliomas. PMID:23816560

  9. Photodynamic therapy on the ultrastructure of glioma cell

    NASA Astrophysics Data System (ADS)

    Hu, Shaoshan; Zhang, Ruyou; Zheng, Yongri

    2005-07-01

    OBJECTIVE :the main purpose of this experiment was to study the change of C6 glioma cells' ultrastructure treated by photodynamic therapy(PDT), observe the change of morphology METHOD :Make the model of rat glioma by transplanted C6 glioma cells into caudate nucleus,treated the glioma rat by PDT after two weeks. Observed the difference of subcellular structure before and after PDT by electron microscope. RESULT : Apoptosis and necrosis can be seen after treated by PDT in the C6 glioma, basal membrance damaged ,number of cellular organ of endothelial cell of blood capillary declined,tight junction of endothelial cell lengthen and the gap enlarge. The PDT has slightly effect on the nomorl rat"s subcellular structue. CONCLUSION: PDT can induce the apoptosis and necrosis of C6 glioma cell. The damage of the ultramicrostructure of mitochondria and endoplasmic reticulum was the foundmentol of the change. PDT initiate the damage of BBB of the C6 glioma cell and weeken the function、and makes it a useful way of treating the glioma combained with chemotherapy.

  10. Aberrant CpG Islands Hypermethylation Profiles in Malignant Gliomas

    PubMed Central

    Kim, Kwang Ryeol; Kim, Ealmaan

    2014-01-01

    Background The authors analyzed whether the promoter hypermethylation of cancer-related genes was involved in the tumorigenesis of malignant gliomas. Methods A total of 29 patients received surgery and histologically confirmed to have malignant gliomas from January 2000 to December 2006. The promoter methylation status of several genes, which were reported to be frequently methylated in malignant gliomas, was investigated using methylation-specific polymerase chain reaction. Results All cases of malignant gliomas represented the promoter hypermethylation in at least 2 or more genes tested. Of 29 tumors, 28 (96.55%) showed concurrent hypermethylation of 3 or more genes. Ras association domain family member 1, epithelial cadherin, O-6 methyl guanine DNA methyltransferase, thrombospondin 1, p14 and adenomatous polyposis coli were frequently methylated in high grade gliomas including glioblastomas, anaplastic astrocytomas, and anaplastic oligodendrogliomas. Conclusion Aberrant hypermethylation profile was closely related with malignant gliomas suggesting that epigenetic change may play a role in the development of malignant gliomas. Two or three target genes may provide useful clues to the development of the useful prognostic as well as diagnostic assays for malignant gliomas. PMID:24926469

  11. Glioma progression is mediated by an addiction to aberrant IGFBP2 expression and can be blocked using anti-IGFBP2 strategies.

    PubMed

    Phillips, Lynette M; Zhou, Xinhui; Cogdell, David E; Chua, Corrine Yingxuan; Huisinga, Anouk; R Hess, Kenneth; Fuller, Gregory N; Zhang, Wei

    2016-07-01

    Insulin-like growth factor binding protein 2 (IGFBP2) overexpression is common in high-grade glioma and is both a strong biomarker of aggressive behaviour and a well-documented prognostic factor. IGFBP2 is a member of the secreted IGFBP family that functions by interacting with circulating IGFs to modulate IGF-mediated signalling. This traditional view of IGFBP2 activities has been challenged by the recognition of the diverse functions and cellular locations of members of the IGFBP family. IGFBP2 has been previously established as a driver of glioma progression to a higher grade. In this study, we sought to determine whether IGFBP2-overexpressing tumours are dependent on continued oncogene expression and whether IGFBP2 is a viable therapeutic target in glioma. We took advantage of the well-characterized RCAS/Ntv-a mouse model to create a doxycycline-inducible IGFBP2 model of glioma and demonstrated that the temporal expression of IGFBP2 has dramatic impacts on tumour progression and survival. Further, we demonstrated that IGFBP2-driven tumours are dependent on the continued expression of IGFBP2, as withdrawal of this oncogenic signal led to a significant decrease in tumour progression and prolonged survival. Inhibition of IGFBP2 also impaired tumour cell spread. To assess a therapeutically relevant inhibition strategy, we evaluated a neutralizing antibody against IGFBP2 and demonstrated that it impaired downstream IGFBP2-mediated oncogenic signalling pathways. The studies presented here indicate that IGFBP2 not only is a driver of glioma progression and a prognostic factor but is also required for tumour maintenance and thus represents a viable therapeutic target in the treatment of glioma. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  12. Brain tumor modeling: glioma growth and interaction with chemotherapy

    NASA Astrophysics Data System (ADS)

    Banaem, Hossein Y.; Ahmadian, Alireza; Saberi, Hooshangh; Daneshmehr, Alireza; Khodadad, Davood

    2011-10-01

    In last decade increasingly mathematical models of tumor growths have been studied, particularly on solid tumors which growth mainly caused by cellular proliferation. In this paper we propose a modified model to simulate the growth of gliomas in different stages. Glioma growth is modeled by a reaction-advection-diffusion. We begin with a model of untreated gliomas and continue with models of polyclonal glioma following chemotherapy. From relatively simple assumptions involving homogeneous brain tissue bounded by a few gross anatomical landmarks (ventricles and skull) the models have been expanded to include heterogeneous brain tissue with different motilities of glioma cells in grey and white matter. Tumor growth is characterized by a dangerous change in the control mechanisms, which normally maintain a balance between the rate of proliferation and the rate of apoptosis (controlled cell death). Result shows that this model closes to clinical finding and can simulate brain tumor behavior properly.

  13. Mutations in chromatin machinery and pediatric high-grade glioma.

    PubMed

    Lulla, Rishi R; Saratsis, Amanda Muhs; Hashizume, Rintaro

    2016-03-01

    Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors. PMID:27034984

  14. Glioma coexisting with angiographically occult cerebrovascular malformation: A case report

    PubMed Central

    Chen, Junhui; Chen, Lei; Zhang, Chunlei; He, Jianqing; Li, Peipei; Zhou, Jingxu; Zhu, Jun; Wang, Yuhai

    2016-01-01

    Angiographically occult cerebrovascular malformation (AOVM) is a type of complex cerebrovascular malformation that is not visible on digital subtraction angiography (DSA). Vascular malformation coexisting with glioma is clinically rare, and glioma coexisting with AOVM is even more rare. To the best of our knowledge, the present study is the first to report glioma coexisting with AOVM in the literature. The present study reports a rare case of glioma coexisting with AOVM in a 30-year-old male patient. Computed tomography (CT) scan revealed calcification, hemorrhage and edema in the right frontal lobe. CT angiography revealed a vascular malformation in the right frontal lobe, which was not observed on DSA. Finally, glioma coexisting with AOVM was confirmed by 2.0T magnetic resonance imaging and postoperative pathological examination. The present patient had a positive outcome and no neurological dysfunctions during the 6-month follow-up subsequent to surgery. PMID:27698825

  15. Glioma coexisting with angiographically occult cerebrovascular malformation: A case report

    PubMed Central

    Chen, Junhui; Chen, Lei; Zhang, Chunlei; He, Jianqing; Li, Peipei; Zhou, Jingxu; Zhu, Jun; Wang, Yuhai

    2016-01-01

    Angiographically occult cerebrovascular malformation (AOVM) is a type of complex cerebrovascular malformation that is not visible on digital subtraction angiography (DSA). Vascular malformation coexisting with glioma is clinically rare, and glioma coexisting with AOVM is even more rare. To the best of our knowledge, the present study is the first to report glioma coexisting with AOVM in the literature. The present study reports a rare case of glioma coexisting with AOVM in a 30-year-old male patient. Computed tomography (CT) scan revealed calcification, hemorrhage and edema in the right frontal lobe. CT angiography revealed a vascular malformation in the right frontal lobe, which was not observed on DSA. Finally, glioma coexisting with AOVM was confirmed by 2.0T magnetic resonance imaging and postoperative pathological examination. The present patient had a positive outcome and no neurological dysfunctions during the 6-month follow-up subsequent to surgery.

  16. Mutations in chromatin machinery and pediatric high-grade glioma

    PubMed Central

    Lulla, Rishi R.; Saratsis, Amanda Muhs; Hashizume, Rintaro

    2016-01-01

    Pediatric central nervous system tumors are the most common solid tumor of childhood. Of these, approximately one-third are gliomas that exhibit diverse biological behaviors in the unique context of the developing nervous system. Although low-grade gliomas predominate and have favorable outcomes, up to 20% of pediatric gliomas are high-grade. These tumors are a major contributor to cancer-related morbidity and mortality in infants, children, and adolescents, with long-term survival rates of only 10 to 15%. The recent discovery of somatic oncogenic mutations affecting chromatin regulation in pediatric high-grade glioma has markedly improved our understanding of disease pathogenesis, and these findings have stimulated the development of novel therapeutic approaches targeting epigenetic regulators for disease treatment. We review the current perspective on pediatric high-grade glioma genetics and epigenetics, and discuss the emerging and experimental therapeutics targeting the unique molecular abnormalities present in these deadly childhood brain tumors. PMID:27034984

  17. Silencing BMI1 eliminates tumor formation of pediatric glioma CD133+ cells not by affecting known targets but by down-regulating a novel set of core genes.

    PubMed

    Baxter, Patricia A; Lin, Qi; Mao, Hua; Kogiso, Mari; Zhao, Xiumei; Liu, Zhigang; Huang, Yulun; Voicu, Horatiu; Gurusiddappa, Sivashankarappa; Su, Jack M; Adesina, Adekunle M; Perlaky, Laszlo; Dauser, Robert C; Leung, Hon-chiu Eastwood; Muraszko, Karin M; Heth, Jason A; Fan, Xing; Lau, Ching C; Man, Tsz-Kwong; Chintagumpala, Murali; Li, Xiao-Nan

    2014-01-01

    Clinical outcome of children with malignant glioma remains dismal. Here, we examined the role of over-expressed BMI1, a regulator of stem cell self-renewal, in sustaining tumor formation in pediatric glioma stem cells. Our investigation revealed BMI1 over-expression in 29 of 54 (53.7%) pediatric gliomas, 8 of 8 (100%) patient derived orthotopic xenograft (PDOX) mouse models, and in both CD133+ and CD133- glioma cells. We demonstrated that lentiviral-shRNA mediated silencing of suppressed cell proliferation in vitro in cells derived from 3 independent PDOX models and eliminated tumor-forming capacity of CD133+ and CD133- cells derived from 2 PDOX models in mouse brains. Gene expression profiling showed that most of the molecular targets of BMI1 ablation in CD133+ cells were different from that in CD133- cells. Importantly, we found that silencing BMI1 in CD133+ cells derived from 3 PDOX models did not affect most of the known genes previously associated with the activated BMI1, but modulated a novel set of core genes, including RPS6KA2, ALDH3A2, FMFB, DTL, API5, EIF4G2, KIF5c, LOC650152, C20ORF121, LOC203547, LOC653308, and LOC642489, to mediate the elimination of tumor formation. In summary, we identified the over-expressed BMI1 as a promising therapeutic target for glioma stem cells, and suggest that the signaling pathways associated with activated BMI1 in promoting tumor growth may be different from those induced by silencing BMI1 in blocking tumor formation. These findings highlighted the importance of careful re-analysis of the affected genes following the inhibition of abnormally activated oncogenic pathways to identify determinants that can potentially predict therapeutic efficacy.

  18. High expression of VEGF and PI3K in glioma stem cells provides new criteria for the grading of gliomas

    PubMed Central

    WANG, LEI; ZHANG, LUYAO; SHEN, WEIGAO; LIU, YANBO; LUO, YINAN

    2016-01-01

    Glioma is a type of tumor derived from glial cells, which is associated with a high level of incidence and mortality. At present, the generation of a fast and efficient method to evaluate the malignancy grade of glioma is required. Cancer stem cells (CSCs) are currently attracting attention in oncological studies; therefore, the present study aimed to investigate novel biomarkers of glioma CSCs, in order to provide new criteria for the grading of glioma. The mRNA expression levels of CD133, (sex determining region Y)-box 2, nestin, vascular endothelial growth factor (VEGF) and phosphoinositide-3-kinase (PI3K) were detected in 15 human samples of high-malignancy glioma and 12 human samples of low-malignancy glioma in vitro. The mRNA expression levels of VEGF and PI3K were higher in the high-malignancy group, as compared with in the low-malignancy group. In conclusion, the mRNA expression levels of VEGF and PI3K in glioma CSCs may be considered a novel criteria for the grading of glioma. PMID:26893649

  19. Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model.

    PubMed

    Ouyang, Mao; White, Ethan E; Ren, Hui; Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R; Zhang, Leying; Vonderfecht, Steven L; Alizadeh, Darya; Berlin, Jacob M; Badie, Behnam

    2016-01-01

    Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG. PMID:26829221

  20. Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model

    PubMed Central

    Guo, Qin; Zhang, Ian; Gao, Hang; Yanyan, Song; Chen, Xuebo; Weng, Yiming; Da Fonseca, Anna; Shah, Sunny; Manuel, Edwin R.; Zhang, Leying; Vonderfecht, Steven L.; Alizadeh, Darya; Berlin, Jacob M.; Badie, Behnam

    2016-01-01

    Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs) can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261) tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc) that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG. PMID:26829221

  1. PCR-Based Simple Subgrouping Is Validated for Classification of Gliomas and Defines Negative Prognostic Copy Number Aberrations in IDH Mutant Gliomas

    PubMed Central

    Nakae, Shunsuke; Sasaki, Hikaru; Hayashi, Saeko; Hattori, Natsuki; Kumon, Masanobu; Nishiyama, Yuya; Adachi, Kazuhide; Nagahisa, Shinya; Hayashi, Takuro; Inamasu, Joji; Abe, Masato; Hasegawa, Mitsuhiro; Hirose, Yuichi

    2015-01-01

    Genetic subgrouping of gliomas has been emphasized recently, particularly after the finding of isocitrate dehydrogenase 1 (IDH1) mutations. In a previous study, we investigated whole-chromosome copy number aberrations (CNAs) of gliomas and have described genetic subgrouping based on CNAs and IDH1 mutations. Subsequently, we classified gliomas using simple polymerase chain reaction (PCR)-based methods to improve the availability of genetic subgrouping. We selected IDH1/2 and TP53 as markers and analyzed 237 adult supratentorial gliomas using Sanger sequencing. Using these markers, we classified gliomas into three subgroups that were strongly associated with patient prognoses. These included IDH mutant gliomas without TP53 mutations, IDH mutant gliomas with TP53 mutations, and IDH wild-type gliomas. IDH mutant gliomas without TP53 mutations, which mostly corresponded to gliomas carrying 1p19q co-deletions, showed lower recurrence rates than the other 2 groups. In the other high-recurrence groups, the median progression-free survival (PFS) and overall survival (OS) of patients with IDH mutant gliomas with TP53 mutations were significantly longer than those of patients with IDH wild-type gliomas. Notably, most IDH mutant gliomas with TP53 mutations had at least one of the CNAs +7q, +8q, −9p, and −11p. Moreover, IDH mutant gliomas with at least one of these CNAs had a significantly worse prognosis than did other IDH mutant gliomas. PCR-based mutation analyses of IDH and TP53 were sufficient for simple genetic diagnosis of glioma that were strongly associated with prognosis of patients and enabled us to detect negative CNAs in IDH mutant gliomas. PMID:26558387

  2. Survival advantage combining a BRAF inhibitor and radiation in BRAF V600E-mutant glioma.

    PubMed

    Dasgupta, Tina; Olow, Aleksandra K; Yang, Xiaodong; Hashizume, Rintaro; Nicolaides, Theodore P; Tom, Maxwell; Aoki, Yasuyuki; Berger, Mitchel S; Weiss, William A; Stalpers, Lukas J A; Prados, Michael; James, C David; Mueller, Sabine; Haas-Kogan, Daphne A

    2016-02-01

    Radiation (RT) is critical to the treatment of high-grade gliomas (HGGs) but cures remain elusive. The BRAF mutation V600E is critical to the pathogenesis of 10-20% of pediatric gliomas, and a small proportion of adult HGGs. Here we aim to determine whether PLX4720, a specific BRAF V600E inhibitor, enhances the activity of RT in human HGGs in vitro and in vivo. Patient-derived HGG lines harboring wild-type BRAF or BRAF V600E were assessed in vitro to determine IC50 values, cell cycle arrest, apoptosis and senescence and elucidate mechanisms of combinatorial activity. A BRAF V600E HGG intracranial xenograft mouse model was used to evaluate in vivo combinatorial efficacy of PLX4720+RT. Tumors were harvested for immunohistochemistry to quantify cell cycle arrest and apoptosis. RT+PLX4720 exhibited greater anti-tumor effects than either monotherapy in BRAF V600E but not in BRAF WT lines. In vitro studies showed increased Annexin V and decreased S phase cells in BRAF V600E gliomas treated with PLX4720+RT, but no significant changes in β-galactosidase levels. In vivo, concurrent and sequential PLX4720+RT each significantly prolonged survival compared to monotherapies, in the BRAF V600E HGG model. Immunohistochemistry of in vivo tumors demonstrated that PLX4720+RT decreased Ki-67 and phospho-MAPK, and increased γH2AX and p21 compared to control mice. BRAF V600E inhibition enhances radiation-induced cytotoxicity in BRAF V600E-mutated HGGs, in vitro and in vivo, effects likely mediated by apoptosis and cell cycle, but not senescence. These studies provide the pre-clinical rationale for clinical trials of concurrent radiotherapy and BRAF V600E inhibitors.

  3. The cyclic AMP pathway is a sex-specific modifier of glioma risk in type I neurofibromatosis patients.

    PubMed

    Warrington, Nicole M; Sun, Tao; Luo, Jingqin; McKinstry, Robert C; Parkin, Patricia C; Ganzhorn, Sara; Spoljaric, Debra; Albers, Anne C; Merkelson, Amanda; Stewart, Douglas R; Stevenson, David A; Viskochil, David; Druley, Todd E; Forys, Jason T; Reilly, Karlyne M; Fisher, Michael J; Tabori, Uri; Allen, Jeffrey C; Schiffman, Joshua D; Gutmann, David H; Rubin, Joshua B

    2015-01-01

    Identifying modifiers of glioma risk in patients with type I neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis, and potentially identify novel therapeutic targets. Here, we report genetic polymorphisms in the human adenylate cyclase gene adenylate cyclase 8 (ADCY8) that correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth-promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.

  4. A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically-Modified Neural Stem Cells Expressing E.Coli Cytosine Deaminase for Treatment of Recurrent High Grade Gliomas

    ClinicalTrials.gov

    2015-03-02

    Adult Anaplastic Astrocytoma; Recurrent Grade III Glioma; Recurrent Grade IV Glioma; Adult Anaplastic Oligodendroglioma; Adult Brain Tumor; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Recurrent Adult Brain Tumor; Adult Anaplastic Oligoastrocytoma; Recurrent High Grade Glioma

  5. Clonal genomic alterations in glioma malignancy stages.

    PubMed

    James, C D; Carlbom, E; Dumanski, J P; Hansen, M; Nordenskjold, M; Collins, V P; Cavenee, W K

    1988-10-01

    Comparison of constitutional and tumor genotypes at chromosomal loci defined by restriction fragment length alleles has proven useful in determining the genomic position and tissue specificity of recessive mutations that predispose to cancer (Hansen, M.F., and Cavenee, W.K. Cancer Res., 47:5518-5527, 1987). Here we have applied this approach to 53 unrelated patients with glial tumors of varying histological malignancy grade. Loss of constitutional heterozygosity for loci on chromosome 10 was observed in 28 of 29 tumors histologically classified as glioblastoma (malignancy grade IV) whereas no similar losses were observed in any of 22 gliomas of lower malignancy grade. Examination of restriction fragment length alleles on other chromosomes revealed that loss of sequences on chromosomes 13, 17, or 22 had occurred at nonrandom frequencies and in at least one instance of each malignancy grade of adult glioma. The tumors in which loss of constitutional heterozygosity was observed were composed of one or a mixture of glial cell subtypes displaying astrocytic, oligodendrocytic, and/or ependymal differentiation. These results demonstrate a close association of the loss of chromosome 10 sequences with the most malignant histological stage of glioma and that glioblastoma arises as the clonal expansion of an earlier staged precursor. Furthermore they suggest that glioblastoma is a common phenotypic and malignancy terminus for glial tumors of various cellular subtypes which is reached through a common molecular pathway. This approach which involves the identification of malignancy stage specific somatic losses of heterozygosity provides a genotypic, rather than phenotypic, analysis of tumor progression.

  6. Vaccine Therapy, Oncolytic Viruses, and Gliomas.

    PubMed

    Desjardins, Annick; Vlahovic, Gordana; Friedman, Henry S

    2016-03-01

    After years of active research and refinement, vaccine therapy and oncolytic viruses are becoming part of the arsenal in the treatment of gliomas. In contrast to standard treatment with radiation therapy and chemotherapy, vaccines are more specific to the patient and the tumor. The majority of ongoing vaccine trials are investigating peptide, heat shock protein, and dendritic cell vaccines. The immunosuppression triggered by the tumor itself and by its treatment is a major obstacle to vaccine and oncolytic virus therapy. Thus, combination therapy with different agents that affect the immune system will probably be necessary. PMID:26984213

  7. Bright solitary waves in malignant gliomas

    NASA Astrophysics Data System (ADS)

    Pérez-García, Víctor M.; Calvo, Gabriel F.; Belmonte-Beitia, Juan; Diego, David; Pérez-Romasanta, Luis

    2011-08-01

    We put forward a nonlinear wave model describing the fundamental dynamical features of an aggressive type of brain tumors. Our model accounts for the invasion of normal tissue by a proliferating and propagating rim of active glioma cancer cells in the tumor boundary and the subsequent formation of a necrotic core. By resorting to numerical simulations, phase space analysis, and exact solutions we prove that bright solitary tumor waves develop in such systems. Possible implications of our model as a tool to extract relevant patient specific tumor parameters in combination with standard preoperative clinical imaging are also discussed.

  8. Hysterical symptoms masking brain stem glioma.

    PubMed

    Burch, E A; Hutchison, C F; Still, C N

    1978-01-01

    To function effectively as primary care specialists, psychiatrists must remain ever alert to the possibility of organic disorders in patients who at first show only psychiatric symptoms. A case is presented in which hysterical overlay led to misdiagnosis in a 31 year woman, who dies of a diffuse medullary glioma 3 1/2 years after onset of "conversion" symptoms. The authors point out how the label "hysterical" clouds longitudinal objective diagnostic observations especially when initial clinical and laboratory data fail to support a definitive organic diagnosis.

  9. Magnetic Resonance (MR) Metabolic Imaging in Glioma.

    PubMed

    Chaumeil, Myriam M; Lupo, Janine M; Ronen, Sabrina M

    2015-11-01

    This review is focused on describing the use of magnetic resonance (MR) spectroscopy for metabolic imaging of brain tumors. We will first review the MR metabolic imaging findings generated from preclinical models, focusing primarily on in vivo studies, and will then describe the use of metabolic imaging in the clinical setting. We will address relatively well-established (1) H MRS approaches, as well as (31) P MRS, (13) C MRS and emerging hyperpolarized (13) C MRS methodologies, and will describe the use of metabolic imaging for understanding the basic biology of glioma as well as for improving the characterization and monitoring of brain tumors in the clinic.

  10. Gene therapy for high-grade glioma

    PubMed Central

    Natsume, Atsushi

    2008-01-01

    The treatment of high-grade gliomas remains difficult despite recent advances in surgery, radiotherapy and chemotherapy. True advances may emerge from the increasing understanding in molecular biology and discovery of novel mechanisms for the delivery of tumoricidal agents. In an attempt to overcome this formidable neoplasm, molecular approaches using gene therapy have been investigated clinically since 1992. The clinical trials have mainly been classified into three approaches: suicide gene therapy, immune gene therapy and oncolytic viral therapy. In this article, we review these approaches, which have been studied in previous and ongoing clinical trials. PMID:19262115

  11. Automatic vessel removal in gliomas from dynamic susceptibility contrast imaging.

    PubMed

    Emblem, Kyrre E; Due-Tonnessen, Paulina; Hald, John K; Bjornerud, Atle

    2009-05-01

    The presence of macroscopic vessels within the tumor region is a potential confounding factor in MR-based dynamic susceptibility contrast (DSC)-enhanced glioma grading. In order to distinguish between such vessels and the elevated cerebral blood volume (CBV) of brain tumors, we propose a vessel segmentation technique based on clustering of multiple parameters derived from the dynamic contrast-enhanced first-pass curve. A total of 77 adult patients with histologically-confirmed gliomas were imaged at 1.5T and glioma regions-of-interest (ROIs) were derived from the conventional MR images by a neuroradiologist. The diagnostic accuracy of applying vessel exclusion by segmentation of glioma ROIs with vessels included was assessed using a histogram analysis method and compared to glioma ROIs with vessels included. For all measures of diagnostic efficacy investigated, the highest values were observed when the glioma diagnosis was based on vessel segmentation in combination with an initial mean transit time (MTT) mask. Our results suggest that vessel segmentation based on DSC parameters may improve the diagnostic efficacy of glioma grading. The proposed vessel segmentation is attractive because it provides a mask that covers all pixels affected by the intravascular susceptibility effect. PMID:19253390

  12. Telomere maintenance and the etiology of adult glioma.

    PubMed

    Walsh, Kyle M; Wiencke, John K; Lachance, Daniel H; Wiemels, Joseph L; Molinaro, Annette M; Eckel-Passow, Jeanette E; Jenkins, Robert B; Wrensch, Margaret R

    2015-11-01

    A growing body of epidemiologic and tumor genomic research has identified an important role for telomere maintenance in glioma susceptibility, initiation, and prognosis. Telomere length has long been investigated in relation to cancer, but whether longer or shorter telomere length might be associated with glioma risk has remained elusive. Recent data address this question and are reviewed here. Common inherited variants near the telomerase-component genes TERC and TERT are associated both with longer telomere length and increased risk of glioma. Exome sequencing of glioma patients from families with multiple affected members has identified rare inherited mutations in POT1 (protection of telomeres protein 1) as high-penetrance glioma risk factors. These heritable POT1 mutations are also associated with increased telomere length in leukocytes. Tumor sequencing studies further indicate that acquired somatic mutations of TERT and ATRX are among the most frequent alterations found in adult gliomas. These mutations facilitate telomere lengthening, thus bypassing a critical mechanism of apoptosis. Although future research is needed, mounting evidence suggests that glioma is, at least in part, a disease of telomere dysregulation. Specifically, several inherited and acquired variants underlying gliomagenesis affect telomere pathways and are also associated with increased telomere length.

  13. PRG3 induces Ras-dependent oncogenic cooperation in gliomas

    PubMed Central

    Yakubov, Eduard; Chen, Daishi; Broggini, Thomas; Sehm, Tina; Majernik, Gökce Hatipoglu; Hock, Stefan W.; Schwarz, Marc; Engelhorn, Tobias; Doerfler, Arnd; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai E.

    2016-01-01

    Malignant gliomas are one of the most devastating cancers in humans. One characteristic hallmark of malignant gliomas is their cellular heterogeneity with frequent genetic lesions and disturbed gene expression levels conferring selective growth advantage. Here, we report on the neuronal-associated growth promoting gene PRG3 executing oncogenic cooperation in gliomas. We have identified perturbed PRG3 levels in human malignant brain tumors displaying either elevated or down-regulated PRG3 levels compared to non-transformed specimens. Further, imbalanced PRG3 levels in gliomas foster Ras-driven oncogenic amplification with increased proliferation and cell migration although angiogenesis was unaffected. Hence, PRG3 interacts with RasGEF1 (RasGRF1/CDC25), undergoes Ras-induced challenges, whereas deletion of the C-terminal domain of PRG3 (PRG3ΔCT) inhibits Ras. Moreover PRG3 silencing makes gliomas resistant to Ras inhibition. In vivo disequilibrated PRG3 gliomas show aggravated proliferation, invasion, and deteriorate clinical outcome. Thus, our data show that the interference with PRG3 homeostasis amplifies oncogenic properties and foster the malignancy potential in gliomas. PMID:27058420

  14. Chlorotoxin inhibits glioma cell invasion via matrix metalloproteinase-2.

    PubMed

    Deshane, Jessy; Garner, Craig C; Sontheimer, Harald

    2003-02-01

    Primary brain tumors (gliomas) have the unusual ability to diffusely infiltrate the normal brain thereby evading surgical treatment. Chlorotoxin is a scorpion toxin that specifically binds to the surface of glioma cells and impairs their ability to invade. Using a recombinant His-Cltx we isolated and identified the principal Cltx receptor on the surface of glioma cells as matrix metalloproteinase-2 (MMP-2). MMP-2 is specifically up-regulated in gliomas and related cancers, but is not normally expressed in brain. We demonstrate that Cltx specifically and selectively interacts with MMP-2 isoforms, but not with MMP-1, -3, and -9, which are also expressed in malignant glioma cells. Importantly, we show that the anti-invasive effect of Cltx on glioma cells can be explained by its interactions with MMP-2. Cltx exerts a dual effect on MMP-2: it inhibits the enzymatic activity of MMP-2 and causes a reduction in the surface expression of MMP-2. These findings suggest that Cltx is a specific MMP-2 inhibitor with significant therapeutic potential for gliomas and other diseases that invoke the activity of MMP-2.

  15. Regulation of C6 glioma cell migration by thymol

    PubMed Central

    LEE, KANG PA; KIM, JAI-EUN; PARK, WON-HWAN; HONG, HEEOK

    2016-01-01

    Tumor cell motility exhibits a crucial role in tumor development. Therefore, the present study aimed to investigate whether thymol could reduce C6 glioma cell migration. Cell viability was determined using the EZ-Cytox Cell Viability kit. The scratch wound healing and Boyden chamber assays were performed to test C6 glioma cell migration in the presence of fetal bovine serum (FBS). Additionally, the study investigated whether signaling proteins relevant to C6 glioma cell migration, i.e., extracellular signal-regulated kinases (ERK)1/2, protein kinase Cα (PKCα), matrix metallopeptidase (MMP)9 and MMP2, were affected by thymol treatment. Up to 30 µM, thymol did not alter cell viability, whereas 100 µM thymol induced the death of ~20% of the cells. Furthermore, thymol (30 µM) significantly reduced FBS-induced migration. In the FBS-stimulated C6 glioma cells, thymol (30 µM) suppressed PKCα and ERK1/2 phosphorylation. MMP9 and MMP2 production was also significantly reduced by treatment with 30 µM thymol in the C6 glioma cells. Taken together, these results indicate that thymol attenuates C6 glioma cell migration. Additionally, the study suggests that the effect of thymol on the FBS-induced migration of C6 glioma cells affects PKCα and ERK1/2 signaling, and suppresses MMP9 and MMP2 production. PMID:27073528

  16. Proteomics of gliomas: initial biomarker discovery and evolution of technology.

    PubMed

    Kalinina, Juliya; Peng, Junmin; Ritchie, James C; Van Meir, Erwin G

    2011-09-01

    Gliomas are a group of aggressive brain tumors that diffusely infiltrate adjacent brain tissues, rendering them largely incurable, even with multiple treatment modalities and agents. Mostly asymptomatic at early stages, they present in several subtypes with astrocytic or oligodendrocytic features and invariably progress to malignant forms. Gliomas are difficult to classify precisely because of interobserver variability during histopathologic grading. Identifying biological signatures of each glioma subtype through protein biomarker profiling of tumor or tumor-proximal fluids is therefore of high priority. Such profiling not only may provide clues regarding tumor classification but may identify clinical biomarkers and pathologic targets for the development of personalized treatments. In the past decade, differential proteomic profiling techniques have utilized tumor, cerebrospinal fluid, and plasma from glioma patients to identify the first candidate diagnostic, prognostic, predictive, and therapeutic response markers, highlighting the potential for glioma biomarker discovery. The number of markers identified, however, has been limited, their reproducibility between studies is unclear, and none have been validated for clinical use. Recent technological advancements in methodologies for high-throughput profiling, which provide easy access, rapid screening, low sample consumption, and accurate protein identification, are anticipated to accelerate brain tumor biomarker discovery. Reliable tools for biomarker verification forecast translation of the biomarkers into clinical diagnostics in the foreseeable future. Herein we update the reader on the recent trends and directions in glioma proteomics, including key findings and established and emerging technologies for analysis, together with challenges we are still facing in identifying and verifying potential glioma biomarkers.

  17. Cy5.5 conjugated MnO nanoparticles for magnetic resonance/near-infrared fluorescence dual-modal imaging of brain gliomas.

    PubMed

    Chen, Ning; Shao, Chen; Li, Shuai; Wang, Zihao; Qu, Yanming; Gu, Wei; Yu, Chunjiang; Ye, Ling

    2015-11-01

    The fusion of molecular and anatomical modalities facilitates more reliable and accurate detection of tumors. Herein, we prepared the PEG-Cy5.5 conjugated MnO nanoparticles (MnO-PEG-Cy5.5 NPs) with magnetic resonance (MR) and near-infrared fluorescence (NIRF) imaging modalities. The applicability of MnO-PEG-Cy5.5 NPs as a dual-modal (MR/NIRF) imaging nanoprobe for the detection of brain gliomas was investigated. In vivo MR contrast enhancement of the MnO-PEG-Cy5.5 nanoprobe in the tumor region was demonstrated. Meanwhile, whole-body NIRF imaging of glioma bearing nude mouse exhibited distinct tumor localization upon injection of MnO-PEG-Cy5.5 NPs. Moreover, ex vivo CLSM imaging of the brain slice hosting glioma indicated the preferential accumulation of MnO-PEG-Cy5.5 NPs in the glioma region. Our results therefore demonstrated the potential of MnO-PEG-Cy5.5 NPs as a dual-modal (MR/NIRF) imaging nanoprobe in improving the diagnostic efficacy by simultaneously providing anatomical information from deep inside the body and more sensitive information at the cellular level.

  18. Differential expression of novH and CTGF in human glioma cell lines

    PubMed Central

    Xin, L W; Martinerie, C; Zumkeller, W; Westphal, M; Perbal, B

    1996-01-01

    Aims—(1) To investigate the expression in human derived glioblastoma cell lines of two structurally related genes, novH (nephroblastoma overexpressed gene) and CTGF (connective tissue growth factor), which encode putative insulin-like growth factor binding proteins of a novel type. (2) To investigate whether the same transcription factors regulate CTGF and novH expression. Methods—Expression of novH and CTGF was analysed in 24 glioblastoma derived cell lines by northern blotting. The CTGF promoter region was characterised by nucleotide sequencing, RNase protection experiments, by transient transfections, and CAT assays. Results—CTGF and novH mRNA levels differed in the glioma cell lines studied. NovH and CTGF genes were not co-expressed in all cell lines. The CTGF promoter region was highly conserved compared with the corresponding region in the mouse (FISP12) and exhibited in vitro transcriptional activity. Conclusions—Although the coding regions of novH and CTGF are highly homologous, their promoter regions are substantially different, suggesting that these two genes may be regulated by different mechanisms. Considering that novH and CTGF are likely to be, respectively, negative and positive regulators of growth and that some glioma cell lines expressing novH are not tumorigenic, expression of these two genes might represent a key element in determining the stage of differentiation or the malignant potential, or both, of some tumour cell lines. Images PMID:16696057

  19. Selective Targeting to Glioma with Nucleic Acid Aptamers

    PubMed Central

    Aptekar, Shraddha; Arora, Mohit; Lawrence, Clare Louise; Lea, Robert William; Ashton, Katherine; Dawson, Tim; Alder, Jane Elizabeth; Shaw, Lisa

    2015-01-01

    Malignant glioma is characterised by a rapid growth rate and high capacity for invasive infiltration to surrounding brain tissue; hence, diagnosis and treatment is difficult and patient survival is poor. Aptamers contribute a promising and unique technology for the in vitro imaging of live cells and tissues, with a potentially bright future in clinical diagnostics and therapeutics for malignant glioma. The binding selectivity, uptake capacity and binding target of two DNA aptamers, SA43 and SA44, were investigated in glioma cells and patient tissues. The binding assay showed that SA43 and SA44 bound with strong affinity (Kd, 21.56 ± 4.60 nM and Kd, 21.11 ± 3.30 nM respectively) to the target U87MG cells. Quantitative analysis by flow cytometry showed that the aptamers were able to actively internalise in U87MG and 1321N1 glioma cells compared to the non-cancerous and non-glioma cell types. Confocal microscopy confirmed staining in the cytoplasm, and co-localisation studies with endoplasmic reticulum, Golgi apparatus and lysosomal markers suggested internalisation and compartmentalisation within the endomembrane system. Both aptamers selectively bound to Ku 70 and Ku 80 DNA repair proteins as determined by aptoprecipitation (AP) followed by mass spectrometry analysis and confirmation by Western blot. In addition, aptohistochemical (AHC) staining on paraffin embedded, formalin fixed patient tissues revealed that the binding selectivity was significantly higher for SA43 aptamer in glioma tissues (grade I, II, III and IV) compared to the non-cancerous tissues, whereas SA44 did not show selectivity towards glioma tissues. The results indicate that SA43 aptamer can differentiate between glioma and non-cancerous cells and tissues and therefore, shows promise for histological diagnosis of glioma. PMID:26252900

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

    SciTech Connect

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

    2015-07-15

    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

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

    PubMed Central

    2015-01-01

    BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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

  2. Season of Birth and Risk for Adult Onset Glioma

    PubMed Central

    Efird, Jimmy T.

    2010-01-01

    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. PMID:20623001

  3. Fluorescent Cancer-Selective Alkylphosphocholine Analogs For Intraoperative Glioma Detection

    PubMed Central

    Swanson, Kyle I.; Clark, Paul A.; Zhang, Ray R.; Kandela, Irawati K.; Farhoud, Mohammed; Weichert, Jamey P.; Kuo, John S.

    2015-01-01

    Background 5-ALA induced tumor fluorescence aids brain tumor resections but is not approved for routine use in the United States. We developed and describe testing of two novel fluorescent, cancer-selective alkylphosphocholine analogs, CLR1501 (green) and CLR1502 (near-infrared), in a proof-of-principle study for fluorescence-guided glioma surgery. Objective To demonstrate CLR1501 and CLR1502 are cancer cell-selective fluorescence agents in glioblastoma models and compare tumor (T) to normal brain (N) fluorescence ratios with 5-ALA. Methods CLR1501, CLR1502, 5-ALA were administered to mice with MRI-verified orthotopic U251 GBM and GSC-derived xenografts. Harvested brains were imaged using confocal microscopy (CLR1501), IVIS Spectrum imaging system (CLR1501, CLR1502, and 5-ALA), or Fluobeam near-infrared fluorescence imaging system (CLR1502). Imaging and quantitative analysis of T:N fluorescence ratios were performed. Results Excitation/emission peaks are 500/517nm for CLR1501, and 760/778nm for CLR1502. The observed T:N ratio of CLR1502 (9.28±1.08) was significantly higher (p<0.01) than CLR1501 (3.51±0.44 on confocal imaging; 7.23±1.63 on IVIS imaging) and 5-ALA (4.81±0.92). Near-infrared Fluobeam CLR1502 imaging in a mouse xenograft model demonstrated high contrast tumor visualization compatible with surgical applications. Conclusion CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain. CLR1501 exhibits a tumor to brain fluorescence ratio similar to 5-ALA, whereas CLR1502 has a superior tumor to brain fluorescence ratio. This study demonstrates the potential use of CLR1501 and CLR1502 in fluorescence-guided tumor surgery. PMID:25549194

  4. Restoration of Immune Responsiveness to Glioma by Vaccination of Mice with Established Brain Gliomas with a Semi-Allogeneic Vaccine.

    PubMed

    Gattoni-Celli, Sebastiano; Young, M Rita I

    2016-01-01

    Prior studies had shown the clinical efficacy of a semi-allogeneic glioma vaccine in mice with lethal GL261 gliomas. This was confirmed in the present study. As subcutaneous vaccination resulted in protection against tumor in the brain, the present study assessed the impact of this vaccination of mice bearing established GL261 brain gliomas on their cytokine production upon in vitro exposure to tumor-derived products. Mice with established GL261 brain gliomas were vaccinated subcutaneously with H-2(b) GL261 glioma cells fused with H-2(d) RAG-neo cells or with a mock vaccine of phosphate-buffered saline. The results of these analyses show that the presence of GL261 tumor-conditioned medium resulted in increased production of Th1, inflammatory and inhibitory cytokines by spleen cells from control mice and from vaccinated glioma-bearing mice. In contrast, spleen cells of tumor-bearing, mock-vaccinated mice produced lower levels of cytokines in the presence of tumor-conditioned media. However, these results also show that there was not a heightened level of cytokine production in the presence of tumor-conditioned medium by spleen cells of vaccinated mice over the production by spleen cells of control mice. Overall, these results show that vaccination slows growth of the GL261 tumors to the point where GL261-vaccinated mice do not show the signs of morbidly or splenic dysfunction exhibited by unvaccinated, late stage glioma-bearing mice. PMID:27598146

  5. Restoration of Immune Responsiveness to Glioma by Vaccination of Mice with Established Brain Gliomas with a Semi-Allogeneic Vaccine

    PubMed Central

    Gattoni-Celli, Sebastiano; Young, M. Rita I.

    2016-01-01

    Prior studies had shown the clinical efficacy of a semi-allogeneic glioma vaccine in mice with lethal GL261 gliomas. This was confirmed in the present study. As subcutaneous vaccination resulted in protection against tumor in the brain, the present study assessed the impact of this vaccination of mice bearing established GL261 brain gliomas on their cytokine production upon in vitro exposure to tumor-derived products. Mice with established GL261 brain gliomas were vaccinated subcutaneously with H-2b GL261 glioma cells fused with H-2d RAG-neo cells or with a mock vaccine of phosphate-buffered saline. The results of these analyses show that the presence of GL261 tumor-conditioned medium resulted in increased production of Th1, inflammatory and inhibitory cytokines by spleen cells from control mice and from vaccinated glioma-bearing mice. In contrast, spleen cells of tumor-bearing, mock-vaccinated mice produced lower levels of cytokines in the presence of tumor-conditioned media. However, these results also show that there was not a heightened level of cytokine production in the presence of tumor-conditioned medium by spleen cells of vaccinated mice over the production by spleen cells of control mice. Overall, these results show that vaccination slows growth of the GL261 tumors to the point where GL261-vaccinated mice do not show the signs of morbidly or splenic dysfunction exhibited by unvaccinated, late stage glioma-bearing mice. PMID:27598146

  6. Facing contrast-enhancing gliomas: perfusion MRI in grade III and grade IV gliomas according to tumor area.

    PubMed

    Di Stefano, Anna Luisa; Bergsland, Niels; Berzero, Giulia; Farina, Lisa; Rognone, Elisa; Gastaldi, Matteo; Aquino, Domenico; Frati, Alessandro; Tomasello, Francesco; Ceroni, Mauro; Marchioni, Enrico; Bastianello, Stefano

    2014-01-01

    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.

  7. Advances in Oncolytic Virus Therapy for Glioma

    PubMed Central

    Haseley, Amy; Alvarez-Breckenridge, Christopher; Chaudhury, Abhik Ray; Kaur, Balveen

    2009-01-01

    The World Health Organization grossly classifies the various types of astrocytomas using a grade system with grade IV gliomas having the worst prognosis. Oncolytic virus therapy is a novel treatment option for GBM patients. Several patents describe various oncolytic viruses used in preclinical and clinical trials to evaluate safety and efficacy. These viruses are natural or genetically engineered from different viruses such as HSV-1, Adenovirus, Reovirus, and New Castle Disease Virus. While several anecdotal studies have indicated therapeutic advantage, recent clinical trials have revealed the safety of their usage, but demonstration of significant efficacy remains to be established. Oncolytic viruses are being redesigned with an interest in combating the tumor microenvironment in addition to defeating the cancerous cells. Several patents describe the inclusion of tumor microenvironment modulating genes within the viral backbone and in particular those which attack the tumor angiotome. The very innovative approaches being used to improve therapeutic efficacy include: design of viruses which can express cytokines to activate a systemic antitumor immune response, inclusion of angiostatic genes to combat tumor vasculature, and also enzymes capable of digesting tumor extra cellular matrix (ECM) to enhance viral spread through solid tumors. As increasingly more novel viruses are being tested and patented, the future battle against glioma looks promising. PMID:19149710

  8. Diffuse intrinsic pontine glioma: poised for progress.

    PubMed

    Warren, Katherine E

    2012-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) are amongst the most challenging tumors to treat. Surgery is not an option, the effects of radiation therapy are temporary, and no chemotherapeutic agent has demonstrated significant efficacy. Numerous clinical trials of new agents and novel therapeutic approaches have been performed over the course of several decades in efforts to improve the outcome of children with DIPG, yet without success. The diagnosis of DIPG is based on radiographic findings in the setting of a typical clinical presentation, and tissue is not routinely obtained as the standard of care. The paradigm for treating children with these tumors has been based on that for supratentorial high-grade gliomas in adults as the biology of these lesions were presumed to be similar. However, recent pivotal studies demonstrate that DIPGs appear to be their own entity. Simply identifying this fact releases a number of constraints and opens opportunities for biologic investigation of these lesions, setting the stage to move forward in identifying DIPG-specific treatments. This review will summarize the current state of knowledge of DIPG, discuss obstacles to therapy, and summarize results of recent biologic studies.

  9. Photodynamic therapy of recurrent cerebral glioma

    NASA Astrophysics Data System (ADS)

    Zhu, Shu-Gan; Wu, Si-En; Chen, Zong-Qian; Sun, Wei

    1993-03-01

    Photodynamic therapy (PDT) was performed on 11 cases of recurrent cerebral glioma, including 3 cases of recurrent glioblastoma, 7 of recurrent anaplastic astrocytoma, and 1 recurrent ependymoma. Hematoporphyrin derivative (HPD) was administered intravenously at a dose of 4 - 7 mg/kg 5 - 24 hours before the operation. All patients underwent a craniotomy with a nearly radical excision of the tumor following which the tumor bed was irradiated with 630 nm laser light emitting either an argon pumped dye laser or frequency double YAG pumped dye laser for 30 to 80 minutes with a total dose of 50 J/cm2 (n equals 1), 100 J/cm2 (n equals 2), 200 J/cm2 (n equals 7), and 300 J/cm2 (n equals 1). The temperature was kept below 37 degree(s)C by irrigation. Two patients underwent postoperative radiotherapy. There was no evidence of increased cerebral edema, and no other toxicity by the therapy. All patients were discharged from the hospital within 15 days after surgery. We conclude that PDT using 4 - 7 mg/kg of HPD and 630 nm light with a dose of up to 300 J/cm2 can be used as an adjuvant therapy with no additional complications. Adjuvant PDT in the treatment of recurrent glioma is better than simple surgery.

  10. Gene Therapy and Targeted Toxins for Glioma

    PubMed Central

    Castro, Maria G.; Candolfi, Marianela; Kroeger, Kurt; King, Gwendalyn D.; Curtin, James F.; Yagiz, Kader; Mineharu, Yohei; Assi, Hikmat; Wibowo, Mia; Muhammad, AKM Ghulam; Foulad, David; Puntel, Mariana; Lowenstein, Pedro R.

    2011-01-01

    The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of nine to twelve months from diagnosis to death. Current treatment modalities are unable to significantly prolong survival in patients diagnosed with glioblastoma. As such, glioma is an attractive target for developing novel therapeutic approaches utilizing gene therapy. This review will examine the available preclinical models for glioma including xenographs, syngeneic and genetic models. Several promising therapeutic targets are currently being pursued in pre-clinical investigations. These targets will be reviewed by mechanism of action, i.e., conditional cytotoxic, targeted toxins, oncolytic viruses, tumor suppressors/oncogenes, and immune stimulatory approaches. Preclinical gene therapy paradigms aim to determine which strategies will provide rapid tumor regression and long-term protection from recurrence. While a wide range of potential targets are being investigated preclinically, only the most efficacious are further transitioned into clinical trial paradigms. Clinical trials reported to date are summarized including results from conditionally cytotoxic, targeted toxins, oncolytic viruses and oncogene targeting approaches. Clinical trial results have not been as robust as preclinical models predicted; this could be due to the limitations of the GBM models employed. Once this is addressed, and we develop effective gene therapies in models that better replicate the clinical scenario, gene therapy will provide a powerful approach to treat and manage brain tumors. PMID:21453286

  11. Survivin and gliomas: A literature review

    PubMed Central

    Varughese, Rosilin Kotakkathu; Torp, Sverre Helge

    2016-01-01

    Gliomas are the most common primary brain tumor, the diagnosis of which is challenging. In this respect, the use of immunohistochemical proliferation markers may aid diagnosis; survivin, also known as Baculoviral IAP Repeat Containing 5, is one such marker. Survivin is a unique member of the inhibitors of apoptosis protein gene family, and is known for its dual function as an apoptosis inhibitor and mitosis regulator. Furthermore, survivin has been demonstrated to be overexpressed in a number of malignancies. The purpose of the present literature review was to gain an overview of studies published on the diagnostic and/or prognostic use of survivin in gliomas. Using PubMed, 19 studies matching the inclusion criteria were ultimately included in the present review. The majority of the studies identified revealed that survivin was significantly associated with other proliferation markers, histological malignancy grade, and inversely associated with prognosis. However, there were a number of inconsistencies between studies, which suggests a requirement for standardization of immunohistochemical procedures. PMID:27588117

  12. SC-37THE ROLE OF NG2 EXPRESSING PROGENITOR CELLS IN DIFFUSE INTRINSIC PONTINE GLIOMA

    PubMed Central

    Yadavilli, Sridevi; Becher, Oren J.; Kambhampati, Madhuri; Packer, Roger J.; Nazarian, Javad

    2014-01-01

    Pediatric diffuse intrinsic pontine glioma (DIPG) is one of the most difficult cancers to treat. pLys27Met (K27M) driver mutation in the H3F3A (H3.3) and HIST1H3B (H3.1) genes of histone are correlated with a subgroup of DIPGs. Other genomic aberrations include p53 mutations and amplification of signaling pathways including PDGFRα. We have recently reported the involvement of Hedgehog (Hh) pathway in a subset of DIPGs. Modulation of Hh and tyrosine kinase receptors may alter the self-renewal properties of cancer stem cells (CSC). NG2 Proteoglycan positive cells that co-express PDGFRα and Olig-2 are present in adult gliomas, where NG2 contributes to the neoplastic transformation of glioma cells. We examined NG2 expression in frozen brainstem specimens of DIPGs and observed significant NG2 expression in DIPGs [10 of 14 (71 %), fold change = 33, p < 0.05)] as compared to the adjacent normal tissue. NG2 expression was associated with histone 3 K27M mutation [8 of 10 (80 %)]. Two mechanisms of NG2 regulation in DIPG were identified: i) histone 3 binds to NG2 promoter, and ii) miR 129-2 negatively regulates NG2. We detected downregulation of miR129-2 in 85.7% (6 of 7) of DIPG tumors compared to normal tissue (FC = -30.79, n = 7 pairs). We also found overall hypermethylation at 8 CpG loci corresponding to the miR129-2 promoter. NG2 knockdown in vitro (shRNA, miR129-2 or demethylating drugs) retards cellular migration. Luciferase assay in primary mouse glioma cells co-transfected with 3'UTR of NG2 and miR129-2 revealed regulation of NG2 by miR129-2. This was further confirmed in vivo by injection of NG2-dsRed transgenic mice with mir129-2 lentivirus. Orthotopic injection of NG2+ cells results in rapid tumor formation while NG2-KD cells fail to form tumors. Our study offers a potential model for the expansion of tumor stem cells and their self-renewal properties in DIPGs.

  13. Insulin-like growth factor-binding protein 2-driven glioma progression is prevented by blocking a clinically significant integrin, integrin-linked kinase, and NF-κB network

    PubMed Central

    Holmes, Kristen M.; Annala, Matti; Chua, Corrine Y. X.; Dunlap, Sarah M.; Liu, Yuexin; Hugen, Niek; Moore, Lynette M.; Cogdell, David; Hu, Limei; Nykter, Matti; Hess, Kenneth; Fuller, Gregory N.; Zhang, Wei

    2012-01-01

    Insulin-like growth factor-binding protein 2 (IGFBP2) is increasingly recognized as a glioma oncogene, emerging as a target for therapeutic intervention. In this study, we used an integrative approach to characterizing the IGFBP2 network, combining transcriptional profiling of human glioma with validation in glial cells and the replication-competent ASLV long terminal repeat with a splice acceptor/tv-a glioma mouse system. We demonstrated that IGFBP2 expression is closely linked to genes in the integrin and integrin-linked kinase (ILK) pathways and that these genes are associated with prognosis. We further showed that IGFBP2 activates integrin β1 and downstream invasion pathways, requires ILK to induce cell motility, and activates NF-κB. Most significantly, the IGFBP2/integrin/ILK/NF-κB network functions as a physiologically active signaling pathway in vivo by driving glioma progression; interfering with any point in the pathway markedly inhibits progression. The results of this study reveal a signaling pathway that is both targetable and highly relevant to improving the survival of glioma patients. PMID:22345562

  14. Erlotinib and Temsirolimus in Treating Patients With Recurrent Malignant Glioma

    ClinicalTrials.gov

    2015-05-29

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

  15. Cancer metabolism as a central driving force of glioma pathogenesis.

    PubMed

    Masui, Kenta; Cavenee, Webster K; Mischel, Paul S

    2016-07-01

    The recent identification of distinct genetic and epigenetic features in each glioma entity is leading to a multilayered, integrated diagnostic approach combining histologic features with molecular genetic information. Somatic mutations in isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways are key oncogenic events in diffuse gliomas, including lower grade (grade II and III) gliomas (LGG) and the highly lethal brain tumor glioblastoma (GBM), respectively, where they reprogram the epigenome, transcriptome, and metabolome to drive tumor growth. However, the mechanisms by which these genetic aberrations are translated into the aggressive nature of gliomas through metabolic reprogramming have just begun to be unraveled. The intricate interactions between the oncogenic signaling and cancer metabolism have also been recently demonstrated. Here, we describe a set of recent discoveries on cancer metabolism driven by IDH mutation and mutations in RTK pathways, highlighting the integration of genetic mutations, metabolic reprogramming, and epigenetic shifts, potentially providing new therapeutic opportunities. PMID:27295313

  16. Treatment Option Overview (Childhood Brain Stem Glioma Treatment)

    MedlinePlus

    ... before the cancer is diagnosed and continue for months or years. Childhood brain stem gliomas may cause ... after treatment. Some cancer treatments cause side effects months or years after treatment has ended. These are ...

  17. Terahertz pulsed spectroscopy of paraffin-embedded brain glioma

    NASA Astrophysics Data System (ADS)

    Meng, Kun; Chen, Tu-nan; Chen, Tao; Zhu, Li-guo; Liu, Qiao; Li, Zhao; Li, Fei; Zhong, Sen-cheng; Li, Ze-ren; Feng, Hua; Zhao, Jian-heng

    2014-07-01

    The refractive indices, absorption coefficients, and complex dielectric constants of paraffin-embedded brain glioma and normal brain tissues have been measured by a terahertz time-domain spectroscopy (THz-TDS) system in the 0.2- to 2.0-THz range. The spectral differences between gliomas and normal brain tissues were obtained. Compared with normal brain tissue, our results indicate that paraffin-embedded brain gliomas have a higher refractive index, absorption coefficient, and dielectric constant. Based on these results, the best THz frequencies for different methods of paraffin-embedded brain glioma imaging, such as intensity imaging, coherent imaging with continuum THz sources, and THz pulsed imaging with short-pulsed THz sources, are analyzed.

  18. Glioma Stemlike Cells Enhance the Killing of Glioma Differentiated Cells by Cytotoxic Lymphocytes.

    PubMed

    Bassoy, Esen Yonca; Chiusolo, Valentina; Jacquemin, Guillaume; Riccadonna, Cristina; Walker, Paul R; Martinvalet, Denis

    2016-01-01

    Glioblastoma multiforme, the most aggressive primary brain tumor, is maintained by a subpopulation of glioma cells with self-renewal properties that are able to recapitulate the entire tumor even after surgical resection or chemo-radiotherapy. This typifies the vast heterogeneity of this tumor with the two extremes represented on one end by the glioma stemlike cells (GSC) and on the other by the glioma differentiated cells (GDC). Interestingly, GSC are more sensitive to immune effector cells than the GDC counterpart. However, how GSC impact on the killing on the GDC and vice versa is not clear. Using a newly developed cytotoxicity assay allowing to simultaneously monitor cytotoxic lymphocytes-mediated killing of GSC and GDC, we found that although GSC were always better killed and that their presence enhanced the killing of GDC. In contrast, an excess of GDC had a mild protective effect on the killing of GSC, depending on the CTL type. Overall, our results suggest that during combination therapy, immunotherapy would be the most effective after prior treatment with conventional therapies. PMID:27073883

  19. Neurofibromatosis type 1 associated low grade gliomas: A comparison with sporadic low grade gliomas.

    PubMed

    Helfferich, Jelte; Nijmeijer, Ronald; Brouwer, Oebele F; Boon, Maartje; Fock, Annemarie; Hoving, Eelco W; Meijer, Lisethe; den Dunnen, Wilfred F A; de Bont, Eveline S J M

    2016-08-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, associated with a variable clinical phenotype including café-au-lait spots, intertriginous freckling, Lisch nodules, neurofibromas, optic pathway gliomas and distinctive bony lesions. NF1 is caused by a mutation in the NF1 gene, which codes for neurofibromin, a large protein involved in the MAPK- and the mTOR-pathway through RAS-RAF signalling. NF1 is a known tumour predisposition syndrome, associated with different tumours of the nervous system including low grade gliomas (LGGs) in the paediatric population. The focus of this review is on grade I pilocytic astrocytomas (PAs), the most commonly observed histologic subtype of low grade gliomas in NF1. Clinically, these PAs have a better prognosis and show different localisation patterns than their sporadic counterparts, which are most commonly associated with a KIAA1549:BRAF fusion. In this review, possible mechanisms of tumourigenesis in LGGs with and without NF1 will be discussed, including the contribution of different signalling pathways and tumour microenvironment. Furthermore we will discuss how increased understanding of tumourigenesis may lead to new potential targets for treatment. PMID:27263935

  20. Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature.

    PubMed

    Schleicher, Stephen M; Thotala, Dinesh K; Linkous, Amanda G; Hu, Rong; Leahy, Kathleen M; Yazlovitskaya, Eugenia M; Hallahan, Dennis E

    2011-01-01

    Despite wide margins and high dose irradiation, unresectable malignant glioma (MG) is less responsive to radiation and is uniformly fatal. We previously found that cytosolic phospholipase A2 (cPLA(2)) is a molecular target for radiosensitizing cancer through the vascular endothelium. Autotaxin (ATX) and lysophosphatidic acid (LPA) receptors are downstream from cPLA(2) and highly expressed in MG. Using the ATX and LPA receptor inhibitor, α-bromomethylene phosphonate LPA (BrP-LPA), we studied ATX and LPA receptors as potential molecular targets for the radiosensitization of tumor vasculature in MG. Treatment of Human Umbilical Endothelial cells (HUVEC) and mouse brain microvascular cells bEND.3 with 5 µmol/L BrP-LPA and 3 Gy irradiation showed decreased clonogenic survival, tubule formation, and migration. Exogenous addition of LPA showed radioprotection that was abrogated in the presence of BrP-LPA. In co-culture experiments using bEND.3 and mouse GL-261 glioma cells, treatment with BrP-LPA reduced Akt phosphorylation in both irradiated cell lines and decreased survival and migration of irradiated GL-261 cells. Using siRNA to knock down LPA receptors LPA1, LPA2 or LPA3 in HUVEC, we demonstrated that knockdown of LPA2 but neither LPA1 nor LPA3 led to increased viability and proliferation. However, knockdown of LPA1 and LPA3 but not LPA2 resulted in complete abrogation of tubule formation implying that LPA1 and LPA3 on endothelial cells are likely targets of BrP-LPA radiosensitizing effect. Using heterotopic tumor models of GL-261, mice treated with BrP-LPA and irradiation showed a tumor growth delay of 6.8 days compared to mice treated with irradiation alone indicating that inhibition of ATX and LPA receptors may significantly improve malignant glioma response to radiation therapy. These findings identify ATX and LPA receptors as molecular targets for the development of radiosensitizers for MG.

  1. Plexin-B2 promotes invasive growth of malignant glioma.

    PubMed

    Le, Audrey P; Huang, Yong; Pingle, Sandeep C; Kesari, Santosh; Wang, Huaien; Yong, Raymund L; Zou, Hongyan; Friedel, Roland H

    2015-03-30

    Invasive growth is a major determinant of the high lethality of malignant gliomas. Plexin-B2, an axon guidance receptor important for mediating neural progenitor cell migration during development, is upregulated in gliomas, but its function therein remains poorly understood. Combining bioinformatic analyses, immunoblotting and immunohistochemistry of patient samples, we demonstrate that Plexin-B2 is consistently upregulated in all types of human gliomas and that its expression levels correlate with glioma grade and poor survival. Activation of Plexin-B2 by Sema4C ligand in glioblastoma cells induced actin-based cytoskeletal dynamics and invasive migration in vitro. This proinvasive effect was associated with activation of the cell motility mediators RhoA and Rac1. Furthermore, costimulation of Plexin-B2 and the receptor tyrosine kinase Met led to synergistic Met phosphorylation. In intracranial glioblastoma transplants, Plexin-B2 knockdown hindered invasive growth and perivascular spreading, and resulted in decreased tumor vascularity. Our results demonstrate that Plexin-B2 promotes glioma invasion and vascularization, and they identify Plexin-B2 as a potential novel prognostic marker for glioma malignancy. Targeting the Plexin-B2 pathway may represent a novel therapeutic approach to curtail invasive growth of glioblastoma.

  2. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA.

    PubMed

    Kaneko, Sadahiro; Kaneko, Sadao

    2016-01-01

    Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

  3. Prospective, high-throughput molecular profiling of human gliomas

    PubMed Central

    Batchelor, Tracy T.; Dias-Santagata, Dora; Borger, Darrell; Stiles, Charles D.; Wang, Daphne L.; Curry, William T.; Wen, Patrick Y.; Ligon, Keith L.; Ellisen, Leif; Louis, David N.; Iafrate, A. John

    2013-01-01

    Gliomas consist of multiple histologic and molecular subtypes with different clinical phenotypes and responsiveness to treatment. However, enrollment criteria for clinical trials still largely do not take into account these underlying molecular differences. We have incorporated a high-throughput tumor genotyping program based on the ABI SNaPshot platform as well as other molecular diagnostic tests into the standard evaluation of glioma patients in order to assess whether prospective molecular profiling would allow rational patient selection onto clinical trials. From 218 gliomas we prospectively collected SNaPshot genotyping data on 68 mutated loci from 15 key cancer genes along with data from clinical assays for gene amplification (EGFR, PDGFRA, MET), 1p/19q co-deletion and MGMT promoter methylation. SNaPshot mutations and focal gene amplifications were detected in 38.5 and 47.1 % of glioblastomas, respectively. Genetic alterations in EGFR, IDH1 and PIK3CA closely matched frequencies reported in recent studies. In addition, we identified events that are rare in gliomas although are known driver mutations in other cancer types, such as mutations of AKT1, BRAF and KRAS. Patients with genetic alterations that activate signaling pathways were enrolled onto genetically selective clinical trials for malignant glioma as well as for other solid cancers. High-throughput molecular profiling incorporated into the routine clinical evaluation of glioma patients may enable the rational selection of patients for targeted therapy clinical trials and thereby improve the likelihood that such trials succeed. PMID:22821383

  4. Ion channel gene expression predicts survival in glioma patients.

    PubMed

    Wang, Rong; Gurguis, Christopher I; Gu, Wanjun; Ko, Eun A; Lim, Inja; Bang, Hyoweon; Zhou, Tong; Ko, Jae-Hong

    2015-08-03

    Ion channels are important regulators in cell proliferation, migration, and apoptosis. The malfunction and/or aberrant expression of ion channels may disrupt these important biological processes and influence cancer progression. In this study, we investigate the expression pattern of ion channel genes in glioma. We designate 18 ion channel genes that are differentially expressed in high-grade glioma as a prognostic molecular signature. This ion channel gene expression based signature predicts glioma outcome in three independent validation cohorts. Interestingly, 16 of these 18 genes were down-regulated in high-grade glioma. This signature is independent of traditional clinical, molecular, and histological factors. Resampling tests indicate that the prognostic power of the signature outperforms random gene sets selected from human genome in all the validation cohorts. More importantly, this signature performs better than the random gene signatures selected from glioma-associated genes in two out of three validation datasets. This study implicates ion channels in brain cancer, thus expanding on knowledge of their roles in other cancers. Individualized profiling of ion channel gene expression serves as a superior and independent prognostic tool for glioma patients.

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

    PubMed Central

    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. PMID:24212625

  6. Fluorescence-Guided Resection of Malignant Glioma with 5-ALA

    PubMed Central

    Kaneko, Sadahiro

    2016-01-01

    Malignant gliomas are extremely difficult to treat with no specific curative treatment. On the other hand, photodynamic medicine represents a promising technique for neurosurgeons in the treatment of malignant glioma. The resection rate of malignant glioma has increased from 40% to 80% owing to 5-aminolevulinic acid-photodynamic diagnosis (ALA-PDD). Furthermore, ALA is very useful because it has no serious complications. Based on previous research, it is apparent that protoporphyrin IX (PpIX) accumulates abundantly in malignant glioma tissues after ALA administration. Moreover, it is evident that the mechanism underlying PpIX accumulation in malignant glioma tissues involves an abnormality in porphyrin-heme metabolism, specifically decreased ferrochelatase enzyme activity. During resection surgery, the macroscopic fluorescence of PpIX to the naked eye is more sensitive than magnetic resonance imaging, and the alert real time spectrum of PpIX is the most sensitive method. In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments. In this paper, we provide an overview and present the results of our clinical research on ALA-PDD. PMID:27429612

  7. GLIOMA STEM CELL HOMING TO THE HUMAN SUBVENTRICULAR ZONE

    PubMed Central

    Sanai, Nader; Kusne, Yael; Su, Ning; Hemdan, Sandy; Mirzadeh, Zaman; Shi, Fu-Dong

    2014-01-01

    BACKGROUND: (blind field) METHODS: Using intraoperatively-derived human tissue, we employ a combination of cell culture, FACS-sorting, and immunohistochemistry techniques to characterize human glioma and GSC homing to the SVZ, as well as identify new, targetable cytokine pathways relevant to this niche. RESULTS: Our analysis identifies glioma cells homing to human SVZ and co-opting the gap layer for tangential migration. Interestingly, we find that human SVZ-invasive glioma cells are 50-fold more likely to function as glioma stem cells. Organotypic slice culture and co-culture assays also identify chemotactic effects, associated integrins, and related extracellular matrix proteins of 3 SVZ-enriched ligands (EGF, PDGF-BB, and SDF1) known to drive pro-migratory glioma pathways. CONCLUSIONS: Despite its quiescence, the adult human SVZ retains the signaling machinery to support cell migration and these mechanisms may be co-opted by glioma stem cells during subependymal spread in humans. SECONDARY CATEGORY: n/a.

  8. Galunisertib inhibits glioma vasculogenic mimicry formation induced by astrocytes.

    PubMed

    Zhang, Chao; Chen, Wenliang; Zhang, Xin; Huang, Bin; Chen, Aanjing; He, Ying; Wang, Jian; Li, Xingang

    2016-03-15

    Gliomas are among the most lethal primary brain tumors found in humans. In high-grade gliomas, vasculogenic mimicry is often detected and has been correlated with prognosis, thus suggesting its potential as a therapeutic target. Vasculogenic mimicry mainly forms vascular-like channels independent of endothelial cells; however, little is known about the relationship between astrocytes and vasculogenic mimicry. In our study, we demonstrated that the presence of astrocytes promoted vasculogenic mimicry. With suspension microarray technology and in vitro tube formation assays, we identified that astrocytes relied on TGF-β1 to enhance vasculogenic mimicry. We also found that vasculogenic mimicry was inhibited by galunisertib, a promising TGF-β1 inhibitor currently being studied in an ongoing trial in glioma patients. The inhibition was partially attributed to a decrease in autophagy after galunisertib treatment. Moreover, we observed a decrease in VE-cadherin and smooth muscle actin-α expression, as well as down-regulation of Akt and Flk phosphorylation in galunisertib-treated glioma cells. By comparing tumor weight and volume in a xenograft model, we acquired promising results to support our theory. This study expands our understanding of the role of astrocytes in gliomas and demonstrates that galunisertib inhibits glioma vasculogenic mimicry induced by astrocytes.

  9. Expression and prognostic significance of CTBP2 in human gliomas

    PubMed Central

    Wang, Yong; Che, Shusheng; Cai, Gang; He, Yuchao; Chen, Jialei; Xu, Wei

    2016-01-01

    Deregulated expression of C-terminal-binding protein 2 (CTBP2) has been observed previously in a number of tumors, such as hepatocellular carcinoma and prostatic cancer, in the colorectal cancer SW480 cell line and in the human embryonic kidney 293 cell line. In the present study, western blot analysis and immunohistochemistry were performed to investigate whether gliomas exhibit deregulated CTBP2 expression. Kaplan-Meier survival analyses were performed to evaluate the associations between CTBP2 expression, clinicopathological data and patient survival in glioma patients. The results revealed that CTBP2 expression was significantly upregulated in high grade glioma tissues compared with that in low grade glioma and normal brain tissues. Furthermore, increased CTBP2 expression in gliomas was significantly associated with a higher World Health Organization (WHO) tumor grade (P<0.005) and poorer disease-specific survival (P<0.005). In conclusion, these results suggest that CTBP2 may act as an intrinsic regulator of progression in glioma cells and thus may serve as an important prognostic factor for the disease.

  10. Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase*

    PubMed Central

    Ohkawa, Yuki; Momota, Hiroyuki; Kato, Akira; Hashimoto, Noboru; Tsuda, Yusuke; Kotani, Norihiro; Honke, Koichi; Suzumura, Akio; Furukawa, Keiko; Ohmi, Yuhsuke; Natsume, Atsushi; Wakabayashi, Toshihiko; Furukawa, Koichi

    2015-01-01

    There have been a few studies on the ganglioside expression in human glioma tissues. However, the role of these gangliosides such as GD3 and GD2 has not been well understood. In this study we employed a genetically engineered mouse model of glioma to clarify the functions of GD3 in gliomas. Forced expression of platelet-derived growth factor B in cultured astrocytes derived from p53-deficient mice resulted in the expression of GD3 and GD2. GD3-positive astrocytes exhibited increased cell growth and invasion activities along with elevated phosphorylation of Akt and Yes kinase. By enzyme-mediated activation of radical sources reaction and mass spectrometry, we identified PDGF receptor α (PDGFRα) as a GD3-associated molecule. GD3-positive astrocytes showed a significant amount of PDGFRα in glycolipid-enriched microdomains/rafts compared with GD3-negative cells. Src kinase family Yes was co-precipitated with PDGFRα, and its pivotal role in the increased cell invasion of GD3-positive astrocytes was demonstrated by silencing with anti-Yes siRNA. Direct association between PDGFRα and GD3 was also shown, suggesting that GD3 forms ternary complex with PDGFRα and Yes. The fact that GD3, PDGFRα, and activated Yes were colocalized in lamellipodia and the edge of tumors in cultured cells and glioma tissues, respectively, suggests that GD3 induced by platelet-derived growth factor B enhances PDGF signals in glycolipid-enriched microdomain/rafts, leading to the promotion of malignant phenotypes such as cell proliferation and invasion in gliomas. PMID:25940087

  11. Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase.

    PubMed

    Ohkawa, Yuki; Momota, Hiroyuki; Kato, Akira; Hashimoto, Noboru; Tsuda, Yusuke; Kotani, Norihiro; Honke, Koichi; Suzumura, Akio; Furukawa, Keiko; Ohmi, Yuhsuke; Natsume, Atsushi; Wakabayashi, Toshihiko; Furukawa, Koichi

    2015-06-26

    There have been a few studies on the ganglioside expression in human glioma tissues. However, the role of these gangliosides such as GD3 and GD2 has not been well understood. In this study we employed a genetically engineered mouse model of glioma to clarify the functions of GD3 in gliomas. Forced expression of platelet-derived growth factor B in cultured astrocytes derived from p53-deficient mice resulted in the expression of GD3 and GD2. GD3-positive astrocytes exhibited increased cell growth and invasion activities along with elevated phosphorylation of Akt and Yes kinase. By enzyme-mediated activation of radical sources reaction and mass spectrometry, we identified PDGF receptor α (PDGFRα) as a GD3-associated molecule. GD3-positive astrocytes showed a significant amount of PDGFRα in glycolipid-enriched microdomains/rafts compared with GD3-negative cells. Src kinase family Yes was co-precipitated with PDGFRα, and its pivotal role in the increased cell invasion of GD3-positive astrocytes was demonstrated by silencing with anti-Yes siRNA. Direct association between PDGFRα and GD3 was also shown, suggesting that GD3 forms ternary complex with PDGFRα and Yes. The fact that GD3, PDGFRα, and activated Yes were colocalized in lamellipodia and the edge of tumors in cultured cells and glioma tissues, respectively, suggests that GD3 induced by platelet-derived growth factor B enhances PDGF signals in glycolipid-enriched microdomain/rafts, leading to the promotion of malignant phenotypes such as cell proliferation and invasion in gliomas.

  12. [A unusual brain cortical tumor: angiocentric glioma].

    PubMed

    Tauziède-Espariat, Arnault; Fohlen, Martine; Ferrand-Sorbets, Sarah; Polivka, Marc

    2015-04-01

    We report the case of an 11-year-old girl, who was admitted for surgery of an epilepsy-associated brain tumor. The radiological and clinical hypothesis was dysembryoplasic neuroepithelial tumor. Histopathological examination revealed a tumoral proliferation composed of spindle-shaped cells with palisade arrangements around vessels. Tumor cells have small, round and regular nuclei without atypia or mitosis. On immunohistochemistry, the neoplastic cells strongly expressed GFAP and showed a characteristic cytoplasmic dot-like staining with EMA (epithelial membrane antigen). Ki-67 labeling index was low. Molecular analysis failed to reveal the V600E mutation of BRAF gene. The patient was free of seizures after surgery. Angiocentric glioma is a rare brain tumor occuring preferably in children and young adults and is associated with seizures. The precise histogenesis remains debated. The treatment of choice is total resection. The prognosis is favorable if totally resected.

  13. Efficacy of radiotherapy in optic gliomas.

    PubMed

    Gould, R J; Hilal, S K; Chutorian, A M

    1987-01-01

    Twenty-five children with optic gliomas were evaluated over a seven year period by sequential computed axial tomography in order to determine the efficacy of radiotherapy as a treatment modality. Indices of tumor progression or regression included both size and contrast enhancement characteristics. Twenty of 25 patients followed during this period received radiotherapy. Of these patients, ten had tumor regression, nine were stable, and one was worse. This result contrasts with five untreated patients, four of whom had tumor progression and one who was stable (x2 = 18.37, p less than .001). One of the children with tumor progression later received radiotherapy and demonstrated marked tumor regression. Of the 18 treated patients who could be tested reliably, visual function and/or regression occurred in seven children. None of the untreated patients improved. There were no definite complications of radiotherapy in this small group.

  14. Three-dimensional cultured glioma cell lines

    NASA Technical Reports Server (NTRS)

    Gonda, Steve R. (Inventor); Marley, Garry M. (Inventor)

    1991-01-01

    Three-dimensional glioma spheroids were produced in vitro with size and histological differentiation previously unattained. The spheroids were grown in liquid media suspension in a Johnson Space Center (JSC) Rotating Wall Bioreactor without using support matrices such as microcarrier beads. Spheroid volumes of greater than 3.5 cu mm and diameters of 2.5 mm were achieved with a viable external layer or rim of proliferating cells, a transitional layer beneath the external layer with histological differentiation, and a degenerative central region with a hypoxic necrotic core. Cell debris was evident in the degenerative central region. The necrotics centers of some of the spheroids had hyaline droplets. Granular bodies were detected predominantly in the necrotic center.

  15. Neurosarcoidosis mimicking a malignant optic glioma.

    PubMed

    Pollock, Jeffrey M; Greiner, Francis G; Crowder, Jason B; Crowder, Jessica W; Quindlen, Eugene

    2008-09-01

    A 55-year-old African-American man developed progressive unilateral optic neuropathy and periocular pain. MRI showed thickening and enhancement of the mid-orbital segment of the ipsilateral optic nerve. Optic neuritis was diagnosed, and he was treated with corticosteroids without improvement. After being lost to follow-up, he returned with worsening vision in the affected eye, aggravated pain, and proptosis. MRI now showed thickening and enhancement of the entire orbital and intracranial segments of the optic nerve. Because the patient had no light perception vision in that eye and a malignant glioma was suspected, he underwent optic nerve biopsy that revealed non-caseating granulomas throughout the optic nerve tissue. CT body imaging failed to disclose other evidence of sarcoidosis. Neurosarcoidosis limited to the optic nerve is rare but should always be suspected in such circumstances. An exhaustive effort to find extracranial evidence for this diagnosis should be undertaken before resorting to optic nerve biopsy.

  16. History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC).

    PubMed

    Amirian, E Susan; Scheurer, Michael E; Zhou, Renke; Wrensch, Margaret R; Armstrong, Georgina N; Lachance, Daniel; Olson, Sara H; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; 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

    2016-06-01

    Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted.

  17. MiR-203 sensitizes glioma cells to temozolomide and inhibits glioma cell invasion by targeting E2F3.

    PubMed

    Tang, Guodong; Wu, Jun; Xiao, Gelei; Huo, Lei

    2015-04-01

    Glioma is the most common malignant and fatal primary tumor in the central nervous system in adults. Recent data has suggested a profound role for microRNAs (miRs) in cancer progression. The present study demonstrated, via quantitative polymerase chain reaction (qPCR) analysis, that miR-203 expression was markedly lower in highly invasive U87MG glioma cells and glioma tissues. Wound healing and Transwell assays demonstrated that restoration of miR-203 expression inhibited U87MG cell migration and invasion. Restoration of miR-203 expression additionally sensitized the cells to temozolomide (TMZ) as determined by MTS assay. By contrast, miR-203 inhibition in A172 cells exerted opposite effects. Bioinformatic analysis combined with experimental analysis revealed that miR-203 directly targeted E2F3 via the conserved miR-203 target site within the E2F3 3'-untranslational region. E2F3 knockdown with specific small hairpin RNA also inhibited U87MG cell migration and invasion, and sensitized them to TMZ. Importantly, miR-203 and E2F3 showed inverse expression patterns in invasive glioma tissues, as demonstrated by qPCR and luciferase assay. These results suggested that miR-203 may function as a tumor suppressor in glioma progression and that the miR-203/E2F3 axis may be a novel candidate in the development of rational therapeutic strategies for glioma.

  18. History of chickenpox in glioma risk: a report from the glioma international case-control study (GICC).

    PubMed

    Amirian, E Susan; Scheurer, Michael E; Zhou, Renke; Wrensch, Margaret R; Armstrong, Georgina N; Lachance, Daniel; Olson, Sara H; Lau, Ching C; Claus, Elizabeth B; Barnholtz-Sloan, Jill S; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; 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

    2016-06-01

    Varicella zoster virus (VZV) is a neurotropic α-herpesvirus that causes chickenpox and establishes life-long latency in the cranial nerve and dorsal root ganglia of the host. To date, VZV is the only virus consistently reported to have an inverse association with glioma. The Glioma International Case-Control Study (GICC) is a large, multisite consortium with data on 4533 cases and 4171 controls collected across five countries. Here, we utilized the GICC data to confirm the previously reported associations between history of chickenpox and glioma risk in one of the largest studies to date on this topic. Using two-stage random-effects restricted maximum likelihood modeling, we found that a positive history of chickenpox was associated with a 21% lower glioma risk, adjusting for age and sex (95% confidence intervals (CI): 0.65-0.96). Furthermore, the protective effect of chickenpox was stronger for high-grade gliomas. Our study provides additional evidence that the observed protective effect of chickenpox against glioma is unlikely to be coincidental. Future studies, including meta-analyses of the literature and investigations of the potential biological mechanism, are warranted. PMID:26972449

  19. Proton Beam Radiation Therapy in Treating Patients With Low Grade Gliomas

    ClinicalTrials.gov

    2015-12-14

    Adult Brain Tumor; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Ependymoma; Adult Grade II Meningioma; Adult Melanocytic Lesion; Adult Meningeal Hemangiopericytoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pineal Gland Astrocytoma; Adult Pineocytoma; Recurrent Adult Brain Tumor

  20. Functionally Active Gap Junctions between Connexin 43-Positive Mesenchymal Stem Cells and Glioma Cells.

    PubMed

    Gabashvili, A N; Baklaushev, V P; Grinenko, N F; Levinskii, A B; Mel'nikov, P A; Cherepanov, S A; Chekhonin, V P

    2015-05-01

    The formation of functional gap junctions between mesenchymal stem cells and cells of low-grade rat glioma C6 cells was studied in in vitro experiments. Immunocytochemical analysis with antibodies to connexin 43 extracellular loop 2 showed that mesenchymal stem cells as well as C6 glioma cells express the main astroglial gap junction protein connexin 43. Analysis of migration activity showed that mesenchymal stem cells actively migrate towards C6 glioma cells. During co-culturing, mesenchymal stem cells and glioma C6 form functionally active gap junctions mediating the transport of cytoplasmic dye from glioma cells to mesenchymal stem cells in the opposite direction. Fluorometry showed that the intensity of transport of low-molecular substances through heterologous gap junctions between mesenchymal stem cells and glioma cells is similar to that through homologous gap junctions between glioma cells. This phenomenon can be used for the development of new methods of cell therapy of high-grade gliomas.

  1. Roles of microRNA-99 family in human glioma

    PubMed Central

    Zhang, Mingyu; Guo, Yong; Wu, Jun; Chen, Fenghua; Dai, Zhijie; Fan, Shuangshi; Li, Pengcheng; Song, Tao

    2016-01-01

    Objective Deregulation of microRNA (miR)-99 family members (miR-99a, miR-99b, and miR-100) has been reported to play a crucial role in many cancer types. However, their roles in human gliomas have not been fully elucidated. This study aimed to investigate the expression patterns of miR-99a, miR-99b, and miR-100 in glioma tissues and to evaluate their expression profiles with respect to tumor progression. Methods Quantitative real-time polymerase chain reaction was performed to detect the expression levels of miR-99a, miR-99b, and miR-100 in glioma and matched non-neoplastic brain tissues. Then, the associations of their expression with various clinicopathological features of glioma patients were statistically analyzed. Moreover, the roles of miR-99a, miR-99b, and miR-100 in regulating glioma cell migration and invasion were determined via transwell assay in vitro. Results Compared with non-neoplastic brain tissues, miR-99a, miR-99b, and miR-100 expression levels were all significantly decreased in glioma tissues (all P<0.001). miR-99a-low, miR-99b-low, and miR-100-low expression more frequently occurred in glioma patients with low Karnofsky performance score (<90) and high World Health Organization grade (III–IV). Further functional experiments revealed that the enforced expression of miR-99a, miR-99b, and miR-100 resulted in the inhibition of cellular migration and invasion in glioma cells. Conclusion Our results strongly suggest that the aberrant expression of miR-99a, miR-99b, and miR-100 may be a common feature in human gliomas with aggressive clinicopathological features and may participate in malignant phenotypes of the tumors. These findings highlight the potential of the three miR-99 family members as novel therapeutic targets for human gliomas. PMID:27382299

  2. Comparative characterization of the human and mouse third ventricle germinal zones.

    PubMed

    Dahiya, Sonika; Lee, Da Yong; Gutmann, David H

    2011-07-01

    Recent evidence indicates differences in neural stem cell biology in different brain regions. For example, we demonstrated that neurofibromatosis 1 (NF1) tumor suppressor gene inactivation leads to increased neural stem cell proliferation and gliogenesis in the optic chiasm and brainstem but not in the cerebral cortex. The differential effect of Nf1 inactivation in the optic nerve and brainstem (in which gliomas commonly form in children with NF1) versus the cortex (in which gliomas rarely develop) suggests the existence of distinct ventricular zones for gliomagenesis in children and in adults. Here, we characterized the third ventricle subventricular zone (tv-SVZ) in young and adult mouse and human brains. In children, but not adult humans, the tv-SVZ contains nestin-positive, glial fibrillary acidic protein-positive, brain fatty acid binding protein-positive, and sox2-positive cells with radial processes and prominent cilia. In contrast, the tv-SVZ in young mice contains sox2-positive progenitor cells and ciliated ependymal lining cells but lacks glial fibrillary acidic protein-positive, nestin-positive radial glia. As in the lateral ventricle SVZ, proliferation in the human and murine tv-SVZ decreases with age. The tv-SVZ in adult mice lacks the hypocellular subventricular zone observed in adult human specimens. Collectively, these data indicate the existence of a subventricular zone relevant to our understanding of glioma formation in children and will assist interpretation of genetically engineered mouse glioma models. PMID:21666496

  3. Use of Labelled tLyP-1 as a Novel Ligand Targeting the NRP Receptor to Image Glioma

    PubMed Central

    Wu, Hu-bing; Wang, Zhen; Wang, Quan-shi; Han, Yan-jian; Wang, Meng; Zhou, Wen-lan; Li, Hong-sheng

    2015-01-01

    Background Neuropilin (NRP) receptors are overexpressed in glioma tumor tissue, and therefore may be a potential target for imaging markers. We investigated whether labelled tLyP-1, an NRP targeting peptide, could be used as the targeting ligand for developing reagents for imaging glioma tumors. Methods The tLyP-1 peptide (CGNKRTR) was labeled with 5-carboxyfluorescein (FAM) or 18F-fluoride. A control peptide (MAQKTSH) was also labeled with FAM. The in vitro binding between FAM-tLyP-1 and U87MG cells and in vivo biodistribution of FAM-tLyP-1 in a U87MG glioblastoma xenograft model (nude mouse) were determined. The in vivo biodistribution of 18F-tLyP-1 was also determined by microPET/CT. Results In vitro, FAM-tLyP-1 was strongly taken up by U87MG cells at very low concentrations (1μM). In vivo, FAM-tLyP-1 accumulated in glioma (U87MG) tumors, but uptake was minimal in the normal brain tissue 1 h after administration. The distribution of FAM-tLyP-1 in the tumor tissue was consistent with expression of NRP1. The tumor/brain fluorescence intensity ratio in mice treated with FAM-tLyP-1 was significantly higher than the control FAM-labeled peptide 1 h after administration (3.44 ± 0.83 vs. 1.32 ± 0.15; t = 5.547, P = 0.001). Uptake of FAM-tLyP-1 in glioma tumors could be blocked by administering an excess of non-conjugated tLyP-1 peptide. [Lys4] tLyP-1 was labeled with 18F to synthesis a PET (18F-tLyP-1). MicroPET/CT imaging showed the tumor was visualized clearly with a high tumor/brain radiolabel ratio at 60 min (2.69 ± 0.52) and 120 min (3.11±0.25). Conclusion Taken together, our results suggest that tLyP-1 could be developed as a novel fluorescent or radio labelled tracer for imaging glioma. PMID:26398657

  4. IDH1 mutation detection by droplet digital PCR in glioma.

    PubMed

    Wang, Jing; Zhao, Yi-ying; Li, Jian-feng; Guo, Cheng-cheng; Chen, Fu-rong; Su, Hong-kai; Zhao, Hua-fu; Long, Ya-kang; Shao, Jian-yong; To, Shing shun Tony; Chen, Zhong-ping

    2015-11-24

    Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation.

  5. ZIP4 is a novel molecular marker for glioma

    PubMed Central

    Lin, Yi; Chen, Yong; Wang, Yongzhi; Yang, Jingxuan; Zhu, Vivian F.; Liu, Yulun; Cui, Xiaobo; Chen, Leon; Yan, Wei; Jiang, Tao; Hergenroeder, Georgene W.; Fletcher, Stephen A.; Levine, Jonathan M.; Kim, Dong H.; Tandon, Nitin; Zhu, Jay-Jiguang; Li, Min

    2013-01-01

    Background Dysregulated zinc transport has been observed in many cancers. However, the status of zinc homeostasis and the expression profile of zinc transporters in brain and brain tumors have not been reported. Methods The gene profiles of 14 zinc importers (ZIPs) and 10 zinc exporters (ZnTs) in patients with glioma were studied by investigating the association between the zinc transporters and brain tumor characteristics (tumor grade and overall survival time). Three independent cohorts were analyzed to cross-validate the findings: the Chinese Glioma Genome Atlas (CGCA) cohort (n = 186), the US National Cancer Institute Repository for Molecular Brain Neoplasia Data (REMBRANDT) cohort (n = 335), and The University of Texas (UT) cohort (n = 34). Results The expression of ZIP3, 4, 8, 14, ZnT5, 6, and 7 were increased, and the expression of ZnT10 was decreased in grade IV gliomas, compared with grade II gliomas. Among all 24 zinc transporters, ZIP4 is most significantly associated with tumor grade and overall survival; this finding is consistent across 2 independent cohorts (CGCA and REMBRANDT) and is partially validated by the third cohort (UT). High ZIP4 expression was significantly associated with higher grade of gliomas and shorter overall survival (hazard ratio = 1.61, 95% confidence interval = 1.02–2.53, P = .040 in CGCA cohort; hazard ratio = 1.32, 95% confidence interval = 1.08–1.61, P = .007 in REMBRANDT cohort). Conclusions Dysregulated expression of zinc transporters is involved in the progression of gliomas. Our results suggest that ZIP4 may serve as a potential diagnostic and prognostic marker for gliomas. PMID:23595627

  6. The role of drebrin in glioma migration and invasion

    SciTech Connect

    Terakawa, Yuzo; Agnihotri, Sameer; Golbourn, Brian; Nadi, Mustafa; Sabha, Nesrin; Smith, Christian A.; Croul, Sidney E.; Rutka, James T.

    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.

  7. Surgical Outcomes of High-Grade Spinal Cord Gliomas

    PubMed Central

    Hida, Kazutoshi; Yano, Syunsuke; Aoyama, Takeshi; Koyanagi, Izumi; Houkin, Kiyohiro

    2015-01-01

    Study Design A retrospective study. Purpose The purpose of this study was to obtain useful information for establishing the guidelines for treating high-grade spinal cord gliomas. Overview of Literature The optimal management of high-grade spinal cord gliomas remains controversial. We report the outcomes of the surgical management of 14 high-grade spinal glioma. Methods We analyzed the outcomes of 14 patients with high-grade spinal cord gliomas who were surgically treated between 1989 and 2012. Survival was charted with the Kaplan-Meier plots and comparisons were made with the log-rank test. Results None of the patients with high-grade spinal cord gliomas underwent total resection. Subtotal resection was performed in two patients, partial resection was performed in nine patients, and open biopsy was performed in three patients. All patients underwent postoperative radiotherapy and six patients further underwent radiation cordotomy. The median survival time for patients with high-grade spinal cord gliomas was 15 months, with a 5-year survival rate of 22.2%. The median survival time for patients with World Health Organization grade III tumors was 25.5 months, whereas the median survival time for patients with glioblastoma multiforme was 12.5 months. Both univariate and multivariate Cox proportional hazards models demonstrated a significant effect only in the group that did not include cervical cord lesion as a factor associated with survival (p=0.04 and 0.03). Conclusions The surgical outcome of patients diagnosed with high-grade spinal cord gliomas remains poor. Notably, only the model which excluded cervical cord lesions as a factor significantly predicted survival. PMID:26713128

  8. IDH1 mutation detection by droplet digital PCR in glioma

    PubMed Central

    Wang, Jing; Zhao, Yi-ying; Li, Jian-feng; Guo, Cheng-cheng; Chen, Fu-rong; Su, Hong-kai; Zhao, Hua-fu; Long, Ya-kang; Shao, Jian-yong; Tony To, Shing-shun; Chen, Zhong-ping

    2015-01-01

    Glioma is the most frequent central nervous system tumor in adults. The overall survival of glioma patients is disappointing, mostly due to the poor prognosis of glioblastoma (Grade IV glioma). Isocitrate dehydrogenase (IDH) is a key factor in metabolism and catalyzes the oxidative decarboxylation of isocitrate. Mutations in IDH genes are observed in over 70% of low-grade gliomas and some cases of glioblastoma. As the most frequent mutation, IDH1(R132H) has been served as a predictive marker of glioma patients. The recently developed droplet digital PCR (ddPCR) technique generates a large amount of nanoliter-sized droplets, each of which carries out a PCR reaction on one template. Therefore, ddPCR provides high precision and absolute quantification of the nucleic acid target, with wide applications for both research and clinical diagnosis. In the current study, we collected 62 glioma tissue samples (Grade II to IV) and detected IDH1 mutations by Sanger direct sequencing, ddPCR, and quantitative real-time PCR (qRT-PCR). With the results from Sanger direct sequencing as the standard, the characteristics of ddPCR were compared with qRT-PCR. The data indicated that ddPCR was much more sensitive and much easier to interpret than qRT-PCR. Thus, we demonstrated that ddPCR is a reliable and sensitive method for screening the IDH mutation. Therefore, ddPCR is able to applied clinically in predicting patient prognosis and selecting effective therapeutic strategies. Our data also supported that the prognosis of Grade II and III glioma was better in patients with an IDH mutation than in those without mutation. PMID:26485760

  9. Corpus callosum involvement and postoperative outcomes of patients with gliomas.

    PubMed

    Chen, Ko-Ting; Wu, Tai-Wei Erich; Chuang, Chi-Cheng; Hsu, Yung-Hsin; Hsu, Peng-Wei; Huang, Yin-Cheng; Lin, Tzu-Kang; Chang, Chen-Nen; Lee, Shih-Tseng; Wu, Chieh-Tsai; Tseng, Chen-Kan; Wang, Chun-Chieh; Pai, Ping-Ching; Wei, Kuo-Chen; Chen, Pin-Yuan

    2015-09-01

    Corpus callosum involvement is associated with poorer survival in high grade glioma (HGG), but the prognostic value in low grade glioma (LGG) is unclear. To determine the prognostic impact of corpus callosum involvement on progression free survival (PFS) and overall survival (OS) in HGG and LGG, the records of 233 glioma patients treated from 2008 to 2011 were retrospectively reviewed. Preoperative magnetic resonance (MR) images were used to identify corpus callosum involvement. Age, sex, preoperative Karnofsky performance scale, postoperative Eastern Cooperative Oncology Group (ECOG) score and extent of resection (EOR) were evaluated with respect to PFS and OS. The incidence of corpus callosum involvement was similar among HGG (14 %) and LGG (14.5 %). Univariate analysis revealed that PFS and OS were significantly shorter in both WHO grade II and grade IV glioma with corpus callosum involvement (both, p < 0.05). Multivariate analysis showed that grade II glioma with corpus callosum involvement have shorter PFS (p = 0.03), while EOR, instead of corpus callosum involvement (p = 0.16), was an independent factor associated with PFS in grade IV glioma (p < 0.05). Corpus callosum involvement was no longer significantly associated with OS after adjusting age, gender, EOR, preoperative and postoperative performance status (p = 0.16, 0.17 and 0.56 in grade II, III and IV gliomas, respectively). Corpus callosum involvement happened in both LGG and HGG, and is associated with lower EOR and higher postoperative ECOG score both in LGG and HGG. Corpus callosum involvement tends to be an independent prognostic factor for PFS in LGG, but not for OS in LGG or in HGG.

  10. Glioma cells escaped from cytotoxicity of temozolomide and vincristine by communicating with human astrocytes.

    PubMed

    Chen, Weiliang; Wang, Donghai; Du, Xinwen; He, Ying; Chen, Songyu; Shao, Qianqian; Ma, Chao; Huang, Bin; Chen, Anjing; Zhao, Peng; Qu, Xun; Li, Xingang

    2015-03-01

    Resistance to chemotherapeutic drugs remains a great obstacle to successful treatment of gliomas. Understanding the mechanism of glioma chemoresistance is conducive to develop effective strategies to overcome resistance. Astrocytes are the major stromal cells in the brain and have been demonstrated to play a key role in the malignant phenotype of gliomas. However, little is known regarding its role in glioma chemoresistance. In our study, we established a co-culture system of human astrocytes and glioma in vitro to simulate tumor microenvironment. Our results showed that astrocytes significantly reduced glioma cell apoptosis induced by the chemotherapeutic drugs temozolomide and vincristine. This protective effect was dependent on direct contact between astrocytes and glioma cells through Cx43-GJC. Moreover, in human glioma specimens, we found astrocytes infiltrating around the tumor, with a reactive appearance, suggesting that these astrocytes would play the same chemoprotective effect on gliomas in vivo. Our results expand the understanding of the interaction between astrocytes and glioma cells and provide a possible explanation for unsatisfactory clinical outcomes of chemotherapeutic drugs. Cx43-GJC between astrocytes and glioma cells may be a potential target for overcoming chemoresistance in gliomas clinically. PMID:25631631

  11. Glioma cell integrin expression and their interactions with integrin antagonists

    PubMed Central

    Mattern, Ralph-Heiko; Read, Susana B.; Pierschbacher, Michael D.; Sze, Chun-I; Eliceiri, Brian P.; Kruse, Carol A.

    2005-01-01

    Summary A panel of human glioma cell explants was screened for integrin expression by flow cytometry using ανβ-specific antibodies. A lower percentage of the glioma cells were positive for the ανβ3 (mean % positive = 20.8%) integrin, whereas higher percentages were positive for the ανβ5 (mean % positive = 72.7%), VLA5α (mean % positive = 87%) and VLAβ1 (mean % positive = 41.7%) integrins. A series of RGD peptides was designed, synthesized and tested for binding to integrin receptors. Based on the results of the binding to the isolated integrin receptors and the expression of integrins on glioma cell lines, a peptide that binds potently to the ανβ3, ανβ5 and α5β1 was selected for further investigations with regards to its effect on glioma cells. The peptide, Ac-c[(Pen)-Tyr(Me)-Ala-Arg-Gly-Asp-Asn-Tic-Cys]NH2 (RGD peptide), exhibited high potential for use in clinical intracranial administration since it had good stability in rat brain cell homogenates placed into artificial cerebrospinal fluid. Using an HPLC method for quantification of peptides in rat brain cell homogenates, we could demonstrate the half-life of the RGD peptide approximated 20 hr. Relative to a scrambled peptide control (non-RGD sequence, same amino acids), the experimental RGD peptide significantly decreased glioma cell proliferation of the entire panel of rat and human glioma cells tested. Adhesion of recently passaged glioma cells to glioma-derived extracellular matrix protein-coated plates was inhibited significantly by the RGD peptide. The peptide also reversed attachment of plated glioma cells. The RGD peptide caused some, but not substantial, glioma cell injury, as evidenced by a quantitative in vitro nuclear DNA morphologic assay and by a flow cytometric assay employing 7-amino actinomycin D (7AAD). We histologically monitored for toxicity caused by various doses of the RGD peptide infused repeatedly into normal cannulated rat brain. At safe doses, the experimental RGD

  12. Molecular analysis of diffuse intrinsic brainstem gliomas in adults.

    PubMed

    Reyes-Botero, German; Giry, Marine; Mokhtari, Karima; Labussière, Marianne; Idbaih, Ahmed; Delattre, Jean-Yves; Laigle-Donadey, Florence; Sanson, Marc

    2014-01-01

    Diffuse intrinsic brainstem gliomas (DIBG) account for 1-2 % of adult gliomas. Their biological characteristics are scarcely understood and whether DIBG are biologically different from supratentorial gliomas remains to be established. We analyzed 17 DIBG samples for IDH1 R132H, alpha internexin, p53, and Ki67 expression, and, in a subset with sufficient DNA amount, for IDH1 and histone H3 mutational status, genomic profiling and MGMT promoter methylation status. A series of 738 adult supratentorial gliomas was used for comparison. Median age at diagnosis was 41 years (range 18.9-65.3 years). Median overall survival was 48.7 months (57 months for low-grade vs. 16 months for high-grade gliomas, p < 0.01). IDH1 sequencing revealed two mutations (IDH1 (R132G) , IDH1 (R132C) ) out of 7 DIBG whereas the R132H IDH1 enzyme was detected in 1/17 DIBG, suggesting that IDH1 mutations are mostly non R132H in DIBG (2/2), in contrast to supratentorial gliomas (31/313; p = 0.01). Mutations in histone genes H3F3A (encoding H3.3) and HIST1H3B (encoding H3.1) were found in 3/8 (37.5 %) of the DIBG (two H3F3A (K27M) and one HIST1H3B (K27M) ) versus 6/205 (2.9 %) of the supratentorial high-grade gliomas (four H3F3A (G34R) and two H3F3A (K27M) ) (p = 0.002). The CGH array showed a higher frequency of chromosome arm 1q gain, 9q gain and 11q loss in DIBG compared to the supratentorial high-grade gliomas, which had a less frequent chromosome 7 gain, and a less frequent chromosome 10 loss. No EGFR amplification was found. These data suggest that adult DIBG differ from adult supratentorial gliomas. In particular, histone genes (H3F3A (K27M) , HIST1H3B (K27M) ) mutations are frequent in adult DIBG whereas IDH1 (R132H) mutations are rare. PMID:24242757

  13. Targeting the erythropoietin receptor on glioma cells reduces tumour growth

    SciTech Connect

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

    2011-10-01

    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.

  14. Diffuse Intrinsic Pontine Glioma: Time for Cautious Optimism.

    PubMed

    Hennika, Tammy; Becher, Oren J

    2016-10-01

    Diffuse intrinsic pontine glioma is a lethal brain cancer that arises in the pons of children. The median survival for children with diffuse intrinsic pontine glioma is less than 1 year from diagnosis, and no improvement in survival has been realized in more than 30 years. Currently, the standard of care for diffuse intrinsic pontine glioma is focal radiation therapy, which provides only temporary relief. Recent genomic analysis of tumors from biopsies and autopsies, have resulted in the discovery of K27M H3.3/H3.1 mutations in 80% and ACVR1 mutations in 25% of diffuse intrinsic pontine gliomas, providing renewed hope for future success in identifying effective therapies. In addition, as stereotactic tumor biopsies at diagnosis at specialized centers have been demonstrated to be safe, biopsies have now been incorporated into several prospective clinical trials. This article summarizes the epidemiology, clinical presentation, diagnosis, prognosis, molecular genetics, current treatment, and future therapeutic directions for diffuse intrinsic pontine glioma.

  15. microRNA-149 targets caspase-2 in glioma progression

    PubMed Central

    Liao, Wenfeng; Wang, Jiwen; Chen, Huanjun; Yao, Yanli; Liu, Houbao; Ding, Kan

    2016-01-01

    Malignant gliomas are the most common form of intrinsic primary brain tumors worldwide. Alterations in microRNAs play a role in highly invasive malignant glioma, but detail mechanism still unknown. In this study, the role and mechanism of microRNA-149 (miR-149) in glioma are investigated. We show that miR-149 is expressed at substantially higher levels in glioma than in normal tissues. Stable overexpression of miR-149 augments potent prosurvival activity, as evidenced by promotion of cell viability, inhibition of apoptosis, and induced xenografted tumor growth in vivo. We further show that Caspase-2 is identified as a functional target of miR-149 and expression of caspase-2 is inversely associated with miR-149 in vitro. In addition, miR-149 promotes tumor survival in the U87-MG and A172 cell lines and it targets caspase-2 via inactivation of the p53 and p21 pathways. There results support a special role for miR-149 by targeting Caspase-2 to impact on p53 signaling pathway. We speculate that miR-149 has distinct biological functions in p53 wild type cells and p53 mutation cells, and the mechanisms involved remain to be explored in future. Our study suggests that targeting miR-149 may be a novel therapy strategy for treating p53 wild type glioma tumors in humans. PMID:27049919

  16. Multidimensional assessment of empathic abilities in patients with insular glioma.

    PubMed

    Chen, Peng; Wang, Guangming; Ma, Ru; Jing, Fang; Zhang, Yongjun; Wang, Ying; Zhang, Peng; Niu, Chaoshi; Zhang, Xiaochu

    2016-10-01

    Recent studies have provided evidence that there are two possible systems for empathy: affective empathy (AE) and cognitive empathy (CE). Neuroimaging paradigms have proven that the insular cortex is involved in empathy processing, particularly in AE. However, these observations do not provide causal evidence for the role of the insula in empathy. Although impairments in empathy have been described following insular damage in a few case studies, it is not clear whether insular cortex is involved in CE and whether these two systems are impaired independently or laterally in patients with insular gliomas. In this study, we assessed 17 patients with an insular glioma, 17 patients with a noninsular glioma, and 30 healthy controls using a method that combined a self-report empathy questionnaire with the emotion recognition task, assessment of empathy for others' pain, and the emotional perspective-taking paradigm. We found that patients with an insular glioma had lower scores for empathic concern and perspective taking than did either healthy controls or lesion controls. The patients' abilities to recognize facial emotions, perceive others' pain, and understand the emotional perspectives of others were also significantly impaired. Furthermore, we did not observe a laterality effect on either AE or CE among those with insular lesions. These findings revealed that both AE and CE are impaired in patients with an insular glioma and that the insular cortex may be a central neuroanatomical structure in both the AE and CE systems. PMID:27456973

  17. Concurrent thermochemoradiotherapy for brain high-grade glioma

    NASA Astrophysics Data System (ADS)

    Ryabova, A. I.; Novikov, V. A.; Choinzonov, E. L.; Gribova, O. V.; Startseva, Zh. A.; Bober, E. E.; Frolova, I. G.; Baranova, A. V.

    2016-08-01

    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.

  18. Decreased Expression of Cystathionine β-Synthase Promotes Glioma Tumorigenesis

    PubMed Central

    Takano, Naoharu; Sarfraz, Yasmeen; Gilkes, Daniele M.; Chaturvedi, Pallavi; Xiang, Lisha; Suematsu, Makoto; Zagzag, David; Semenza, Gregg L.

    2014-01-01

    Cystathionine β-synthase (CBS) catalyzes metabolic reactions that convert homocysteine to cystathionine. To assess the role of CBS in human glioma, cells were stably transfected with lentiviral vectors encoding short hairpin RNA (shRNA) targeting CBS or a non-targeting control shRNA and subclones were injected into immunodeficient mice. Interestingly, decreased CBS expression did not affect proliferation in vitro but decreased the latency period prior to rapid tumor xenograft growth after subcutaneous injection and increased tumor incidence and volume following orthotopic implantation into the caudate-putamen. In soft agar colony formation assays, CBS knockdown subclones displayed increased anchorage-independent growth. Molecular analysis revealed that CBS knockdown subclones expressed higher basal levels of the transcriptional activator hypoxia-inducible factor 2α (HIF-2α/EPAS1). HIF-2α knockdown counteracted the effect of CBS knockdown on anchorage-independent growth. Bioinformatic analysis of mRNA expression data from human glioma specimens revealed a significant association between low expression of CBS mRNA and high expression of angiopoietin-like 4 (ANGPTL4) and vascular endothelial growth factor (VEGF) transcripts, which are HIF-2 target gene products that were also increased in CBS knockdown subclones. These results suggest that decreased CBS expression in glioma increases HIF-2α protein levels and HIF-2 target gene expression, which promotes glioma tumor formation. Implications CBS loss of function promotes glioma growth. PMID:24994751

  19. Pathology and Genetics of Diffuse Gliomas in Adults

    PubMed Central

    KOMORI, Takashi

    2015-01-01

    The current World Health Organization (WHO) classification of tumors of the central nervous system (CNS) is essentially a lineage-oriented classification based on a presumable developmental tree of CNS. A four-tiered WHO grading scheme has been successfully applied to a spectrum of diffusely infiltrative astrocytomas, but it is not fully applicable to other gliomas, including oligodendrogliomas and ependymomas. Recent genetic studies have revealed that the major categories of gliomas, such as circumscribe astrocytomas, infiltrating astrocytomas/oligodendrogliomas, and glioblastoma, roughly correspond to major genetic alterations, including isocitrate dehydrogenases (IDHs) 1/2 mutations, TP53 mutations, co-deletion of chromosome arms 1p/19q, and BRAF mutation/fusion. These genetic alterations are clinically significant in terms of the response to treatment(s) and/or the prognosis. It is, thus, rational that future classification of gliomas should be based on genotypes, rather than phenotypes, although the genetic features of each tumor are not sufficiently understood at present to draw a complete map of the gliomas, and genetic testing is not yet available worldwide, particularly in Asian and African countries. This review summarizes the current concepts of the WHO classification, as well as the current understanding of the major genetic alterations in glioma and the potential use of these alterations as diagnostic criteria. PMID:25744348

  20. Deciphering the 8q24.21 association for glioma

    PubMed Central

    Enciso-Mora, Victor; Hosking, Fay J.; Kinnersley, Ben; Wang, Yufei; Shete, Sanjay; Zelenika, Diana; Broderick, Peter; Idbaih, Ahmed; Delattre, Jean-Yves; Hoang-Xuan, Khe; Marie, Yannick; Di Stefano, Anna Luisa; Labussière, Marianne; Dobbins, Sara; Boisselier, Blandine; Ciccarino, Pietro; Rossetto, Marta; Armstrong, Georgina; Liu, Yanhong; Gousias, Konstantinos; Schramm, Johannes; Lau, Ching; Hepworth, Sarah J.; Strauch, Konstantin; Müller-Nurasyid, Martina; Schreiber, Stefan; Franke, Andre; Moebus, Susanne; Eisele, Lewin; Forsti, Asta; Hemminki, Kari; Tomlinson, Ian P.; Swerdlow, Anthony; Lathrop, Mark; Simon, Matthias; Bondy, Melissa; Sanson, Marc; Houlston, Richard S

    2013-01-01

    We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10−38) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10−67). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10−28). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10−94). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development. PMID:23399484

  1. Malignant glioma - timing of response to radiation therapy

    SciTech Connect

    Gaspar, L.E.; Fisher, B.J.; MacDonald, D.R.; Cairncross, J.G. London Regional Cancer Centre, Ontario ); LeBer, D.V. ); Halperin, E.C.; Schold, S.C. Jr. )

    1993-04-02

    The response of malignant gliomas to radiation was examined retrospectively in 71 patients with newly diagnosed supratentorial malignant gliomas. Questions asked included frequency, timing and clinical significance of response. After surgery, all were treated with whole brain plus boost radiotherapy followed 8 weeks later by chemotherapy. The rate, degree, and timing of response to radiation were determined by comparing postoperative, end of radiation, and prechemotherapy CT scans on each patient. Postoperative residual tumor was evident on 63/71 postoperative scans. Twenty-two of 63 tumors (35%) had a partial or complete response to radiation. Twenty (32%) had responded by the end of radiation; 17 maximally. Six to 8 weeks later, three responding tumors had responded further and two previously stable ones had begun to respond. Only three tumors (5%) responded completely. A greater proportion of anaplastic gliomas than glioblastomas responded to radiation (52% vs. 26%). Protracted or delayed responses were only observed in patients with anaplastic glioma. Patients who responded to radiation did not live significantly longer than non-responders. However, tumor progression prior to chemotherapy was associated with significantly shorter survival. This CT scan-based analysis demonstrates that malignant gliomas are only moderately radioresponsive tumors and also demonstrates that response to radiation, if it is going to occur, is usually evident by the end of treatment. 6 refs., 1 fig., 1 tab.

  2. Mcl-1 downregulation sensitizes glioma to bortezomib-induced apoptosis.

    PubMed

    Zhang, Yang; Zhu, Xiaobo; Hou, Kun; Zhao, Jinchuan; Han, Zhiguo; Zhang, Xiaona

    2015-05-01

    Glioma is the most aggressive form of primary brain tumor, with dismal patient outcome and no effective therapeutic approaches available. Targeting the ubiquitin-proteasome pathway has recently emerged as a potent rational anticancer strategy. Bortezomib, a specific proteasome inhibitor, has been approved for the treatment of relapsed or refractory multiple myeloma and other hematological malignancies as a single agent or as part of a combination therapy. However, bortezomib alone or in combination showed only minimal effects in the treatment of solid tumors. Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein which protects tumor cells against spontaneous and chemotherapy-induced apoptosis. In multiple myeloma, specific downregulation of Mcl-1 induces apoptosis. Furthermore, previous studies demonstrated that proteasome inhibitors induce Mcl-1 accumulation that, in turn, slows down their pro-apoptotic effects, and the cell survival in multiple myeloma is highly dependent on Mcl-1. In the present study, we investigated the role of Mcl-1 downregulation in bortezomib-induced apoptosis in gliomas. We observed that bortezomib triggers caspase-3 and PARP activation, upregulates cytochrome c expression and induces apoptosis. Furthermore, we demonstrated that effective targeting of Mcl-1 in glioma cells by gene silencing technology augments the glioma cell sensitivity to bortezomib-induced apoptosis. In conclusion, the present study demonstrates that Mcl-1 plays a critical role in bortezomib-induced apoptosis. Mcl-1 inhibitor in combination with bortezomib present a promising novel strategy to trigger cell death pathways in the treatment of gliomas.

  3. The molecular biology of WHO grade II gliomas.

    PubMed

    Marko, Nicholas F; Weil, Robert J

    2013-02-01

    The WHO grading scheme for glial neoplasms assigns Grade II to 5 distinct tumors of astrocytic or oligodendroglial lineage: diffuse astrocytoma, oligodendroglioma, oligoastrocytoma, pleomorphic xanthoastrocytoma, and pilomyxoid astrocytoma. Although commonly referred to collectively as among the "low-grade gliomas," these 5 tumors represent molecularly and clinically unique entities. Each is the subject of active basic research aimed at developing a more complete understanding of its molecular biology, and the pace of such research continues to accelerate. Additionally, because managing and predicting the course of these tumors has historically proven challenging, translational research regarding Grade II gliomas continues in the hopes of identifying novel molecular features that can better inform diagnostic, prognostic, and therapeutic strategies. Unfortunately, the basic and translational literature regarding the molecular biology of WHO Grade II gliomas remains nebulous. The authors' goal for this review was to present a comprehensive discussion of current knowledge regarding the molecular characteristics of these 5 WHO Grade II tumors on the chromosomal, genomic, and epigenomic levels. Additionally, they discuss the emerging evidence suggesting molecular differences between adult and pediatric Grade II gliomas. Finally, they present an overview of current strategies for using molecular data to classify low-grade gliomas into clinically relevant categories based on tumor biology.

  4. A graphic method for identification of novel glioma related genes.

    PubMed

    Gao, Yu-Fei; Shu, Yang; Yang, Lei; He, Yi-Chun; Li, Li-Peng; Huang, GuaHua; Li, Hai-Peng; Jiang, Yang

    2014-01-01

    Glioma, as the most common and lethal intracranial tumor, is a serious disease that causes many deaths every year. Good comprehension of the mechanism underlying this disease is very helpful to design effective treatments. However, up to now, the knowledge of this disease is still limited. It is an important step to understand the mechanism underlying this disease by uncovering its related genes. In this study, a graphic method was proposed to identify novel glioma related genes based on known glioma related genes. A weighted graph was constructed according to the protein-protein interaction information retrieved from STRING and the well-known shortest path algorithm was employed to discover novel genes. The following analysis suggests that some of them are related to the biological process of glioma, proving that our method was effective in identifying novel glioma related genes. We hope that the proposed method would be applied to study other diseases and provide useful information to medical workers, thereby designing effective treatments of different diseases.

  5. Chemotherapy for gliomas in mainland China: An overview

    PubMed Central

    SAI, KE; YANG, QUN-YING; SHEN, DONG; CHEN, ZHONG-PING

    2013-01-01

    Chemotherapy is currently the standard treatment modality for malignant gliomas. Many patients with gliomas are treated in mainland China every year. The history and development of chemotherapy for glioma, however, are not well documented. In this study, an extensive literature search of Pubmed and major Chinese electronic databases was performed to identify clinical studies. A total of 210 publications were identified, with a total of 10,105 patients. Among these studies, 76.2% were retrospective and 23.8% were prospective. Chemotherapy was found to have been administered by the Department of Neurosurgery in 143 studies (68.1%). Oral or intravenous administration was found in 55.7% of studies, followed by intra-arterial (26.7%) and interstitial (15.7%) chemotherapy. Nitrosoureas were the most frequently used chemotherapeutic agents, as found in 133 studies (63.3%). Since 2003, 56 studies on temozolomide (TMZ) have been published. Studies on chemotherapy for gliomas began in the 1970s in mainland China but well-designed randomized controlled trials (RCTs) are rare. Much effort and collaboration should be made to carry out high-quality multicenter RCTs on chemotherapy for gliomas. PMID:23761809

  6. 2-Hydroxyglutarate as a Magnetic Resonance Biomarker for Glioma Subtyping1

    PubMed Central

    Esmaeili, Morteza; Vettukattil, Riyas; Bathen, Tone Frost

    2013-01-01

    Mutations in the isocitrate dehydrogenase (IDH) genes are frequently found in gliomas and in a fraction of acute myeloid leukemia patients. This results in the production of an oncometabolite, 2-hydroxyglutarate (2-HG). Glioma patients harboring IDH mutations have a longer survival than their wild-type counterparts. 2-HG has been detected noninvasively in gliomas with IDH mutations using magnetic resonance spectroscopy (MRS), suggesting its potential clinical relevance for identifying glioma subtypes with better prognosis. In this paper, the recent developments in the MRS detection of the 2-HG in gliomas are reviewed, including the therapeutic potentials and translational values. PMID:23544162

  7. Relapse of herpes encephalitis induced by temozolomide-based chemoradiation in a patient with malignant glioma.

    PubMed

    Okada, Masaki; Miyake, Keisuke; Shinomiya, Aya; Kawai, Nobuyuki; Tamiya, Takashi

    2013-02-01

    The authors report on a case of concurrent herpes simplex encephalitis (HSE) and malignant glioma. The co-occurrence of HSE and malignant glioma is very rare, but it can occur during glioma treatment. Both radiotherapy and chemoradiation with temozolomide can induce viral reactivation, leading to HSE relapse. Careful observation for HSE is necessary when administering chemoradiation to patients with a history of HSE. Antiviral therapy for HSE must be initiated immediately, and the chemoradiation for glioma should be stopped; however, it is not clear what antitumor therapy is optimal when HSE co-occurs during the treatment of glioma.

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

    PubMed

    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. PMID:22440864

  9. Noninvasive Imaging of Natural Killer Cell-Mediated Apoptosis in a Mouse Tumor Model.

    PubMed

    Singh, Thoudam Debraj; Lee, Jaetae; Jeon, Yong Hyun

    2016-01-01

    Natural killer (NK) cells are cytotoxic lymphocytes that induce apoptosis in cancer cells infected with viruses and bacteria through a caspase-3-dependent pathway. Effective NK cell-based immunotherapy requires highly sensitive imaging tools for in vivo monitoring of the dynamic events involved in apoptosis. Here, we describe a noninvasive bioluminescence imaging approach to determine the antitumor effects of NK cell-based therapy by serial imaging of caspase-3-dependent apoptosis in a mouse model of human glioma. PMID:27177676

  10. Novel therapeutic delivery approaches in development for pediatric gliomas.

    PubMed

    Warren, Katherine E

    2013-09-01

    Pediatric gliomas are a heterogeneous group of diseases, ranging from relatively benign pilocytic astrocytomas with >90% 5-year survival, to glioblastomas and diffuse intrinsic pontine gliomas with <20% 5-year survival. Chemotherapy plays an important role in the management of these tumors, particularly in low-grade gliomas, but many high-grade tumors are resistant to chemotherapy. A major obstacle and contributor to this resistance is the blood–brain barrier, which protects the CNS by limiting entry of potential toxins, including chemotherapeutic agents. Several novel delivery approaches that circumvent the blood–brain barrier have been developed, including some currently in clinical trials. This review describes several of these novel approaches to improve delivery of chemotherapeutic agents to their site of action at the tumor, in attempts to improve their efficacy and the prognosis of children with this disease.

  11. Glioma-initiating cells and molecular pathology: implications for therapy.

    PubMed

    Natsume, Atsushi; Kinjo, Sayano; Yuki, Kanako; Kato, Takenori; Ohno, Masasuke; Motomura, Kazuya; Iwami, Kenichiro; Wakabayashi, Toshihiko

    2011-02-01

    There is now compelling evidence that gliomas harbor a small population of cells, termed glioma-initiating cells (GICs), characterized by their ability to undergo self-renewal and initiate tumorigenesis. The development of therapeutic strategies targeted toward GIC signaling may improve the treatment of malignant gliomas. The characterization of GICs provides a clue to elucidating histological heterogeneity and treatment failure. The role of the stem cell marker CD133 in the initiation and progression of brain tumors is still uncertain. Here, we review some of the signaling mechanisms involved in GIC biology, such as phosphatase and tensin homolog (PTEN), sonic hedgehog, Notch, and WNT signaling pathways, maternal embryonic leucine-zipper kinase (MELK), BMI1, and Janus kinase signal transducer and activator of transcription (JAK-STAT) signaling. In addition, we discuss the role of microRNAs in GICs by focusing on microRNA-21 regulation by type I interferon.

  12. Effects of photodynamic therapy on human glioma spheroids

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Sun, Chung-Ho; Chu, Eugene A.; Hirschberg, Henry; Tromberg, Bruce J.

    1999-07-01

    The poor prognosis for patients with malignant brain neoplasm has led to a search for better treatment modalities. Although gliomas are considered to be disseminated tumors in the brain, most recur at the site of the previous tumor resection. Improved local control would thus be of clear benefit. The utility of photodynamic therapy (PDT) in the treatment of brain neoplasms is investigated using a human glioma spheroid model. Specifically, the effects of PDT on human glioma spheroids are investigated using PhotofrinTM and 56-aminolevulinic acid (ALA). The effects of various irradiation schemes were monitored using a simple growth assay. A growth delay was observed at an optical fluence of approximately 35 J cm-2 for spheroids incubated in Photofrin. Spheroids incubated in ALA were unaffected by the PDT treatment regimens examined in this study. This was most likely a result of inadequate photosensitizer concentration.

  13. Targeting autophagy to sensitive glioma to temozolomide treatment.

    PubMed

    Yan, Yuanliang; Xu, Zhijie; Dai, Shuang; Qian, Long; Sun, Lunquan; Gong, Zhicheng

    2016-02-02

    Temozolomide (TMZ), an alkylating agent, is widely used for treating primary and recurrent high-grade gliomas. However, the efficacy of TMZ is often limited by the development of resistance. Recently, studies have found that TMZ treatment could induce autophagy, which contributes to therapy resistance in glioma. To enhance the benefit of TMZ in the treatment of glioblastomas, effective combination strategies are needed to sensitize glioblastoma cells to TMZ. In this regard, as autophagy could promote cell survival or autophagic cell death, modulating autophagy using a pharmacological inhibitor, such as chloroquine, or an inducer, such as rapamycin, has received considerably more attention. To understand the effectiveness of regulating autophagy in glioblastoma treatment, this review summarizes reports on glioblastoma treatments with TMZ and autophagic modulators from in vitro and in vivo studies, as well as clinical trials. Additionally, we discuss the possibility of using autophagy regulatory compounds that can sensitive TMZ treatment as a chemotherapy for glioma treatment.

  14. The Microenvironment in Gliomas: Phenotypic Expressions

    PubMed Central

    Schiffer, Davide; Annovazzi, Laura; Mazzucco, Marta; Mellai, Marta

    2015-01-01

    The microenvironment of malignant gliomas is described according to its definition in the literature. Beside tumor cells, a series of stromal cells (microglia/macrophages, pericytes, fibroblasts, endothelial cells, normal and reactive astrocytes) represents the cell component, whereas a complex network of molecular signaling represents the functional component. Its most evident expressions are perivascular and perinecrotic niches that are believed to be the site of tumor stem cells or progenitors in the tumor. Phenotypically, both niches are not easily recognizable; here, they are described together with a critical revision of their concept. As for perinecrotic niches, an alternative interpretation is given about their origin that regards the tumor stem cells as the residue of those that populated hyperproliferating areas in which necroses develop. This is based on the concept that the stem-like is a status and not a cell type, depending on the microenvironment that regulates a conversion of tumor non-stem cells and tumor stem cells through a cell reprogramming. PMID:26633514

  15. Epigenetic aberrations and therapeutic implications in gliomas.

    PubMed

    Natsume, Atsushi; Kondo, Yutaka; Ito, Motokazu; Motomura, Kazuya; Wakabayashi, Toshihiko; Yoshida, Jun

    2010-06-01

    Almost all cancer cells have multiple epigenetic abnormalities, which combine with genetic changes to affect many cellular processes, including cell proliferation and invasion, by silencing tumor-suppressor genes. In this review, we focus on the epigenetic mechanisms of DNA hypomethylation and CpG island hypermethylation in gliomas. Aberrant hypermethylation in promoter CpG islands has been recognized as a key mechanism involved in the silencing of cancer-associated genes and occurs at genes with diverse functions related to tumorigenesis and tumor progression. Such promoter hypermethylation can modulate the sensitivity of glioblastomas to drugs and radiotherapy. As an example, the methylation of the O6-methylguanine DNA methyltransferase (MGMT) promoter is a specific predictive biomarker of tumor responsiveness to chemotherapy with alkylating agents. Further, we reviewed reports on pyrosequencing - a simple technique for the accurate and quantitative analysis of DNA methylation. We believe that the quantification of MGMT methylation by pyrosequencing might enable the selection of patients who are most likely to benefit from chemotherapy. Finally, we also evaluated the potential of de novo NY-ESO-1, the most immunogenic cancer/testis antigen (CTA) discovered thus far, as an immunotherapy target. The use of potent epigenetics-based therapy for cancer cells might restore the abnormally regulated epigenomes to a more normal state through epigenetic reprogramming. Thus, epigenetic therapy may be a promising and potent treatment for human neoplasia.

  16. Protein Markers Predict Survival in Glioma Patients.

    PubMed

    Stetson, Lindsay C; Dazard, Jean-Eudes; Barnholtz-Sloan, Jill S

    2016-07-01

    Glioblastoma multiforme (GBM) is a genomically complex and aggressive primary adult brain tumor, with a median survival time of 12-14 months. The heterogeneous nature of this disease has made the identification and validation of prognostic biomarkers difficult. Using reverse phase protein array data from 203 primary untreated GBM patients, we have identified a set of 13 proteins with prognostic significance. Our protein signature predictive of glioblastoma (PROTGLIO) patient survival model was constructed and validated on independent data sets and was shown to significantly predict survival in GBM patients (log-rank test: p = 0.0009). Using a multivariate Cox proportional hazards, we have shown that our PROTGLIO model is distinct from other known GBM prognostic factors (age at diagnosis, extent of surgical resection, postoperative Karnofsky performance score (KPS), treatment with temozolomide (TMZ) chemoradiation, and methylation of the MGMT gene). Tenfold cross-validation repetition of our model generation procedure confirmed validation of PROTGLIO. The model was further validated on an independent set of isocitrate dehydrogenase wild-type (IDHwt) lower grade gliomas (LGG)-a portion of these tumors progress rapidly to GBM. The PROTGLIO model contains proteins, such as Cox-2 and Annexin 1, involved in inflammatory response, pointing to potential therapeutic interventions. The PROTGLIO model is a simple and effective predictor of overall survival in glioblastoma patients, making it potentially useful in clinical practice of glioblastoma multiforme. PMID:27143410

  17. Fluorescent Affibody Peptide Penetration in Glioma Margin Is Superior to Full Antibody

    PubMed Central

    Sexton, Kristian; Tichauer, Kenneth; Samkoe, Kimberley S.; Gunn, Jason; Hoopes, P. Jack; Pogue, Brian W.

    2013-01-01

    Object Fluorescence imaging has the potential to significantly improve neurosurgical resection of oncologic lesions through improved differentiation between normal and cancerous tissue at the tumor margins. In order to successfully mark glioma tissue a fluorescent tracer must have the ability to penetrate through the blood brain barrier (BBB) and provide delineation in the tumor periphery where heterogeneously intact BBB may exist. In this study it was hypothesized that, due to its smaller size, fluorescently labeled anti-EGFR Affibody protein (∼7 kDa) would provide a more clear delineation of the tumor margin than would fluorescently labeled cetuximab, a full antibody (∼150 kDa) to the epidermal growth factor receptor (EGFR). Methods Cetuximab and anti-EGFR targeted Affibody were conjugated to two different fluorescent dyes (both emitting in the near-infrared) and injected intravenously into 6 athymic mice which were inoculated orthotopically with green fluorescent protein (GFP) expressing human U251 glioma cells. Each mouse was sacrificed at 1-h post injection, at which time brains were removed, snap frozen, sectioned and quantitatively analyzed for fluorescence distribution. Results Ex vivo analysis showed on average, nearly equal concentrations of cetuximab and Affibody within the tumor (on average Affibody made up 49±6% of injected protein), however, the cetuximab was more confined to the center of the tumor with Affibody showing significantly higher concentrations at the tumor periphery (on average Affibody made up 72±15% of injected protein in the outer 50 um of the tumor). Further ex vivo analysis of detection studies showed that the Affibody provided superior discrimination for differentiation of tumor from surrounding normal brain. Conclusions The present study indicates that fluorescently labeled anti-EGFR Affibody can provide significantly better delineation of tumor margins than a fluorescently labeled anti-EGFR antibody and shows considerable

  18. Diffusion tensor imaging suggests extrapontine extension of pediatric diffuse intrinsic pontine gliomas

    PubMed Central

    Wagner, Matthias W.; Bell, W. Robert; Kern, Jason; Bosemani, Thangamadhan; Mhlanga, Joyce; Carson, Kathryn A.; Cohen, Kenneth J.; Raabe, Eric H.; Rodriguez, Fausto; Huisman, Thierry A.G.M.; Poretti, Andrea

    2016-01-01

    Purpose To apply DTI to detect early extrapontine extension of pediatric diffuse intrinsic pontine glioma along the corticospinal tracts. Methods In children with diffuse intrinsic pontine glioma, low-grade brainstem glioma, and age-matched controls, DTI metrics were measured in the posterior limb of the internal capsule and posterior centrum semiovale. Histological examination was available in one patient. Results 6 diffuse intrinsic pontine glioma, 8 low-grade brainstem glioma, and two groups of 25 controls were included. In diffuse intrinsic pontine glioma compared to controls, fractional anisotropy was lower in the bilateral posterior limb of the internal capsule, axial diffusivity was lower in the bilateral posterior centrum semiovale and posterior limb of the internal capsule, while radial diffusivity was higher in the bilateral posterior limb of the internal capsule. No significant differences were found between low-grade brainstem glioma and controls. In diffuse intrinsic pontine glioma compared to low-grade brainstem glioma, axial diffusivity was lower in the bilateral posterior limb of the internal capsule. Histological examination in one child showed tumor cells in the posterior limb of the internal capsule. Conclusion Reduction in fractional anisotropy and axial diffusivity and increase in radial diffusivity in diffuse intrinsic pontine glioma may reflect tumor extension along the corticospinal tracts as shown by histology. DTI may detect early extrapontine tumor extension in diffuse intrinsic pontine glioma before it becomes apparent on conventional MRI sequences. PMID:26971411

  19. Role of IL-6 in the invasiveness and prognosis of glioma.

    PubMed

    Shan, Yongzhi; He, Xin; Song, Wei; Han, Dong; Niu, Jianxing; Wang, Jianzhen

    2015-01-01

    IL-6 is a cytokine secreted by glioma cells and plays an important role in the tumor growth. However, the impact of IL-6 on the invasiveness and prognosis of glioma is still unclear. In this study, immunohistochemistry was performed to determine the expression of IL-6 in 86 glioma tissues, and ELISA to measure IL-6 in the serum and cerebrospinal fluid (CSF) of these patients. Results showed, as ccompared with normal controls, the IL-6 in the glioma, CSF and serumincreased remarkably, and increased with the elevation of glioma grade. In addition, IL-6 in the supernatant was also detectable in glioma cell lines U251, U87, A172 and T98G. Transwell invasion assay showed that the invasiveness of glioma U87 cells and U251 cells increased remarkably after exogenous IL-6 treatment. Survival analysis indicated higher IL-6 before surgery and significantly reduction in IL-6 after operation in the serum and CSF predicted a poor prognosis. Thus, we speculate that, the poor prognosis of glioma is related to the IL-6 autocrine in the glioma and the IL-6 induced tumor growth and invasion. IL-6 may serve as a therapeutic target for glioma patients and IL-6 in the CSF and serum of glioma may be used to predict the prognosis of these patients. PMID:26309566

  20. Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain.

    PubMed

    Zagzag, David; Salnikow, Konstantin; Chiriboga, Luis; Yee, Herman; Lan, Li; Ali, M Aktar; Garcia, Roberto; Demaria, Sandra; Newcomb, Elizabeth W

    2005-03-01

    Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechip technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex (MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo. Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT-PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for beta2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo, respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a 'stealth'-like manner.

  1. Pleiotrophin, an angiogenic and mitogenic growth factor, is expressed in human gliomas.

    PubMed

    Mentlein, Rolf; Held-Feindt, Janka

    2002-11-01

    Pleiotrophin (PTN) is a mitogenic/angiogenic, 15.3 kDa heparin-binding peptide that is found in embryonic or early postnatal, but rarely in adult, tissues. Since developmentally regulated factors often re-appear in malignant cells, we examined PTN expression in human glioma cell lines, cell cultures derived from solid gliomas and glioma sections. PTN mRNA or protein was detected by reverse transcriptase-polymerase chain reaction, immunohistochemistry, western blot or enzyme-linked immunoassay in all WHO III and IV grade gliomas and cells analyzed in vitro or in situ. One WHO II grade glioma investigated was PTN negative. In vitro, PTN was synthesized in perinuclear regions of glioma cells, secreted into the cultivation medium, but its production varied considerably between glioma cells cultivated from different solid gliomas or glioma cell lines. In situ, PTN expression was restricted to distinct parts/cells of the tumour. PTN did not influence the proliferation of glioma cells themselves, but stimulated [3H]thymidine incorporation into DNA of microglial cells. Furthermore, in Boyden chamber assays, PTN showed a strong chemotactic effect on murine BV-2 microglial cells. PTN is supposed to be a paracrine growth/angiogenic factor that is produced by gliomas and contributes to their malignancy by targeting endothelial and microglial cells.

  2. Autophagy contributes to gefitinib-induced glioma cell growth inhibition

    SciTech Connect

    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

    2014-09-10

    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.

  3. Mathematical modeling of efficient protocols to control glioma growth.

    PubMed

    Branco, J R; Ferreira, J A; de Oliveira, Paula

    2014-09-01

    In this paper we propose a mathematical model to describe the evolution of glioma cells taking into account the viscoelastic properties of brain tissue. The mathematical model is established considering that the glioma cells are of two phenotypes: migratory and proliferative. The evolution of the migratory cells is described by a diffusion-reaction equation of non Fickian type deduced considering a mass conservation law with a non Fickian migratory mass flux. The evolution of the proliferative cells is described by a reaction equation. A stability analysis that leads to the design of efficient protocols is presented. Numerical simulations that illustrate the behavior of the mathematical model are included.

  4. Molecular biology of gliomas: present and future challenges

    PubMed Central

    Altieri, R.; Agnoletti, A.; Quattrucci, F.; Garbossa, D.; Calamo Specchia, F. M.; Bozzaro, M.; Fornaro, R.; Mencarani, C.; Lanotte, M.; Spaziante, R.; Ducati, A.

    2014-01-01

    Malignant brain tumours are one of the most relevant causes of morbidity and mortality across a wide range of individuals. Malignant glioma is the most common intra axial tumor in the adult. Many researches on this theme brought advances in the knowledge of gliomas biology and pathogenesis and to the development of new agents for targeted molecular therapy. Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors. This Review summarizes these developments analyzing molecular pathology and possible further developments for targeted therapies. PMID:25147764

  5. Molecular biology of gliomas: present and future challenges.

    PubMed

    Altieri, R; Agnoletti, A; Quattrucci, F; Garbossa, D; Calamo Specchia, F M; Bozzaro, M; Fornaro, R; Mencarani, C; Lanotte, M; Spaziante, R; Ducati, A

    2014-09-01

    Malignant brain tumours are one of the most relevant causes of morbidity and mortality across a wide range of individuals. Malignant glioma is the most common intra axial tumor in the adult. Many researches on this theme brought advances in the knowledge of gliomas biology and pathogenesis and to the development of new agents for targeted molecular therapy. Recent studies focused on either tumor metabolism analysis or epigenetic regulation in the pathogenesis or maintenance of brain tumors. This Review summarizes these developments analyzing molecular pathology and possible further developments for targeted therapies.

  6. Destruction of vasculogenic mimicry channels by targeting epirubicin plus celecoxib liposomes in treatment of brain glioma

    PubMed Central

    Ju, Rui-Jun; Zeng, Fan; Liu, Lei; Mu, Li-Min; Xie, Hong-Jun; Zhao, Yao; Yan, Yan; Wu, Jia-Shuan; Hu, Ying-Jie; Lu, Wan-Liang

    2016-01-01

    The efficacy of chemotherapy for brain glioma is restricted by the blood–brain barrier (BBB), and surgery or radiotherapy cannot eliminate the glioma cells because of their unique location. Residual brain glioma cells can form vasculogenic mimicry (VM) channels that can cause a recurrence of brain glioma. In the present study, targeting liposomes incorporating epirubicin and celecoxib were prepared and used for the treatment of brain glioma, along with the destruction of their VM channels. Evaluations were performed on the human brain glioma U87MG cells in vitro and on intracranial brain glioma-bearing nude mice. Targeting epirubicin plus celecoxib liposomes in the circulatory blood system were able to be transported across the BBB, and accumulated in the brain glioma region. Then, the liposomes were internalized by brain glioma cells and killed glioma cells by direct cytotoxic injury and the induction of apoptosis. The induction of apoptosis was related to the activation of caspase-8- and -3-signaling pathways, the activation of the proapoptotic protein Bax, and the suppression of the antiapoptotic protein Mcl-1. The destruction of brain glioma VM channels was related to the downregulation of VM channel-forming indictors, which consisted of MMP-2, MMP-9, FAK, VE-Cad, and VEGF. The results demonstrated that the targeting epirubicin plus celecoxib liposomes were able to effectively destroy the glioma VM channels and exhibited significant efficacy in the treatment of intracranial glioma-bearing nude mice. Therefore, targeting epirubicin plus celecoxib liposomes could be a potential nanostructured formulation to treat gliomas and destroy their VM channels. PMID:27042063

  7. Pharmacokinetics of Gd(DO3A-Lys) and MR imaging studies in an orthotopic U87MG glioma tumor model.

    PubMed

    Chandrasekharan, Prashant; Yang, Chang-Tong; Nasrallah, Fatima Ali; Tay, Hui Chien; Chuang, Kai-Hsiang; Robins, Edward G

    2015-01-01

    Pharmacokinetics of Gd(DO3A-Lys), a macrocyclic gadolinium-based magnetic resonance imaging (MRI) contrast agent functionalized with a lysine derivative, was studied in Wistar rats. Kinetic data were fitted using a two-compartment model and revealed Gd(DO3A-Lys) to have a distribution half-life, t1/2 (α), of 1.3 min, an elimination half-life, t1/2 (β), of 24.9 min and a large volume of distribution, VD , of 0.49 L/kg indicative of the agent being able to rapidly distribute into tissues and organs. Contrast-enhanced magnetic resonance angiography (CE-MRA) in an orthotopic U87MG glioma mouse model demonstrated considerable enhancement of both the tumor and surrounding vasculature after intravenous administration of Gd(DO3A-Lys). Applying dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the glioma of different sizes further showed distinct uptake characteristics and patterns of enhancement, which suggests the potential for differentiating changes at different stages of tumor growth. Our results indicate that Gd(DO3A-Lys) could be a promising candidate for glioma MR imaging. PMID:25612157

  8. Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

    NASA Astrophysics Data System (ADS)

    Quarles, C. A.; Ballmann, Charles; Yang, S. H.

    2009-04-01

    The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. While early results suggested a small decrease in o-Ps pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.

  9. Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

    NASA Astrophysics Data System (ADS)

    Yang, SH.; Ballmann, C.; Quarles, C. A.

    2009-03-01

    The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported [G. Liu, et al. phys. stat. sol. (C) 4, Nos. 10, 3912-3915 (2007)]. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. For the rat glioma model, 200,000 C6 cells were implanted in the basal ganglion of adult Sprague Dawley rats. The rats were sacrificed at 21 days after implantation. The brains were harvested, sliced into 2 mm thick coronal sections, and fixed in 4% formalin. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. The lifetime spectra were analyzed into two lifetime components. While early results suggested a small decrease in ortho-Positronium (o-Ps) pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. The o-Ps lifetime in formalin alone was lower than either the normal tissue or glioma sample. So annihilation in the formalin absorbed in the samples would lower the o-Ps lifetime and this may have masked any difference due to the glioma itself. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.

  10. Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

    SciTech Connect

    Yang, SH.; Ballmann, C.; Quarles, C. A.

    2009-03-10

    The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported [G. Liu, et al. phys. stat. sol. (C) 4, Nos. 10, 3912-3915 (2007)]. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. For the rat glioma model, 200,000 C6 cells were implanted in the basal ganglion of adult Sprague Dawley rats. The rats were sacrificed at 21 days after implantation. The brains were harvested, sliced into 2 mm thick coronal sections, and fixed in 4% formalin. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. The lifetime spectra were analyzed into two lifetime components. While early results suggested a small decrease in ortho-Positronium (o-Ps) pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. The o-Ps lifetime in formalin alone was lower than either the normal tissue or glioma sample. So annihilation in the formalin absorbed in the samples would lower the o-Ps lifetime and this may have masked any difference due to the glioma itself. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.

  11. Andrographolide Induces Apoptosis of C6 Glioma Cells via the ERK-p53-Caspase 7-PARP Pathway

    PubMed Central

    Yang, Shih-Hung; Wang, Seu-Mei; Syu, Jhih-Pu; Chen, Ying; Wang, Sheng-De; Peng, Yu-Sen; Kuo, Meng-Fai; Kung, Hsiu-Ni

    2014-01-01

    Background. Glioma is the most malignant tumor of the central nervous system. Efforts on the development of new chemotherapy are mandatory. Andrographolide (AND), a diterpenoid lactone isolated from the Andrographis paniculata, has been shown to have antitumor activities in several types of cancer cells. Whether AND can exert its antitumor activity in glioblastoma cells remains unknown. This study examined the anticancer effects of AND, both in vitro and in vivo. Methods. Cell apoptosis was assayed by flow cytometry and nuclear staining. The signaling pathway for AND was determined by western blotting. The effects of AND on tumor growth was evaluated in a mouse model. Results and Conclusion. In vitro, with application of specific inhibitors and siRNA, AND-induced apoptosis was proven through ROS-ERK-P53-caspase 7-PARP signaling pathway. In vivo, AND significantly retarded tumor growth and caused regression of well-formed tumors in vivo. Furthermore, AND did not induce apoptosis or activate ERK and p53 in primary cultured astrocyte cells, and it may serve as a potential therapeutic candidate for the treatment of glioma. PMID:25162007

  12. Conditional deletion of the focal adhesion kinase FAK alters remodeling of the blood-brain barrier in glioma

    PubMed Central

    Lee, Jisook; Borboa, Alexandra; Chun, Hyun Bae; Baird, Andrew; Eliceiri, Brian

    2010-01-01

    Gliomas generally infiltrate the surrounding normal brain parenchyma, a process associated with increased vascular permeability (VP) and dysregulation of the blood-brain barrier (BBB). However, the molecular mechanisms underlying glioma-induced VP in the brain remain poorly understood. Utilizing a conditional, endothelial-specific deletion of the focal adhesion kinase FAK in the mouse (FAK CKO), we show that FAK is critical for destabilization of the tumor endothelium in tumor-bearing mice, with mutant mice exhibiting a relatively stabilized vasculature to wild-type mice (FAK WT). Tumor vessels in the FAK CKO mice displayed reduced VP compared to FAK WT mice, resulting in reduced tumor growth. Additionally, FAK CKO mice displayed partial restoration of cell-cell junction proteins in the tumor vessels and astrocyte-endothelial interactions in tumors, revealing an additional role of astrocytes in mediating tumor-induced VP. Together, these results provide genetic evidence that FAK is a mediator of tumor-induced VP in the brain. Our findings may help understand how therapeutics might be used to regulate cell type-specific interactions to restore BBB structure/function in cancer and perhaps other pathological conditions. PMID:21159635

  13. Dihydropyrimidine Dehydrogenase Is a Prognostic Marker for Mesenchymal Stem Cell-Mediated Cytosine Deaminase Gene and 5-Fluorocytosine Prodrug Therapy for the Treatment of Recurrent Gliomas

    PubMed Central

    Chung, Taemoon; Na, Juri; Kim, Young-il; Chang, Da-Young; Kim, Young Il; Kim, Hyeonjin; Moon, Ho Eun; Kang, Keon Wook; Lee, Dong Soo; Chung, June-Key; Kim, Sung-Soo; Suh-Kim, Haeyoung; Paek, Sun Ha; Youn, Hyewon

    2016-01-01

    We investigated a therapeutic strategy for recurrent malignant gliomas using mesenchymal stem cells (MSC), expressing cytosine deaminase (CD), and prodrug 5-Fluorocytosine (5-FC) as a more specific and less toxic option. MSCs are emerging as a novel cell therapeutic agent with a cancer-targeting property, and CD is considered a promising enzyme in cancer gene therapy which can convert non-toxic 5-FC to toxic 5-Fluorouracil (5-FU). Therefore, use of prodrug 5-FC can minimize normal cell toxicity. Analyses of microarrays revealed that targeting DNA damage and its repair is a selectable option for gliomas after the standard chemo/radio-therapy. 5-FU is the most frequently used anti-cancer drug, which induces DNA breaks. Because dihydropyrimidine dehydrogenase (DPD) was reported to be involved in 5-FU metabolism to block DNA damage, we compared the survival rate with 5-FU treatment and the level of DPD expression in 15 different glioma cell lines. DPD-deficient cells showed higher sensitivity to 5-FU, and the regulation of DPD level by either siRNA or overexpression was directly related to the 5-FU sensitivity. For MSC/CD with 5-FC therapy, DPD-deficient cells such as U87MG, GBM28, and GBM37 showed higher sensitivity compared to DPD-high U373 cells. Effective inhibition of tumor growth was also observed in an orthotopic mouse model using DPD- deficient U87MG, indicating that DPD gene expression is indeed closely related to the efficacy of MSC/CD-mediated 5-FC therapy. Our results suggested that DPD can be used as a biomarker for selecting glioma patients who may possibly benefit from this therapy. PMID:27446484

  14. Dihydropyrimidine Dehydrogenase Is a Prognostic Marker for Mesenchymal Stem Cell-Mediated Cytosine Deaminase Gene and 5-Fluorocytosine Prodrug Therapy for the Treatment of Recurrent Gliomas.

    PubMed

    Chung, Taemoon; Na, Juri; Kim, Young-Il; Chang, Da-Young; Kim, Young Il; Kim, Hyeonjin; Moon, Ho Eun; Kang, Keon Wook; Lee, Dong Soo; Chung, June-Key; Kim, Sung-Soo; Suh-Kim, Haeyoung; Paek, Sun Ha; Youn, Hyewon

    2016-01-01

    We investigated a therapeutic strategy for recurrent malignant gliomas using mesenchymal stem cells (MSC), expressing cytosine deaminase (CD), and prodrug 5-Fluorocytosine (5-FC) as a more specific and less toxic option. MSCs are emerging as a novel cell therapeutic agent with a cancer-targeting property, and CD is considered a promising enzyme in cancer gene therapy which can convert non-toxic 5-FC to toxic 5-Fluorouracil (5-FU). Therefore, use of prodrug 5-FC can minimize normal cell toxicity. Analyses of microarrays revealed that targeting DNA damage and its repair is a selectable option for gliomas after the standard chemo/radio-therapy. 5-FU is the most frequently used anti-cancer drug, which induces DNA breaks. Because dihydropyrimidine dehydrogenase (DPD) was reported to be involved in 5-FU metabolism to block DNA damage, we compared the survival rate with 5-FU treatment and the level of DPD expression in 15 different glioma cell lines. DPD-deficient cells showed higher sensitivity to 5-FU, and the regulation of DPD level by either siRNA or overexpression was directly related to the 5-FU sensitivity. For MSC/CD with 5-FC therapy, DPD-deficient cells such as U87MG, GBM28, and GBM37 showed higher sensitivity compared to DPD-high U373 cells. Effective inhibition of tumor growth was also observed in an orthotopic mouse model using DPD- deficient U87MG, indicating that DPD gene expression is indeed closely related to the efficacy of MSC/CD-mediated 5-FC therapy. Our results suggested that DPD can be used as a biomarker for selecting glioma patients who may possibly benefit from this therapy. PMID:27446484

  15. Overexpressed homeobox B9 regulates oncogenic activities by transforming growth factor-β1 in gliomas

    SciTech Connect

    Fang, Liping; Xu, Yinghui; Zou, Lijuan

    2014-03-28

    Highlights: • HOXB9 is overexpressed in gliomas. • HOXB9 over expression had shorter survival time than down expression in gliomas. • HOXB9 stimulated the proliferation, migration and sphere formation of glioma cells. • Activation of TGF-β1 contributed to HOXB9-induced oncogenic activities. - Abstract: Glioma is the leading cause of deaths related to tumors in the central nervous system. The mechanisms of gliomagenesis remain elusive to date. Homeobox B9 (HOXB9) has a crucial function in the regulation of gene expression and cell survival, but its functions in glioma formation and development have yet to be elucidated. This study showed that HOXB9 expression in glioma tissues was significantly higher than that in nontumor tissues. Higher HOXB9 expression was also significantly associated with advanced clinical stage in glioma patients. HOXB9 overexpression stimulated the proliferation, migration, and sphere formation of glioma cells, whereas HOXB9 knockdown elicited an opposite effect. HOXB9 overexpression also increased the tumorigenicity of glioma cells in vivo. Moreover, the activation of transforming growth factor-β1 contributed to HOXB9-induced oncogenic activities. HOXB9 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in glioma for diagnosis or prognosis.

  16. Expression and Prognostic Significance of p53 in Glioma Patients: A Meta-analysis.

    PubMed

    Jin, Yueling; Xiao, Weizhong; Song, Tingting; Feng, Guangjia; Dai, Zhensheng

    2016-07-01

    Glioma is a brain tumor deriving from the neoplastic glial cells or neuroglia. Due to its resistance to anticancer drugs and different disease progress of individuals, patients with high-grade glioma are difficult to completely cure, leading to a poor prognosis and low overall survival. Therefore, there is an urgent need to look for prognostic and diagnostic indicators that can predict glioma grades. P53 is one of the widely studied biomarkers in human glioma. The purpose of this study was to comprehensively evaluate the significance of p53 expression in glioma grades and overall survival. We searched commonly used electronic databases to retrieve related articles of p53 expression in glioma. Overall, a total of 21 studies including 1322 glioma patients were finally screened out. We observed that the frequency of p53 immuno-positivity was higher in high-grade patients than that in low-grade category (63.8 vs. 41.6 %), and our statistic analysis indicated that p53 expression was associated with pathological grade of glioma (OR 2.93, 95 % CI 1.87-4.60, P < 0.00001). This significant correction was also found in 1-, 3- and 5-year overall survival. However, no positive relationship was found between age, sex, tumor size and p53 expression in patients with glioma. In conclusion, our results suggested that p53 immunohistochemical expression might have an effective usefulness in predicting the prognosis in patients with glioma.

  17. Expression and Prognostic Significance of p53 in Glioma Patients: A Meta-analysis.

    PubMed

    Jin, Yueling; Xiao, Weizhong; Song, Tingting; Feng, Guangjia; Dai, Zhensheng

    2016-07-01

    Glioma is a brain tumor deriving from the neoplastic glial cells or neuroglia. Due to its resistance to anticancer drugs and different disease progress of individuals, patients with high-grade glioma are difficult to completely cure, leading to a poor prognosis and low overall survival. Therefore, there is an urgent need to look for prognostic and diagnostic indicators that can predict glioma grades. P53 is one of the widely studied biomarkers in human glioma. The purpose of this study was to comprehensively evaluate the significance of p53 expression in glioma grades and overall survival. We searched commonly used electronic databases to retrieve related articles of p53 expression in glioma. Overall, a total of 21 studies including 1322 glioma patients were finally screened out. We observed that the frequency of p53 immuno-positivity was higher in high-grade patients than that in low-grade category (63.8 vs. 41.6 %), and our statistic analysis indicated that p53 expression was associated with pathological grade of glioma (OR 2.93, 95 % CI 1.87-4.60, P < 0.00001). This significant correction was also found in 1-, 3- and 5-year overall survival. However, no positive relationship was found between age, sex, tumor size and p53 expression in patients with glioma. In conclusion, our results suggested that p53 immunohistochemical expression might have an effective usefulness in predicting the prognosis in patients with glioma. PMID:27038932

  18. Aplysin induces apoptosis in glioma cells through HSP90/AKT pathway

    PubMed Central

    Gong, An-jing; Gong, Li-li; Yao, Wei-cheng; Ge, Na; Lu, Lu-xiang

    2015-01-01

    Glioma is one of the most common malignancies in the world. However, an effective regiment is lacking. Increasing evidence indicated that PI3K/AKT signaling is critical for the survival of glioma. In this study, we aimed to study the effect of aplysin on the survival and proliferation of GL26 glioma cells and the involved mechanisms. The data showed that aplysin suppressed the viability of glioma cells in both dose- and time-dependent manners. It also induced G0/G1 arrest and apoptosis in glioma cells. Western blot assays revealed that aplysin treatment changed p-AKT expression by impairing the formation of Heat shock protein 90/AKT complex. Aplysin significantly increased the survival time of mice-bearing glioma and reduced the weights of the established gliomas. Collectively, aplysin can inhibit the proliferation of GL26 glioma cells and induce apoptosis in vitro, perhaps through suppressing PI3K/AKT pathway. It can also inhibit glioma growth in vivo and prolong the survival of mice. Thus, aplysin may be a novel therapeutic drug for glioma. PMID:25377176

  19. Cell surface GRP78 as a biomarker and target for suppressing glioma cells

    PubMed Central

    Kang, Bo Ram; Yang, Seung-Hoon; Chung, Bo-Ryehn; Kim, Woong; Kim, YoungSoo

    2016-01-01

    High-grade glioma is a highly malignant and metastatic brain cancer, resistant to many existing anticancer treatments. In such glioma cancer cells, the glucose-regulated protein 78 kDa (GRP78) is particularly highly up-regulated. Former studies have thus targeted mutation-free GRP78 not only to detect glioma cancer cells specifically but also to enhance cytotoxic effect. We focus on cell surface-expressed GRP78 as a target for suppressing high-grade glioma cell lines. Glioblastoma multiforme (GBM) cell line, highly malignant glioma cells, was first injected into 5-week-old athymic mice to confirm and compare GRP78 expression in vivo in xenografted and normal brain tissue. Immunofluorescence and immunoblotting were utilized to detect surface-localized GRP78 in diverse high-grade glioma cell lines. By treating glioma cell lines with the polyclonal N-20 antibody against surface-localized GRP78, we subsequently studied the significance of surface GRP78 to the survival and growth of the glioma cell lines. We found that inhibiting the function of surface GRP78 suppressed cancer cell survival and growth proving that the surface-expressed GRP78 is a vital receptor involved in the proliferation of high-grade glioma. Our findings provide opportunities to target surface GRP78 as a biomarker for high-grade glioma and to develop effective cell-specific anticancer therapy. PMID:27713511

  20. Efficient Inhibition of Human Glioma Development by RNA Interference-Mediated Silencing of PAK5

    PubMed Central

    Gu, Xuefeng; Wang, Ce; Wang, Xuefeng; Ma, Guoda; Li, You; Cui, Lili; Chen, Yanyan; Zhao, Bin; Li, Keshen

    2015-01-01

    Glioma is the most common type of primary intracranial tumor and is highly lethal due to its pathogenetic location, high invasiveness, and poor prognosis. Even combined surgery and chemoradiotherapy do not effectively rescue glioma patients. Molecular target therapy is considered a safe and promising therapy for glioma. The identification of a novel, effective target protein in gliomas is of great interest. We found that PAK5 was highly expressed in the tumor tissues of glioma patients and human glioma cell lines. We then used a lentivirus-delivered short hairpin RNA to stably silence PAK5 expression in glioma cells and explore its influence. The results showed that the inhibition of PAK5 reduced cell viability and delayed the cell cycle at the G0/G1 phase in the glioma cells with PAK5 high expression. In addition, silencing PAK5 expression in U87 cells weakened their colony formation ability and in vivo tumorigenesis ability. Further studies demonstrated that PAK5 inhibition led to an increase in cleaved caspase 3 and a decrease in β-catenin. In conclusion, our results suggest that the inhibition of PAK5 by RNA interference might efficiently suppress tumor development of glioma cells with PAK5 high expression. This finding provides a novel, promising therapeutic target for glioma treatment. PMID:25632266

  1. Insulator dysfunction and oncogene activation in IDH mutant gliomas

    PubMed Central

    Flavahan, William A.; Drier, Yotam; Liau, Brian B.; Gillespie, Shawn M.; Venteicher, Andrew S.; Stemmer-Rachamimov, Anat O.; Suvà, Mario L.; Bernstein, Bradley E.

    2015-01-01

    Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas1,2. Mutant IDH protein produces a novel onco-metabolite, 2-hydroxyglutarate (2-HG), that interferes with iron-dependent hydroxylases, including the TET family of 5′-methylcytosine hydroxylases3–7. TET enzymes catalyze a key step in the removal of DNA methylation8,9. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP)10,11, though the functional significance of this altered epigenetic state remains unclear. Here we show that IDH mutant gliomas exhibit hyper-methylation at CTCF binding sites, compromising binding of this methylation-sensitive insulator protein. Reduced CTCF binding is associated with loss of insulation between topological domains and aberrant gene activation. We specifically demonstrate that loss of CTCF at a domain boundary permits a constitutive enhancer to aberrantly interact with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with demethylating agent partially restores insulator function and down-regulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wildtype gliomaspheres up-regulates PDGFRA and increases proliferation. Our study suggests that IDH mutations promote gliomagenesis by disrupting chromosomal topology and allowing aberrant regulatory interactions that induce oncogene expression. PMID:26700815

  2. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma

    PubMed Central

    Nakashima, Hiroshi; Kaufmann, Johanna K.; Wang, Pin-Yi; Nguyen, Tran; Speranza, Maria-Carmela; Kasai, Kazue; Okemoto, Kazuo; Otsuki, Akihiro; Nakano, Ichiro; Fernandez, Soledad; Goins, William F.; Grandi, Paola; Glorioso, Joseph C.; Lawler, Sean; Cripe, Timothy P.; Chiocca, E. Antonio

    2015-01-01

    Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem–like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells. PMID:26524593

  3. Thromboxane synthase regulates the migratory phenotype of human glioma cells.

    PubMed Central

    Giese, A.; Hagel, C.; Kim, E. L.; Zapf, S.; Djawaheri, J.; Berens, M. E.; Westphal, M.

    1999-01-01

    The capacity of glial tumor cells to migrate and diffusely infiltrate normal brain compromises surgical eradication of the disease. Identification of genes associated with invasion may offer novel strategies for anti-invasive therapies. The gene for TXsyn, an enzyme of the arachidonic acid pathway, has been identified by differential mRNA display as being overexpressed in a glioma cell line selected for migration. In this study TXsyn mRNA expression was found in a large panel of glioma cell lines but not in a strain of human astrocytes. Immunohistochemistry demonstrated TXsyn in the parenchyma of glial tumors and in reactive astrocytes, whereas it could not be detected in quiescent astrocytes and oligodendroglia of normal brain. Glioma cell lines showed a wide range of thromboxane B2 formation, the relative expression of which correlated with migration rates of these cells. Migration was effectively blocked by specific inhibitors of TXsyn, such as furegrelate and dazmegrel. Other TXsyn inhibitors and cyclooxygenase inhibitors were less effective. Treatment with specific inhibitors also resulted in a decrease of intercellular adhesion in glioma cells. These data indicate that TXsyn plays a crucial role in the signal transduction of migration in glial tumors and may offer a novel strategy for anti-invasive therapies. PMID:11550298

  4. Intraoperative radiation therapy in malignant glioma: early clinical results.

    PubMed

    Ortiz de Urbina, D; Santos, M; Garcia-Berrocal, I; Bustos, J C; Samblas, J; Gutierrez-Diaz, J A; Delgado, J M; Donckaster, G; Calvo, F A

    1995-08-01

    Intraoperative radiation therapy (IORT) with high energy electron beams is a treatment modality that has been included in multimodal programs in oncology to improve local tumor control. From August 1991 to December 1993, 17 patients with primary (8) or recurrent (9) high grade malignant gliomas, anaplastic astrocytoma (4), anaplastic oligodendroglioma (6) and glioblastoma multiforme (7), underwent surgical resection and a single dose of 10-20 Gy intraoperative radiation therapy was delivered in tumor bed. Fourteen patients received either pre-operative (8) or post-operative (6) external beam radiation therapy. Primary gliomas: 18-months actuarial survival rate has been 56% (range: 1-21+ months) and the median survival time has not yet been achieved. Four patients developed tumor progression (median time to tumor progression: 9 months). Recurrent gliomas: 18-months actuarial survival rate and median survival time has been 47% and 13 months (range: 6-32+ months) respectively. The median time to tumor progression was 11 months. No IORT related mortality has been observed. IORT is an attractive, tolerable and feasible treatment modality as antitumoral intensification procedure in high grade malignant gliomas.

  5. Cell migration in paediatric glioma; characterisation and potential therapeutic targeting

    PubMed Central

    Cockle, J V; Picton, S; Levesley, J; Ilett, E; Carcaboso, A M; Short, S; Steel, L P; Melcher, A; Lawler, S E; Brüning-Richardson, A

    2015-01-01

    Background: Paediatric high grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) are highly aggressive brain tumours. Their invasive phenotype contributes to their limited therapeutic response, and novel treatments that block brain tumour invasion are needed. Methods: Here, we examine the migratory characteristics and treatment effect of small molecule glycogen synthase kinase-3 inhibitors, lithium chloride (LiCl) and the indirubin derivative 6-bromoindirubin-oxime (BIO), previously shown to inhibit the migration of adult glioma cells, on two pHGG cell lines (SF188 and KNS42) and one patient-derived DIPG line (HSJD-DIPG-007) using 2D (transwell membrane, immunofluorescence, live cell imaging) and 3D (migration on nanofibre plates and spheroid invasion in collagen) assays. Results: All lines were migratory, but there were differences in morphology and migration rates. Both LiCl and BIO reduced migration and instigated cytoskeletal rearrangement of stress fibres and focal adhesions when viewed by immunofluorescence. In the presence of drugs, loss of polarity and differences in cellular movement were observed by live cell imaging. Conclusions: Ours is the first study to demonstrate that it is possible to pharmacologically target migration of paediatric glioma in vitro using LiCl and BIO, and we conclude that these agents and their derivatives warrant further preclinical investigation as potential anti-migratory therapeutics for these devastating tumours. PMID:25628092

  6. Neurodevelopmental Outcomes of Children with Low-Grade Gliomas

    ERIC Educational Resources Information Center

    Ris, M. Douglas; Beebe, Dean W.

    2008-01-01

    As a group, children with low-grade gliomas (LGGs) enjoy a high rate of long-term survival and do not require the intensity of neurotoxic treatments used with higher risk pediatric brain tumors. Because they are generally considered to have favorable neurobehavioral outcomes, they have not been studied as thoroughly as higher-grade brain tumors by…

  7. Monoamine oxidase A (MAO A) inhibitors decrease glioma progression.

    PubMed

    Kushal, Swati; Wang, Weijun; Vaikari, Vijaya Pooja; Kota, Rajesh; Chen, Kevin; Yeh, Tzu-Shao; Jhaveri, Niyati; Groshen, Susan L; Olenyuk, Bogdan Z; Chen, Thomas C; Hofman, Florence M; Shih, Jean C

    2016-03-22

    Glioblastoma (GBM) is an aggressive brain tumor which is currently treated with temozolomide (TMZ). Tumors usually become resistant to TMZ and recur; no effective therapy is then available. Monoamine Oxidase A (MAO A) oxidizes monoamine neurotransmitters resulting in reactive oxygen species which cause cancer. This study shows that MAO A expression is increased in human glioma tissues and cell lines. MAO A inhibitors, clorgyline or the near-infrared-dye MHI-148 conjugated to clorgyline (NMI), were cytotoxic for glioma and decreased invasion in vitro. Using the intracranial TMZ-resistant glioma model, clorgyline or NMI alone or in combination with low-dose TMZ reduced tumor growth and increased animal survival. NMI was localized specifically to the tumor. Immunocytochemistry studies showed that the MAO A inhibitor reduced proliferation, microvessel density and invasion, and increased macrophage infiltration. In conclusion, we have identified MAO A inhibitors as potential novel stand-alone drugs or as combination therapy with low dose TMZ for drug-resistant gliomas. NMI can also be used as a non-invasive imaging tool. Thus has a dual function for both therapy and diagnosis.

  8. Gliomas and the vascular fragility of the blood brain barrier

    PubMed Central

    Dubois, Luiz Gustavo; Campanati, Loraine; Righy, Cassia; D’Andrea-Meira, Isabella; Spohr, Tania Cristina Leite de Sampaio e; Porto-Carreiro, Isabel; Pereira, Claudia Maria; Balça-Silva, Joana; Kahn, Suzana Assad; DosSantos, Marcos F.; Oliveira, Marcela de Almeida Rabello; Ximenes-da-Silva, Adriana; Lopes, Maria Celeste; Faveret, Eduardo; Gasparetto, Emerson Leandro; Moura-Neto, Vivaldo

    2014-01-01

    Astrocytes, members of the glial family, interact through the exchange of soluble factors or by directly contacting neurons and other brain cells, such as microglia and endothelial cells. Astrocytic projections interact with vessels and act as additional elements of the Blood Brain Barrier (BBB). By mechanisms not fully understood, astrocytes can undergo oncogenic transformation and give rise to gliomas. The tumors take advantage of the BBB to ensure survival and continuous growth. A glioma can develop into a very aggressive tumor, the glioblastoma (GBM), characterized by a highly heterogeneous cell population (including tumor stem cells), extensive proliferation and migration. Nevertheless, gliomas can also give rise to slow growing tumors and in both cases, the afflux of blood, via BBB is crucial. Glioma cells migrate to different regions of the brain guided by the extension of blood vessels, colonizing the healthy adjacent tissue. In the clinical context, GBM can lead to tumor-derived seizures, which represent a challenge to patients and clinicians, since drugs used for its treatment must be able to cross the BBB. Uncontrolled and fast growth also leads to the disruption of the chimeric and fragile vessels in the tumor mass resulting in peritumoral edema. Although hormonal therapy is currently used to control the edema, it is not always efficient. In this review we comment the points cited above, considering the importance of the BBB and the concerns that arise when this barrier is affected. PMID:25565956

  9. [Molecular Genetics as Best Evidence in Glioma Diagnostics].

    PubMed

    Masui, Kenta; Komori, Takashi

    2016-03-01

    The development of a genomic landscape of gliomas has led to the internally consistent, molecularly-based classifiers. However, development of a biologically insightful classification to guide therapy is still ongoing. Further, tumors are heterogeneous, and they change and adapt in response to drugs. The challenge of developing molecular classifiers that provide meaningful ways to stratify patients for therapy remains a major challenge for the field. Therefore, by incorporating molecular markers into the new World Health Organization (WHO) classification of tumors of the central nervous system, the traditional principle of diagnosis based on histologic criteria will be replaced by a multilayered approach combining histologic features and molecular information in an "integrated diagnosis", to define tumor entities as narrowly as possible. We herein review the current status of diagnostic molecular markers for gliomas, focusing on IDH mutation, ATRX mutation, 1p/19q co-deletion, and TERT promoter mutation in adult tumors, as well as BRAF and H3F3A aberrations in pediatric gliomas, the combination of which will be a promising endeavor to render molecular genetics as a best evidence in the glioma diagnositics. PMID:27001774

  10. Histone deacetylase 6 inhibition enhances oncolytic viral replication in glioma.

    PubMed

    Nakashima, Hiroshi; Kaufmann, Johanna K; Wang, Pin-Yi; Nguyen, Tran; Speranza, Maria-Carmela; Kasai, Kazue; Okemoto, Kazuo; Otsuki, Akihiro; Nakano, Ichiro; Fernandez, Soledad; Goins, William F; Grandi, Paola; Glorioso, Joseph C; Lawler, Sean; Cripe, Timothy P; Chiocca, E Antonio

    2015-11-01

    Oncolytic viral (OV) therapy, which uses genetically engineered tumor-targeting viruses, is being increasingly used in cancer clinical trials due to the direct cytolytic effects of this treatment that appear to provoke a robust immune response against the tumor. As OVs enter tumor cells, intrinsic host defenses have the potential to hinder viral replication and spread within the tumor mass. In this report, we show that histone deacetylase 6 (HDAC6) in tumor cells appears to alter the trafficking of post-entry OVs from the nucleus toward lysosomes. In glioma cell lines and glioma-stem-like cells, HDAC6 inhibition (HDAC6i) by either pharmacologic or genetic means substantially increased replication of oncolytic herpes simplex virus type 1 (oHSV). Moreover, HDAC6i increased shuttling of post-entry oHSV to the nucleus. In addition, electron microscopic analysis revealed that post-entry oHSVs are preferentially taken up into glioma cells through the endosomal pathway rather than via fusion at the cell surface. Together, these findings illustrate a mechanism of glioma cell defense against an incoming infection by oHSV and identify possible approaches to enhance oHSV replication and subsequent lysis of tumor cells. PMID:26524593

  11. Differences between brainstem gliomas in juvenile and adult rats

    PubMed Central

    WANG, YU; TIAN, YONGJI; WAN, HONG; LI, DEZHI; WU, WENHAO; YIN, LUXIN; JIANG, JIAN; WAN, WEIQING; ZHANG, LIWEI

    2013-01-01

    Clinical studies have shown that gliomas of the brainstem behave differently in children and adults. The aim of the present study was to compare and analyze the differences between these gliomas in juvenile and adult rats with regard to tumor growth, survival, pathology and magnetic resonance imaging (MRI). A total of 25 juvenile and 25 adult Wistar rats were divided into groups A (15 juvenile rats), B (10 juvenile rats), C (15 adult rats) and D (10 adult rats). The rats of groups A and C (experimental) were injected with glioma cells, while groups B and D (control) were injected with a physiological saline solution. Rat neurological signs, survival time, tumor size, hematoxylin and eosin (HE) staining and immunohistochemical staining for MMP-2, MMP-9 and β-catenin were compared. The survival time of group A was 19.47±2.232 days, whereas that of group C was 21.47±2.232 days (P<0.05). The tumor sizes were 4.55 and 4.62 mm (P>0.05) in groups A and C, respectively. HE and immunohistochemical staining revealed no differences between the groups. The results suggest that the growth patterns and invasiveness of brainstem gliomas may vary in children compared with adults due to the varied biological behaviors of the tumor cells. PMID:23946812

  12. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma.

    PubMed

    Bhat, Krishna P L; Salazar, Katrina L; Balasubramaniyan, Veerakumar; Wani, Khalida; Heathcock, Lindsey; Hollingsworth, Faith; James, Johanna D; Gumin, Joy; Diefes, Kristin L; Kim, Se Hoon; Turski, Alice; Azodi, Yasaman; Yang, Yuhui; Doucette, Tiffany; Colman, Howard; Sulman, Erik P; Lang, Frederick F; Rao, Ganesh; Copray, Sjef; Vaillant, Brian D; Aldape, Kenneth D

    2011-12-15

    Recent molecular classification of glioblastoma (GBM) has shown that patients with a mesenchymal (MES) gene expression signature exhibit poor overall survival and treatment resistance. Using regulatory network analysis of available expression microarray data sets of GBM, including The Cancer Genome Atlas (TCGA), we identified the transcriptional coactivator with PDZ-binding motif (TAZ), to be highly associated with the MES network. TAZ expression was lower in proneural (PN) GBMs and lower-grade gliomas, which correlated with CpG island hypermethylation of the TAZ promoter compared with MES GBMs. Silencing of TAZ in MES glioma stem cells (GSCs) decreased expression of MES markers, invasion, self-renewal, and tumor formation. Conversely, overexpression of TAZ in PN GSCs as well as murine neural stem cells (NSCs) induced MES marker expression and aberrant osteoblastic and chondrocytic differentiation in a TEAD-dependent fashion. Using chromatin immunoprecipitation (ChIP), we show that TAZ is directly recruited to a majority of MES gene promoters in a complex with TEAD2. The coexpression of TAZ, but not a mutated form of TAZ that lacks TEAD binding, with platelet-derived growth factor-B (PDGF-B) resulted in high-grade tumors with MES features in a murine model of glioma. Our studies uncover a direct role for TAZ and TEAD in driving the MES differentiation of malignant glioma.

  13. Cancer Immunotherapy for Gliomas: Overview and Future Directions.

    PubMed

    Hashimoto, Naoya

    2016-07-15

    Immunotherapy has been highlighted because we have obtained much evidence, which includes theoretical backborn as well as favorable results from clinical trials. As immunotherapy gives an apparently different cytotoxic mechanism and a little adverse event, the promising results are getting a lot of attention. In this article, cancer immunotherapy for gliomas is reviewed thoroughly from the literature, focusing on the clinical trial results.

  14. Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity.

    PubMed

    Yiin, Jia-Jean; Hu, Bo; Jarzynka, Michael J; Feng, Haizhong; Liu, Kui-Wei; Wu, Jane Y; Ma, Hsin-I; Cheng, Shi-Yuan

    2009-12-01

    Acquisition of insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Slit2, a chemorepulsive factor, controls cell migration of neuronal and glial cells during development and inhibits chemotaxic migration of various types of cells in vitro. However, the role of Slit2 in vitro remains controversial, and the biological significance of Slit2 expression in cancer cell invasion in vivo has not yet been determined. In the present study, we characterized the effects of Slit2 expression on the migration and invasion of invasive glioma cells in vitro and in vivo. By reverse transcriptase polymerase chain reaction (PCR) analyses, Slit2 was found to be expressed at lower levels in primary glioma specimens and invasive glioma cells compared with normal human brain cells and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuates cell migration and invasion through inhibition of Cdc42 activity in vitro. Cellular depletion of Robo1, a cognate receptor for Slit2, prevented Slit2 inhibition of Cdc42 activity and glioma cell migration. In vivo, expression of Slit2 by invasive SNB19 glioma cells markedly inhibited glioma cell infiltration into the brain of mice. Moreover, impediment of glioma cell invasion by Slit2 did not affect the expression of N-cadherin and beta-catenin in glioma cells. These results provide the first evidence demonstrating that Slit2-Robo1 inhibits glioma invasion through attenuating Cdc42 activity in vitro and in the brain. Understanding the mechanisms of Slit2-Robo1 inhibition of glioma cell invasion will foster new treatments for malignant gliomas.

  15. Expression of voltage-activated chloride currents in acute slices of human gliomas.

    PubMed

    Ullrich, N; Bordey, A; Gillespie, G Y; Sontheimer, H

    1998-04-01

    Using whole-cell patch-clamp recordings, we identified a novel voltage-activated chloride current that was selectively expressed in glioma cells from 23 patient biopsies. Chloride currents were identified in 64% of glioma cells studied in acute slices of nine patient biopsies. These derived from gliomas of various pathological grades. In addition, 98% of cells acutely isolated or in short-term culture from 23 patients diagnosed with gliomas showed chloride current expression. These currents, which we termed glioma chloride currents activated at potentials >45 mV, showed pronounced outward rectification, and were sensitive to bath application of the presumed Cl- channel specific peptide chlorotoxin (approximately 600 nM) derived from Leiurus scorpion venom. Interestingly, low grade tumours (e.g., pilocytic astrocytomas), containing more differentiated, astrocyte-like cells showed expression of glioma chloride currents in concert with voltage-activated sodium and potassium currents also seen in normal astrocytes. By contrast, high grade tumours (e.g., glioblastoma multiforme) expressed almost exclusively chloride currents, suggesting a gradual loss of Na+ currents and gain of Cl- currents with increasing pathological tumour grade. To expand on the observation that these chloride currents are glioma-specific, we introduced experimental tumours in scid mice by intracranial injection of D54MG glioma cells and subsequently recorded from tumour cells and adjacent normal glial cells in acute slices. We consistently observed expression of chlorotoxin-sensitive chloride channels in implanted glioma cells, but without evidence for expression of chloride channels in surrounding "normal" host glial cells, suggesting that these chloride channels are probably a glioma-specific feature. Finding of this novel glioma specific Cl- channel in gliomas in situ and it's selective binding of chlorotoxin may provide a way to identify or target glioma cells in the future.

  16. The engineered Salmonella typhimurium inhibits tumorigenesis in advanced glioma

    PubMed Central

    Chen, Jian-qiang; Zhan, Yue-fu; Wang, Wei; Jiang, Sheng-nan; Li, Xiang-ying

    2015-01-01

    Objective To explore the antitumor role of the attenuated Salmonella typhimurium ΔppGpp with inducible cytolysin A (ClyA) in advanced stage of glioma. Materials and methods The C6 rat glioma cells were orthotopically implanted by surgery into the caudate nucleus of rat brains. The rats were then randomly divided into the treatment group (SL + ClyA) (n=12), negative control group (SL) (n=12), and control group (phosphate-buffered saline [PBS]) (n=12). In the treatment group, the attenuated S. typhimurium were transformed with the plasmid-encoded antitumor gene ClyA. The expression of ClyA was controlled by the TetR-regulated promoter in response to extracellular doxycycline. The plasmid also contained an imaging gene lux to allow illumination of the tumor infected by the bacteria. The rat glioma C6 cells were implanted into the caudate nucleus of all rats. The engineered S. typhimurium and respective controls were injected intravenously into the rats 21 days after initial tumor implantation. The pathological analysis of the glioma tumor was performed at 21 days and 28 days (7 days after doxycycline treatment) postimplantation. All rats underwent MRI (magnetic resonance imaging) and bioluminescence study at 21 days and 28 days postimplantation to detect tumor volume. The differences between the three groups in tumor volume and survival time were analyzed. Results Advanced stage glioma was detected at 21 days postimplantation. Bioluminescence showed that the engineered S. typhimurium accumulated in glioma tumors and disappeared in the normal reticuloendothelial tissues 3 days after intravenous injection. MRI showed that the tumor volume in the S. typhimurium with ClyA group were significantly reduced compared to the bacteria alone and no bacteria groups 7 days post-doxycycline treatment (P<0.05), while the necrotic tumor volume in the S. typhimurium with ClyA group and S. typhimurium alone group increased significantly compared to the control group (P<0.01). In

  17. Analysis of gene expression profiles associated with glioma progression

    PubMed Central

    HU, GUOZHANG; WEI, BO; WANG, LINA; WANG, LE; KONG, DALIANG; JIN, YING; SUN, ZHIGANG

    2015-01-01

    The present study aimed to investigate changes at the transcript level that are associated with spontaneous astrocytoma progression, and further, to discover novel targets for glioma diagnosis and therapy. GSE4290 microarray data downloaded from Gene Expression Omnibus were used to identify the differentially expressed genes (DGEs) by significant analysis of microarray (SAM). The Short Time Series Expression Miner (STEM) method was then applied to class these DEGs based on their degrees of differentiation in the process of tumor progression. Finally, EnrichNet was used to perform the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis based on a protein-protein interaction (PPI) network. A total of 4,506 DEGs were detected, and the number of DEGs was the highest in grade IV cells (2,580 DEGs). These DEGs were classified into nine clusters by the STEM method. In total, 11 KEGG pathways with XD-scores larger than the threshold (0.96) were obtained. The DEGs enriched in pathways 1 (extracellular matrix-receptor interaction), 3 (phagosome) and 6 (type I diabetes mellitus) mainly belonged to cluster 5. Pathway 2 (long-term potentiation), 4 (Vibrio cholerae infection) and 5 (epithelial cell signaling in Helicobacter pylori infection) was involved with DEGs that belonged to different clusters. Significant changes in gene expression occurred during glioma progression. Pathways 1, 3 and 6 may be important for the deterioration of glioma into glioblastoma, and pathways 2, 4 and 5 may have a role at each stage during glioma progression. The associated DEGs, including SV2, NMDAR and mGluRs, may be suitable as biomarkers or therapeutic targets for gliomas. PMID:25845910

  18. Treatment With Bevacizumab Plus Carboplatin for Recurrent Malignant Glioma

    PubMed Central

    Thompson, Eric M.; Dosa, Edit; Kraemer, Dale F.; Neuwelt, Edward A.

    2016-01-01

    Objective To estimate overall survival (OS), progression-free survival (PFS), imaging responses, and toxicities of bevacizumab plus carboplatin for the treatment of recurrent malignant glioma. The secondary objective was to estimate the agreement between post-contrast T1-weighted and T2-weighted magnetic resonance imaging. Methods A retrospective analysis of 9 patients who received bevacizumab (10 mg/kg intravenously) and carboplatin (AUC 5 intravenously) for recurrent malignant glioma (World Health Organization grades III and IV) is presented. Eight of 9 patients received this regimen at first recurrence. Results The median age and Karnofsky performance score were 51 years and 70, respectively. For the 5 patients with grade III gliomas, the median PFS was 126 days, whereas median OS was not attained at 517 days of follow-up. Six-month PFS was 40%, whereas 6-month OS was 60%. For the 4 patients with grade IV gliomas, the median PFS was 216 days, whereas the median OS was not attained at 482 days of follow-up. Six-month PFS was 50%, whereas 6-month OS was 75%. The agreement between contrast-enhanced T1-weighted and T2-weighted images to determine recurrence was moderate (kappa = 0.5714). Three patients had grade 3 and 4 toxicities including hyponatremia and thrombocytopenia. Conclusion Patients who received the combination of bevacizumab plus carboplatin for recurrent malignant glioma had reasonable PFS, OS, and toxicities. The median OS in our series is promising at well over 1 year. Agreement between postcontrast T1- and T2-weighted images is only moderate in the context of bevacizumab therapy. PMID:20559095

  19. Opposing roles of connexin43 in glioma progression.

    PubMed

    Sin, Wun-Chey; Crespin, Sophie; Mesnil, Marc

    2012-08-01

    Despite the tremendous amount of data over the last 40years, lack of gap junctional intercellular communication (GJIC) or altered expression of gap junction proteins is still a lesser known 'hallmark' of cancer. Expression of astrocytic gap junction protein, connexin43 (Cx43), is often reduced in astrocytomas, the most common neoplasia of the central nervous system (CNS) in adults. Supported by a number of evidences, the global decrease of Cx43 expression appears to be advantageous for the growth of glioma cells. Although the mechanisms by which Cx43 regulates the expression levels of proteins involved in cell growth is unclear, there are evidences to suggest that it might be independent of their channel forming properties. In this regard, the carboxyl tail of Cx43 may have the ability to control the translocation of transcription factor regulators into the nucleus. However, this putative tumor suppressor effect of Cx43 is counterbalanced by its capacity to enhance the migration of glioma cells out of the tumor core through mechanisms that seems to implicate its carboxyl tail, possibly by interacting with the actin cytoskeleton. This ambivalence between the tumor suppressor effect and promotion of cell migration may partly be explained by the heterogeneous expression of Cx43 in the glioma core especially at the malignant glioblastoma stage; some tumor cells would be expected to migrate (Cx43 expressing cells) and others to proliferate (non-expressing Cx43 cells). Moreover, the involvement of Cx43 in glioma progression seems to be more complex since, in addition, GJIC may increase their resistance to apoptosis and Cx43 may also affect cell homeostasis in a paracrine fashion via hemichannel action. In conclusion, Cx43 appears to be involved at different levels of the glioma progression by acting on cell growth regulation, promotion of cell migration and resistance to apoptosis. This article is part of a Special Issue entitled: The Communicating junctions, composition

  20. Limitations of stereotactic biopsy in the initial management of gliomas.

    PubMed Central

    Jackson, R. J.; Fuller, G. N.; Abi-Said, D.; Lang, F. F.; Gokaslan, Z. L.; Shi, W. M.; Wildrick, D. M.; Sawaya, R.

    2001-01-01

    Stereotactic biopsy is often performed for diagnostic purposes before treating patients whose imaging studies highly suggest glioma. Indications cited for biopsy include diagnosis and/or the "inoperability" of the tumor. This study questions the routine use of stereotactic biopsy in the initial management of gliomas. At The University of Texas M. D. Anderson Cancer Center, we retrospectively reviewed a consecutive series of 81 patients whose imaging studies suggested glioma and who underwent stereotactic biopsy followed by craniotomy/resection (within 60 days) between 1993 and 1998. All relevant clinical and imaging information was reviewed, including computerized volumetric analysis of the tumors based on pre- and postoperative MRI. Stereotactic biopsy was performed at institutions other than M. D. Anderson in 78 (96%) of 81 patients. The majority of tumors were located either in eloquent brain (36 of 81 = 44%) or near-eloquent brain (41 of 81 = 51%), and this frequently was the rationale cited for performing stereotactic biopsy. Gross total resection (>95%) was achieved in 46 (57%) of 81 patients, with a median extent of resection of 96% for this series. Diagnoses based on biopsy or resection in the same patient differed in 40 (49%) of 82 cases. This discrepancy was reduced to 30 (38%) of 80 cases when the biopsy slides were reviewed preoperatively by each of three neuropathologists at M. D. Anderson. Major neurologic complications occurred in 10 (12.3%) of 81 surgical patients and 3 (3.7%) of 81 patients undergoing biopsy. Surgical morbidity was probably higher in our series than it would be for glioma patients in general because our patients represent a highly selected subset of glioma patients whose tumors present a technical challenge to remove. Stereotactic biopsy is frequently inaccurate in providing a correct diagnosis and is associated with additional risk and cost. If stereotactic biopsy is performed, expert neuropathology consultation should be sought

  1. Ectopic expression of AP-2α transcription factor suppresses glioma progression.

    PubMed

    Su, Wenjing; Xia, Juan; Chen, Xueqin; Xu, Miao; Nie, Ling; Chen, Ni; Gong, Jing; Li, Xinglan; Zhou, Qiao

    2014-01-01

    The transcriptional factor AP-2α is a tumor suppressor gene and is downregulated in various neoplasms including glioma. Although the level of AP-2α is negatively associated with the grade of human glioma, the specific functions of AP-2α in glioma are still unknown. In this study, we experimentally showed that artificial overexpression of AP-2α in glioma T98G and U251 cells significantly downregulated the mRNA levels of Bcl-xl, Bcl-2, c-IAP2 and survivin, together with upregulation of the Hrk mRNA levels. Reintroduction of AP-2α also induced downregulation of the protein levels of survivin and VEGF in glioma cells. In biological assays with T98G and U251 cells, AP-2α reduced tumor cell growth, increased cell death, attenuated cell migration and endothelial tube formation. The AP-2α transcription factor may play an important role in suppressing glioma progression. PMID:25674231

  2. Ectopic expression of AP-2α transcription factor suppresses glioma progression

    PubMed Central

    Su, Wenjing; Xia, Juan; Chen, Xueqin; Xu, Miao; Nie, Ling; Chen, Ni; Gong, Jing; Li, Xinglan; Zhou, Qiao

    2014-01-01

    The transcriptional factor AP-2α is a tumor suppressor gene and is downregulated in various neoplasms including glioma. Although the level of AP-2α is negatively associated with the grade of human glioma, the specific functions of AP-2α in glioma are still unknown. In this study, we experimentally showed that artificial overexpression of AP-2α in glioma T98G and U251 cells significantly downregulated the mRNA levels of Bcl-xl, Bcl-2, c-IAP2 and survivin, together with upregulation of the Hrk mRNA levels. Reintroduction of AP-2α also induced downregulation of the protein levels of survivin and VEGF in glioma cells. In biological assays with T98G and U251 cells, AP-2α reduced tumor cell growth, increased cell death, attenuated cell migration and endothelial tube formation. The AP-2α transcription factor may play an important role in suppressing glioma progression. PMID:25674231

  3. The Value of Glioma Extent of Resection in the Modern Neurosurgical Era

    PubMed Central

    Hardesty, Douglas A.; Sanai, Nader

    2012-01-01

    Objective: There remains no general consensus in the neurosurgical oncology literature regarding the role of extent of glioma resection in improving patient outcome. Although the value of resection in establishing a diagnosis and alleviating mass effect is clear, there is less certainty in ascertaining the influence of extent of resection (EOR). Here, we review the recent literature to synthesize a comprehensive review of the value of extent of resection for gliomas in the modern neurosurgical era. Methods: We reviewed every major peer-reviewed clinical publication since 1990 on the role of EOR in glioma outcome. Results: Thirty-two high-grade glioma articles and 11 low-grade glioma articles were examined in terms of quality of evidence, expected EOR, and survival benefit. Conclusion: Despite limitations in the quality of data, mounting evidence suggests that more extensive surgical resection is associated with longer life expectancy for both low- and high-grade newly diagnosed gliomas. PMID:23087667

  4. Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment

    PubMed Central

    Rizzo, Daniela; Ruggiero, Antonio; Martini, Maurizio; Rizzo, Valentina; Maurizi, Palma; Riccardi, Riccardo

    2015-01-01

    High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas. PMID:26448930

  5. GCN5 Potentiates Glioma Proliferation and Invasion via STAT3 and AKT Signaling Pathways

    PubMed Central

    Liu, Kun; Zhang, Qing; Lan, Haitao; Wang, Liping; Mou, Pengfei; Shao, Wei; Liu, Dan; Yang, Wensheng; Lin, Zhen; Lin, Qingyuan; Ji, Tianhai

    2015-01-01

    The general control of nucleotide synthesis 5 (GCN5), which is one kind of lysine acetyltransferases, regulates a number of cellular processes, such as cell proliferation, differentiation, cell cycle and DNA damage repair. However, its biological role in human glioma development remains elusive. In the present study, we firstly reported that GCN5 was frequently overexpressed in human glioma tissues and GCN5 was positively correlated with proliferation of cell nuclear antigen PCNA and matrix metallopeptidase MMP9. Meanwhile, down-regulation of GCN5 by siRNA interfering inhibited glioma cell proliferation and invasion. In addition, GCN5 knockdown reduced expression of p-STAT3, p-AKT, PCNA and MMP9 and increased the expression of p21 in glioma cells. In conclusion, GCN5 exhibited critical roles in glioma development by regulating cell proliferation and invasion, which suggested that GCN5 might be a potential molecular target for glioma treatment. PMID:26378521

  6. Methionine and cystine double deprivation stress suppresses glioma proliferation via inducing ROS/autophagy.

    PubMed

    Liu, Huailei; Zhang, Weiguang; Wang, Kaikai; Wang, Xiaoxiong; Yin, Fei; Li, Chenguang; Wang, Chunlei; Zhao, Boxian; Zhong, Chen; Zhang, Jiakang; Peng, Fei; Bi, Yunke; Shen, Chen; Hou, Xu; Zhang, Daming; Liu, Yaohua; Ai, Jing; Zhao, Shiguang

    2015-01-22

    Cancer cells are highly dependent on methionine and cystine (Met-Cys) for survival and proliferation. However, the molecular mechanism is not fully clear. The present study is to investigate the effects of Met-Cys deprivation on glioma cells proliferation. The results showed that Met-Cys double deprivation had synergistic action on elevating ROS level, decreased GSH level and inhibition of glioma cell proliferation. Moreover, both of them deprivation triggered autophagy of glioma cells both in vitro and in vivo. Importantly, Met-Cys double restriction diet inhibited growth of glioma. These results provided a new regulation mechanism of Met-Cys metabolism on affecting glioma cell proliferation, suggesting that targeting Met-Cys metabolism may be a potential strategy for glioma therapy.

  7. Alu methylation serves as a biomarker for non-invasive diagnosis of glioma

    PubMed Central

    Zuo, Hao; Zhao, Longxiang; Huang, Chuanjun; Liu, Xiaojiang; Hou, Shiqiang; Qi, Jing; Shi, Wei

    2016-01-01

    Current techniques for diagnosing glioma are invasive and do not accurately predict prognosis. We developed a novel, non-invasive liquid chip assay to diagnose glioma and predict prognosis. Using this method, we determined the methylation state of the Alu element in cell-free DNA extracted from the serum of 109 glioma patients. Controls included 56 patients with benign intracranial tumors and 50 healthy subjects. Matched tumor tissues were processed for 36 patients. The cfDNA from glioma patients showed lower levels of Alu methylation than the controls (P<0.01). Alu methylation was also lower in high-grade than low-grade gliomas (P<0.01), indicating that Alu methylation correlates negatively with disease severity. Moreover, Alu methylation correlated positively with survival (P<0.01). These findings suggest high-throughput liquid chip could serve as a non-invasive diagnostic assay for glioma. PMID:27028997

  8. Subjective Quality of Life in Persons with Low-Grade Glioma and Their Next of Kin

    ERIC Educational Resources Information Center

    Edvardsson, Tanja I.; Ahlstrom, Gerd I.

    2009-01-01

    Patients with low-grade glioma have a longer survival than patients with highly malignant glioma, and for this reason questions of quality of life (QoL) are of particular importance to such patients as well as to their next of kin. No studies have been found in which both adult patients with low-grade glioma and their next of kin have estimated…

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

    PubMed

    Shen, Shang-Hang; Yu, Ning; Liu, Xi-Yao; Tan, Guo-Wei; Wang, Zhan-Xiang

    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. PMID:26828272

  10. KIF23 is an independent prognostic biomarker in glioma, transcriptionally regulated by TCF-4.

    PubMed

    Sun, Lihua; Zhang, Chuanbao; Yang, Zhengxiang; Wu, Yiping; Wang, Hongjun; Bao, Zhaoshi; Jiang, Tao

    2016-04-26

    Kinesin family member 23 (KIF23), a nuclear protein and a key regulator of cellular cytokinesis, has been found to be overexpressed as an oncogene in glioma. However, the prognostic and clinicopathological features of glioma with KIF23 expression was not clear yet. Here, we analyzed KIF23 expression pattern by using whole genome mRNA expression microarray data from Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn), and found that KIF23 overexpression was significantly associated with high grade glioma as well as the higher mortality in survival analysis (log-rank test, p<0.01). The results of the three other validation datasets showed similar findings. Furthermore, KIF23 also served as an independent prognostic biomarker in glioma patients. Finally, functional assay showed that reduction of KIF23 suppressed glioma cell proliferation both in vivo and vitro. Additionally, we found that KIF23 was regulated by TCF-4 at transcriptionally level. Therefore, this evidence indicates KIF23 over-expression is associated with glioma malignancy and conferred a worse survival time in glioma, which suggests KIF23 is a new novel prognostic biomarker with potential therapeutic implications in glioma. PMID:27013586

  11. KIF23 is an independent prognostic biomarker in glioma, transcriptionally regulated by TCF-4

    PubMed Central

    Yang, Zhengxiang; Wu, Yiping; Wang, Hongjun; Bao, Zhaoshi; Jiang, Tao

    2016-01-01

    Kinesin family member 23 (KIF23), a nuclear protein and a key regulator of cellular cytokinesis, has been found to be overexpressed as an oncogene in glioma. However, the prognostic and clinicopathological features of glioma with KIF23 expression was not clear yet. Here, we analyzed KIF23 expression pattern by using whole genome mRNA expression microarray data from Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn), and found that KIF23 overexpression was significantly associated with high grade glioma as well as the higher mortality in survival analysis (log-rank test, p<0.01). The results of the three other validation datasets showed similar findings. Furthermore, KIF23 also served as an independent prognostic biomarker in glioma patients. Finally, functional assay showed that reduction of KIF23 suppressed glioma cell proliferation both in vivo and vitro. Additionally, we found that KIF23 was regulated by TCF-4 at transcriptionally level. Therefore, this evidence indicates KIF23 over-expression is associated with glioma malignancy and conferred a worse survival time in glioma, which suggests KIF23 is a new novel prognostic biomarker with potential therapeutic implications in glioma. PMID:27013586

  12. Pleiotrophin promotes vascular abnormalization in gliomas and correlates with poor survival in patients with astrocytomas.

    PubMed

    Zhang, Lei; Kundu, Soumi; Feenstra, Tjerk; Li, Xiujuan; Jin, Chuan; Laaniste, Liisi; El Hassan, Tamador Elsir Abu; Ohlin, K Elisabet; Yu, Di; Olofsson, Tommie; Olsson, Anna-Karin; Pontén, Fredrik; Magnusson, Peetra U; Nilsson, Karin Forsberg; Essand, Magnus; Smits, Anja; Dieterich, Lothar C; Dimberg, Anna

    2015-12-01

    Glioblastomas are aggressive astrocytomas characterized by endothelial cell proliferation and abnormal vasculature, which can cause brain edema and increase patient morbidity. We identified the heparin-binding cytokine pleiotrophin as a driver of vascular abnormalization in glioma. Pleiotrophin abundance was greater in high-grade human astrocytomas and correlated with poor survival. Anaplastic lymphoma kinase (ALK), which is a receptor that is activated by pleiotrophin, was present in mural cells associated with abnormal vessels. Orthotopically implanted gliomas formed from GL261 cells that were engineered to produce pleiotrophin showed increased microvessel density and enhanced tumor growth compared with gliomas formed from control GL261 cells. The survival of mice with pleiotrophin-producing gliomas was shorter than that of mice with gliomas that did not produce pleiotrophin. Vessels in pleiotrophin-producing gliomas were poorly perfused and abnormal, a phenotype that was associated with increased deposition of vascular endothelial growth factor (VEGF) in direct proximity to the vasculature. The growth of pleiotrophin-producing GL261 gliomas was inhibited by treatment with the ALK inhibitor crizotinib, the ALK inhibitor ceritinib, or the VEGF receptor inhibitor cediranib, whereas control GL261 tumors did not respond to either inhibitor. Our findings link pleiotrophin abundance in gliomas with survival in humans and mice, and show that pleiotrophin promotes glioma progression through increased VEGF deposition and vascular abnormalization. PMID:26645582

  13. Temsirolimus and Perifosine in Treating Patients With Recurrent or Progressive Malignant Glioma

    ClinicalTrials.gov

    2016-07-06

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Recurrent Adult Brain Neoplasm

  14. Erlotinib Hydrochloride and Isotretinoin in Treating Patients With Recurrent Malignant Glioma

    ClinicalTrials.gov

    2015-07-27

    Adult Anaplastic Astrocytoma; Adult Anaplastic Oligodendroglioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Recurrent Adult Brain Tumor

  15. In vitro enhancement of dendritic cell-mediated anti-glioma immune response by graphene oxide

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Li, Zhongjun; Duan, Jinhong; Wang, Chen; Fang, Ying; Yang, Xian-Da

    2014-06-01

    Malignant glioma has extremely poor prognosis despite combination treatments with surgery, radiation, and chemotherapy. Dendritic cell (DC)-based immunotherapy may potentially serve as an adjuvant treatment of glioma, but its efficacy generally needs further improvement. Here we explored whether graphene oxide (GO) nanosheets could modulate the DC-mediated anti-glioma immune response in vitro, using the T98G human glioma cell line as the study model. Pulsing DCs with a glioma peptide antigen (Ag) generated a limited anti-glioma response compared to un-pulsed DCs. Pulsing DCs with GO alone failed to produce obvious immune modulation effects. However, stimulating DCs with a mixture of GO and Ag (GO-Ag) significantly enhanced the anti-glioma immune reaction ( p < 0.05). The secretion of interferon gamma (IFN-γ) by the lymphocytes was also markedly boosted by GO-Ag. Additionally, the anti-glioma immune response induced by GO-Ag appeared to be target-specific. Furthermore, at the concentration used in this study, GO exhibited a negligible effect on the viability of the DCs. These results suggested that GO might have potential utility for boosting a DC-mediated anti-glioma immune response.

  16. MYB-QKI rearrangements in Angiocentric Glioma drive tumorigenicity through a tripartite mechanism

    PubMed Central

    Bandopadhayay, Pratiti; Ramkissoon, Lori A.; Jain, Payal; Bergthold, Guillaume; Wala, Jeremiah; Zeid, Rhamy; Schumacher, Steven E.; Urbanski, Laura; O’Rourke, Ryan; Gibson, William J.; Pelton, Kristine; Ramkissoon, Shakti H.; Han, Harry J.; Zhu, Yuankun; Choudhari, Namrata; Silva, Amanda; Boucher, Katie; Henn, Rosemary E.; Kang, Yun Jee; Knoff, David; Paolella, Brenton R.; Gladden-Young, Adrianne; Varlet, Pascale; Pages, Melanie; Horowitz, Peleg M.; Federation, Alexander; Malkin, Hayley; Tracy, Adam; Seepo, Sara; Ducar, Matthew; Hummelen, Paul Van; Santi, Mariarita; Buccoliero, Anna Maria; Scagnet, Mirko; Bowers, Daniel C.; Giannini, Caterina; Puget, Stephanie; Hawkins, Cynthia; Tabori, Uri; Klekner, Almos; Bognar, Laszlo; Burger, Peter C.; Eberhart, Charles; Rodriguez, Fausto J.; Hill, D. Ashley; Mueller, Sabine; Haas-Kogan, Daphne A.; Phillips, Joanna J.; Santagata, Sandro; Stiles, Charles D.; Bradner, James E.; Jabado, Nada; Goren, Alon; Grill, Jacques; Ligon, Azra H.; Goumnerova, Liliana; Waanders, Angela J.; Storm, Phillip B.; Kieran, Mark W.; Ligon, Keith L.; Beroukhim, Rameen; Resnick, Adam C.

    2016-01-01

    Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs including 19 Angiocentric Gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in Angiocentric Gliomas. In vitro and in vivo functional studies show MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression, and hemizygous loss of the tumor suppressor QKI. This represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor. PMID:26829751

  17. GSK-3β regulates tumor growth and angiogenesis in human glioma cells

    PubMed Central

    Shi, Zhumei; Li, Charlie; Wang, Lin; Liu, Xue; Jiang, Chengfei; Qian, Xu; You, Yongping; Liu, Ning; Liu, Ling-Zhi; Ding, Lianshu; Jiang, Bing-Hua

    2015-01-01

    Background Glioma accounts for the majority of primary malignant brain tumors in adults. Methods Glioma specimens and normal brain tissues were analyzed for the expression levels of GSK-3β and p-GSK-3β (Ser9) by tissue microarray analysis (TMA) and Western blotting. Glioma cells over-expressing GSK-3β were used to analyze biological functions both in vitro and in vivo. Results The levels of p-GSK-3β (Ser9), but not total GSK-3β, are significantly up-regulated in glioma tissues compared to normal tissues, and are significantly correlated with the glioma grades. Ectopic expression of GSK-3β decreased the phosphorylation levels of mTOR and p70S6K1; and inhibited β-catenin, HIF-1α and VEGF expression. Forced expression of GSK-3β in glioma cells significantly inhibited both tumor growth and angiogenesis in vivo. Conclusions These results reveal that GSK-3β regulates mTOR/p70S6K1 signaling pathway and inhibits glioma progression in vivo; its inactivation via p-GSK-3β (Ser9) is associated with glioma development, which is new mechanism that may be helpful in developing GSK-3β-based treatment of glioma in the future. PMID:26388612

  18. The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma

    PubMed Central

    Yadavilli, Sridevi; Scafidi, Joseph; Becher, Oren J.; Saratsis, Amanda M.; Hiner, Rebecca L.; Kambhampati, Madhuri; Mariarita, Santi; MacDonald, Tobey J.; Codispoti, Kari-Elise; Magge, Suresh N.; Jaiswal, Jyoti K.; Packer, Roger J.; Nazarian, Javad

    2015-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG primary tumor cells in vitro. NG2 expression is altered (symmetric segregation) in mitotic human DIPG and mouse tumor cells. These mitotic cells co-express oligodendrocyte (Olig2) and astrocyte (glial fibrillary acidic protein, GFAP) markers, indicating lack of terminal differentiation. NG2 knockdown retards cellular migration in vitro, while NG2 expressing neurospheres are highly tumorigenic in vivo, resulting in rapid growth of pontine tumors. NG2 expression is targetable in vivo using miR129-2 indicating a potential avenue for therapeutic interventions. This data implicates NG2 as a molecule of interest in DIPGs especially those with H3.3 mutation. PMID:25987129

  19. Armodafinil in Reducing Cancer-Related Fatigue in Patients With High Grade Glioma | Division of Cancer Prevention

    Cancer.gov

    This randomized phase III trial studies armodafinil to see how well it works in reducing cancer-related fatigue in patients with high grade glioma. Armodafinil may help relieve fatigue in patients with high grade glioma. |

  20. Clinical ramifications of "genomic staging" of low-grade gliomas.

    PubMed

    Verma, Vivek; Mehta, Minesh P

    2016-09-01

    "Low-grade gliomas" (LGGs), classification of which is derived from histopathological observations, exhibit significant heterogeneity in clinical behavior. Recently, increasing attention has been paid to genomic analyses of these tumors, to aid in treatment and prognostic decision-making. We discuss herein the recent genomic analysis of gliomas from two major recent publications, and also the results of seminal LGG trials in the context of molecular and genomic stratification, with respect to both prognosis and response to therapy. We also analyze implications of these "molecular classifications". We propose separating out the worst prognostic subsets, whose outcomes resemble those of glioblastoma patients. Lastly, a brief discussion is provided regarding translating this collective knowledge into the clinic and in treatment decisions; also addressed are some of the many questions that still need to be examined in light of these strong and emerging data. PMID:27401152

  1. Trends in Fluorescence Image-guided Surgery for Gliomas

    PubMed Central

    Liu, Jonathan T.C.; Meza, Daphne; Sanai, Nader

    2014-01-01

    Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low-grade and high-grade glioma patients. However, radiographically complete resections are not often achieved in many cases due to the lack of sensitivity and specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins. Here, we provide a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care. PMID:24618801

  2. Intraoperative stimulation techniques for functional pathway preservation and glioma resection.

    PubMed

    Sanai, Nader; Berger, Mitchel S

    2010-02-01

    Although a primary tenet of neurosurgical oncology is that survival can improve with greater tumor resection, this principle must be tempered by the potential for functional loss following a radical removal. Preoperative planning with functional and physiological imaging paradigms, combined with intraoperative strategies such as cortical and subcortical stimulation mapping, can effectively reduce the risks associated with operating in eloquent territory. In addition to identifying critical motor pathways, these techniques can be adapted to identify language function reliably. The authors review the technical nuances of intraoperative mapping for low- and high-grade gliomas, demonstrating their efficacy in optimizing resection even in patients with negative mapping data. Collectively, these surgical strategies represent the cornerstone for operating on gliomas in and around functional pathways.

  3. Trends in fluorescence image-guided surgery for gliomas.

    PubMed

    Liu, Jonathan T C; Meza, Daphne; Sanai, Nader

    2014-07-01

    Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low-grade and high-grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivity and specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins. Here, we provide a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care.

  4. Intraoperative Functional Mapping and Monitoring during Glioma Surgery

    PubMed Central

    SAITO, Taiichi; MURAGAKI, Yoshihiro; MARUYAMA, Takashi; TAMURA, Manabu; NITTA, Masayuki; OKADA, Yoshikazu

    2015-01-01

    Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient’s neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery. PMID:25744346

  5. Intraoperative Functional Mapping and Monitoring during Glioma Surgery.

    PubMed

    Saito, Taiichi; Muragaki, Yoshihiro; Maruyama, Takashi; Tamura, Manabu; Nitta, Masayuki; Okada, Yoshikazu

    2015-01-01

    Glioma surgery represents a significant advance with respect to improving resection rates using new surgical techniques, including intraoperative functional mapping, monitoring, and imaging. Functional mapping under awake craniotomy can be used to detect individual eloquent tissues of speech and/or motor functions in order to prevent unexpected deficits and promote extensive resection. In addition, monitoring the patient’s neurological findings during resection is also very useful for maximizing the removal rate and minimizing deficits by alarming that the touched area is close to eloquent regions and fibers. Assessing several types of evoked potentials, including motor evoked potentials (MEPs), sensory evoked potentials (SEPs) and visual evoked potentials (VEPs), is also helpful for performing surgical monitoring in patients under general anesthesia (GA). We herein review the utility of intraoperative mapping and monitoring the assessment of neurological findings, with a particular focus on speech and the motor function, in patients undergoing glioma surgery. PMID:26236798

  6. Patterns of epidermal growth factor receptor amplification in malignant gliomas.

    PubMed Central

    Sauter, G.; Maeda, T.; Waldman, F. M.; Davis, R. L.; Feuerstein, B. G.

    1996-01-01

    Amplification of the gene for epidermal growth factor receptor (EGFR) is a common finding in malignant gliomas. We found that 18 of 29 grade 3 and grade 4 gliomas had EGFR amplification when assayed using fluorescence in situ hybridization. The amplification pattern suggests that the amplicon is contained within double minute chromosomes in most cases. EGFR copy number can differ by 20-fold in amplified cells within a single case. Polysomy 7 occurs frequently in both EGFR-amplified and -unamplified cells. More than one-third of the cases had < or = 10 percent of cells with amplified EGFR, and it is likely that these cases would not have been identified by methods that do not examine DNA on a cell by cell basis. Images Figure 1 PMID:8644846

  7. The Metabolomic Signature of Malignant Glioma Reflects Accelerated Anabolic Metabolism

    PubMed Central

    Chinnaiyan, Prakash; Kensicki, Elizabeth; Bloom, Gregory; Prabhu, Antony; Sarcar, Bhaswati; Kahali, Soumen; Eschrich, Steven; Qu, Xiaotao; Forsyth, Peter; Gillies, Robert

    2015-01-01

    Although considerable progress has been made toward understanding glioblastoma biology through large-scale genetic and protein expression analyses, little is known about the underlying metabolic alterations promoting their aggressive phenotype. We conducted global metabolomic profiling on patient-derived glioma specimens and identified specific metabolic programs differentiating low- and high-grade tumors, with the metabolic signature of glioblastoma reflecting accelerated anabolic metabolism. When coupled with transcriptional profiles, we identified the metabolic phenotype of the mesenchymal subtype to consist of accumulation of the glycolytic intermediate phosphoenolpyruvate and decreased pyruvate kinase activity. Unbiased hierarchical clustering of metabolomic profiles identified three subclasses, which we term energetic, anabolic, and phospholipid catabolism with prognostic relevance. These studies represent the first global metabolomic profiling of glioma, offering a previously undescribed window into their metabolic heterogeneity, and provide the requisite framework for strategies designed to target metabolism in this rapidly fatal malignancy. PMID:23026133

  8. In Vitro Drug Response and Efflux Transporters Associated with Drug Resistance in Pediatric High Grade Glioma and Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Veringa, Susanna J. E.; Biesmans, Dennis; van Vuurden, Dannis G.; Jansen, Marc H. A.; Wedekind, Laurine E.; Horsman, Ilona; Wesseling, Pieter; Vandertop, William Peter; Noske, David P.; Kaspers, GertJan J. L.; Hulleman, Esther

    2013-01-01

    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. PMID:23637844

  9. Expression of serotonin receptors in human fetal astrocytes and glioma cell lines: a possible role in glioma cell proliferation and migration.

    PubMed

    Merzak, A; Koochekpour, S; Fillion, M P; Fillion, G; Pilkington, G J

    1996-09-01

    Expression of seven serotonin or 5-hydroxytryptamine (5-HT) receptors (5-HT1D alpha, 5-HT1E, 5-HT2, 5-HT1A, 5-HT1C, 5-HT1D beta, and 5-HT6) was investigated in human normal fetal astrocytes and eight glioma cell lines by reverse transcription and polymerase chain reaction (RT-PCR). No expression of 5-HT1D beta and 5-HT6 was observed in any of the cell lines studied. The 5-HT1D alpha receptor was found to be expressed in two human glioma cell lines but not in normal astrocytes. In addition, only three glioma cell lines expressed the 5-HT1E receptor. The 5-HT1C receptor was expressed in six glioma cell lines but not in normal astrocytes while the 5-HT1A was found to be expressed in normal astrocytes from the left hemisphere and in six glioma cell lines but not in normal astrocytes from the cerebellum. Interestingly, the 5-HT2 receptor was expressed in all cells studied but very weakly in normal astrocytes. The effect of 5-HT on glioma cell proliferation, migration, and invasion was also investigated. Serotonin was found to positively modulate these three processes in vitro. These results suggest that 5-HT may play an important role in the control of the biological properties of human glioma cells. PMID:8883928

  10. Modeling cytomegalovirus infection in mouse tumor models.

    PubMed

    Price, Richard Lee; Chiocca, Ennio Antonio

    2015-01-01

    The hypothesis that cytomegalovirus (CMV) modulates cancer is evolving. Originally discovered in glioblastoma in 2002, the number of cancers, where intratumoral CMV antigen is detected, has increased in recent years suggesting that CMV actively affects the pathobiology of certain tumors. These findings are controversial as several groups have also reported inability to replicate these results. Regardless, several clinical trials for glioblastoma are underway or have been completed that target intratumoral CMV with anti-viral drugs or immunotherapy. Therefore, a better understanding of the possible pathobiology of CMV in cancer needs to be ascertained. We have developed genetic, syngeneic, and orthotopic malignant glioma mouse models to study the role of CMV in cancer development and progression. These models recapitulate for the most part intratumoral CMV expression as seen in human tumors. Additionally, we discovered that CMV infection in Trp53(-/+) mice promotes pleomorphic rhabdomyosarcomas. These mouse models are not only a vehicle for studying pathobiology of the viral-tumor interaction but also a platform for developing and testing cancer therapeutics. PMID:25853089

  11. Dracorhodin perchlorate induces the apoptosis of glioma cells.

    PubMed

    Chen, Xin; Luo, Junjie; Meng, Linghu; Pan, Taifeng; Zhao, Binjie; Tang, Zhen-Gang; Dai, Yongjian

    2016-04-01

    Dracorhodin perchlorate (Dp), a synthetic analogue of the antimicrobial anthocyanin red pigment, has recently been shown to induce apoptotic cell death in various types of cancer cells. Yet, the inhibitory effect of Dp on human glioma cells remains uninvestigated. Therefore, in the present study, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometry were used to detect cell viability and cell cycle progression in glioma U87MG and T98G cells, respectively. Annexin V-FITC/propidium iodide double staining and JC-1 staining were separately applied to determine cellular apoptosis and mitochondrial membrane potential damage in the cells. The expression levels of associated proteins involved in cell cycle progression and apoptosis were measured by western blotting. The activities of caspase‑9/-3 were determined by Caspase-Glo-9/3 assay. The results indicated that Dp treatment significantly inhibited cell proliferation in a dose- and time-dependent manner, and blocked cell cycle progression at the G1/S phase in the U87MG and T98G cells via the upregulation of p53 and p21 protein expression, and simultaneous downregulation of Cdc25A, Cdc2 and P-Cdc2 protein expression. Additionally, Dp treatment led to the loss of cellular mitochondrial membrane potential, and the release of cytochrome c, and strongly induced the occurence of apoptosis. Increased expression levels of Bim and Bax protein and the downregulated expression of Bcl-2 protein were observed. Caspase-9/-3 were activated and their activities were elevated after Dp treatment. These findings indicate that Dp inhibits cell proliferation, induces cell cycle arrest and apoptosis in glioma cells, and is a possible candidate for glioma treatment. PMID:26846469

  12. Epilepsy in patients with gliomas: incidence and control of seizures.

    PubMed

    Iuchi, Toshihiko; Hasegawa, Yuzo; Kawasaki, Koichiro; Sakaida, Tsukasa

    2015-01-01

    Brain tumor-related epilepsy (BTRE) is a unique condition that is distinct from primary epilepsy. The aim of this retrospective study was to clarify the epidemiology and results of treatment of BTRE in a single institution. From a database of 121 consecutive patients with supratentorial gliomas treated at Chiba Cancer Center from 2006-2012, the incidence and control of seizures before and after surgery were retrospectively evaluated. Epilepsy occurred in 33.9% of patients before surgery. All patients received prophylactic anti-epileptic drugs (AED) during surgery; however, seizures occurred in 9.1% of patients within the first postoperative week. During follow-up, seizures occurred in 48.3% of patients. The overall incidence of seizures was 73.7% in patients with World Health Organization Grade II gliomas, 66.7% in those with Grade III and 56.8% in those with Grade IV gliomas. Levetiracetam was very well tolerated. However, carbamazepine and phenytoin were poorly tolerated because of adverse effects. AED were discontinued in 56 patients. Fifteen of these patients (26.8%) had further seizures, half occurring within 3 months and 80% within 6 months of AED withdrawal. No clinical factors that indicated it was safe to discontinue AED were identified. The unpredictable epileptogenesis associated with gliomas and their excision requires prolonged administration of AED. To maintain quality of life and to safely and effectively control the tumor, it is necessary to select AED that do not adversely affect cognitive function or interact with other drugs, including anti-cancer agents.

  13. Experience with irinotecan for the treatment of malignant glioma

    PubMed Central

    Vredenburgh, James J.; Desjardins, Annick; Reardon, David A.; Friedman, Henry S.

    2009-01-01

    Malignant glioma is the most commonly occurring primary malignant brain tumor. It is difficult to treat and is usually associated with an inexorable, rapidly fatal clinical course. Chemotherapy, radiotherapy, and surgical excision are core components in the management of malignant glioma. However, chemotherapy, even with the most active regimens currently available, achieves only modest improvement in overall survival. Novel agents and new approaches to therapy are required to improve clinical outcomes. Irinotecan, a first-line treatment for metastatic colorectal cancer and an agent with high activity against solid tumors of the gastrointestinal tract, is an inhibitor of topoisomerase I, a critical enzyme needed for DNA transcription. Irinotecan crosses the blood-brain barrier and, in preclinical investigations, has demonstrated cytotoxic activity against central nervous system tumor xenografts. Its antitumor activity has also been demonstrated against glioblastoma cells with multi-drug resistance. Studies in adult and pediatric patients with recurrent, intractable malignant glioma have evaluated irinotecan as monotherapy and in combination with other agents, including temozolomide, carmustine, thalidomide, and bevacizumab. Studies of irinotecan in combination with other medications, particularly temozolomide and bevacizumab, have yielded promising results. Irinotecan monotherapy has demonstrated efficacy; however, its efficacy appears to be enhanced when used in combination with other chemotherapeutic agents. When administered concurrently with enzyme-inducing antiepileptic drugs, the dosage must be increased to compensate for enhanced cytochrome CY3A4/5 enzyme activity. Toxicities associated with irinotecan have been manageable; the most important dose-limiting toxicities are neutropenia and diarrhea. Irinotecan-based chemotherapy of malignant glioma merits further study. PMID:18784279

  14. Functionally-defined Therapeutic Targets in Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Grasso, Catherine S.; Tang, Yujie; Truffaux, Nathalene; Berlow, Noah E.; Liu, Lining; Debily, Marie-Anne; Quist, Michael J.; Davis, Lara E.; Huang, Elaine C.; Woo, Pamelyn J; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B.; Sun, Wenchao; Kogiso, Mari; Du, Yuchen; Lin, Qi; Huang, Yulun; Hütt-Cabezas, Marianne; Warren, Katherine E.; Dret, Ludivine Le; Meltzer, Paul S.; Mao, Hua; Quezado, Martha; van Vuurden, Dannis G.; Abraham, Jinu; Fouladi, Maryam; Svalina, Matthew N.; Wang, Nicholas; Hawkins, Cynthia; Nazarian, Javad; Alonso, Marta M.; Raabe, Eric; Hulleman, Esther; Spellman, Paul T.; Li, Xiao-Nan; Keller, Charles; Pal, Ranadip; Grill, Jacques; Monje, Michelle

    2015-01-01

    Diffuse Intrinsic Pontine Glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNAseq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated efficacy in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat with histone demethylase inhibitor GSKJ4 revealed synergy. Together, these data suggest a promising therapeutic strategy for DIPG. PMID:25939062

  15. Indocyanine green as an adjunct for resection of insular gliomas

    PubMed Central

    Shah, Abhidha; Rangarajan, Vithal; Kaswa, Amol; Jain, Sonal; Goel, Atul

    2016-01-01

    Objective: Many controversies exist regarding the extent of resection for insular gliomas and the timing of resection. Several techniques and adjuncts are used to maximize safety during resection of these tumors. We describe the use of indocyanine green (ICG) to identify the branches of the middle cerebral artery and discuss its utility to increase safety for resection for insular gliomas. Materials and Methods: Five patients with insular gliomas were surgically treated by the authors from June 2013 to June 2014. The patients presented with complaints of either a headache or recurring episodes of convulsions. All the patients were operated with the aid of neuronavigation and tractography. The long perforating branches of the middle cerebral artery course through the insula and pass onward to supply the corona radiata. It is essential to preserve these vessels to prevent postoperative neurological deficits. ICG (Aurogreen) was used to identify and preserve the long perforating arteries of the middle cerebral artery. Results: ICG dye correctly identified the long perforating branches of the middle cerebral artery and easily distinguished these vessels from the short perforating branches. All the branches of the middle cerebral artery that coursed through the tumor and had an onward course were preserved in all the patients. Only one patient developed a transient right sided hemiparesis that had improved at follow-up. Conclusions: Surgery for insular gliomas is challenging due to its location adjacent to eloquent areas, important white fiber tracts and the course of the middle cerebral artery within it. ICG is useful to identify and preserve the long perforating branches of the middle cerebral artery that course through the tumor and traverse onward to supply the corona radiata. PMID:27366256

  16. Involvement of the Kynurenine Pathway in Human Glioma Pathophysiology

    PubMed Central

    Adams, Seray; Teo, Charles; McDonald, Kerrie L.; Zinger, Anna; Bustamante, Sonia; Lim, Chai K.; Sundaram, Gayathri; Braidy, Nady; Brew, Bruce J.; Guillemin, Gilles J.

    2014-01-01

    The kynurenine pathway (KP) is the principal route of L-tryptophan (TRP) catabolism leading to the production of kynurenine (KYN), the neuroprotectants, kynurenic acid (KYNA) and picolinic acid (PIC), the excitotoxin, quinolinic acid (QUIN) and the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+). The enzymes indoleamine 2,3-dioxygenase-1 (IDO-1), indoleamine 2,3-dioxygenase-2 (IDO-2) and tryptophan 2,3-dioxygenase (TDO-2) initiate the first step of the KP. IDO-1 and TDO-2 induction in tumors are crucial mechanisms implicated to play pivotal roles in suppressing anti-tumor immunity. Here, we report the first comprehensive characterisation of the KP in 1) cultured human glioma cells and 2) plasma from patients with glioblastoma (GBM). Our data revealed that interferon-gamma (IFN-γ) stimulation significantly potentiated the expression of the KP enzymes, IDO-1 IDO-2, kynureninase (KYNU), kynurenine hydroxylase (KMO) and significantly down-regulated 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD) and kynurenine aminotransferase-I (KAT-I) expression in cultured human glioma cells. This significantly increased KP activity but significantly lowered the KYNA/KYN neuroprotective ratio in human cultured glioma cells. KP activation (KYN/TRP) was significantly higher, whereas the concentrations of the neuroreactive KP metabolites TRP, KYNA, QUIN and PIC and the KYNA/KYN ratio were significantly lower in GBM patient plasma (n = 18) compared to controls. These results provide further evidence for the involvement of the KP in glioma pathophysiology and highlight a potential role of KP products as novel and highly attractive therapeutic targets to evaluate for the treatment of brain tumors, aimed at restoring anti-tumor immunity and reducing the capacity for malignant cells to produce NAD+, which is necessary for energy production and DNA repair. PMID:25415278

  17. Cancer Immunotherapy for Gliomas: Overview and Future Directions

    PubMed Central

    HASHIMOTO, Naoya

    2016-01-01

    Immunotherapy has been highlighted because we have obtained much evidence, which includes theoretical backborn as well as favorable results from clinical trials. As immunotherapy gives an apparently different cytotoxic mechanism and a little adverse event, the promising results are getting a lot of attention. In this article, cancer immunotherapy for gliomas is reviewed thoroughly from the literature, focusing on the clinical trial results. PMID:27087194

  18. Tumor infiltrating immune cells in gliomas and meningiomas.

    PubMed

    Domingues, Patrícia; González-Tablas, María; Otero, Álvaro; Pascual, Daniel; Miranda, David; Ruiz, Laura; Sousa, Pablo; Ciudad, Juana; Gonçalves, Jesús María; Lopes, María Celeste; Orfao, Alberto; Tabernero, María Dolores

    2016-03-01

    Tumor-infiltrating immune cells are part of a complex microenvironment that promotes and/or regulates tumor development and growth. Depending on the type of cells and their functional interactions, immune cells may play a key role in suppressing the tumor or in providing support for tumor growth, with relevant effects on patient behavior. In recent years, important advances have been achieved in the characterization of immune cell infiltrates in central nervous system (CNS) tumors, but their role in tumorigenesis and patient behavior still remain poorly understood. Overall, these studies have shown significant but variable levels of infiltration of CNS tumors by macrophage/microglial cells (TAM) and to a less extent also lymphocytes (particularly T-cells and NK cells, and less frequently also B-cells). Of note, TAM infiltrate gliomas at moderate numbers where they frequently show an immune suppressive phenotype and functional behavior; in contrast, infiltration by TAM may be very pronounced in meningiomas, particularly in cases that carry isolated monosomy 22, where the immune infiltrates also contain greater numbers of cytotoxic T and NK-cells associated with an enhanced anti-tumoral immune response. In line with this, the presence of regulatory T cells, is usually limited to a small fraction of all meningiomas, while frequently found in gliomas. Despite these differences between gliomas and meningiomas, both tumors show heterogeneous levels of infiltration by immune cells with variable functionality. In this review we summarize current knowledge about tumor-infiltrating immune cells in the two most common types of CNS tumors-gliomas and meningiomas-, as well as the role that such immune cells may play in the tumor microenvironment in controlling and/or promoting tumor development, growth and control.

  19. Restoring Soluble Guanylyl Cyclase Expression and Function Blocks the Aggressive Course of GliomaS⃞

    PubMed Central

    Zhu, Haifeng; Li, Jessica Tao; Zheng, Fang; Martin, Emil; Kots, Alexander Y.; Krumenacker, Joshua S.; Choi, Byung-Kwon; McCutcheon, Ian E.; Weisbrodt, Norman; Bögler, Oliver; Murad, Ferid

    2011-01-01

    The NO and cGMP signaling pathways are of broad physiological and pathological significance. We compared the NO/soluble guanylyl cyclase (sGC)/cGMP pathway in human glioma tissues and cell lines with that of healthy control samples and demonstrated that sGC expression is significantly lower in glioma preparations. Our analysis of GEO databases (National Cancer Institute) further revealed a statistically significant reduction of sGC transcript levels in human glioma specimens. On the other hand, the expression levels of particulate (membrane) guanylyl cyclases (pGC) and cGMP-specific phosphodiesterase (PDE) were intact in the glioma cells that we have tested. Pharmacologically manipulating endogenous cGMP generation in glioma cells through either stimulating pGC by ANP/BNP, or blocking PDE by 3-isobutyl-1-methylxanthine/zaprinast caused significant inhibition of proliferation and colony formation of glioma cells. Genetically restoring sGC expression also correlated inversely with glioma cells growth. Orthotopic implantation of glioma cells transfected with an active mutant form of sGC (sGCα1β1Cys105) in athymic mice increased the survival time by 4-fold over the control. Histological analysis of xenografts overexpressing α1β1Cys105 sGC revealed changes in cellular architecture that resemble the morphology of normal cells. In addition, a decrease in angiogenesis contributed to glioma inhibition by sGC/cGMP therapy. Our study proposes the new concept that suppressed expression of sGC, a key enzyme in the NO/cGMP pathway, may be associated with an aggressive course of glioma. The sGC/cGMP signaling-targeted therapy may be a favorable alternative to chemotherapy and radiotherapy for glioma and perhaps other tumors. PMID:21908708

  20. MiR-328 promotes glioma cell invasion via SFRP1-dependent Wnt-signaling activation.

    PubMed

    Delic, Sabit; Lottmann, Nadine; Stelzl, Anja; Liesenberg, Franziska; Wolter, Marietta; Götze, Silke; Zapatka, Marc; Shiio, Yuzuru; Sabel, Michael C; Felsberg, Jörg; Reifenberger, Guido; Riemenschneider, Markus J

    2014-01-01

    Background Diffusely infiltrative growth of human astrocytic gliomas is one of the major obstacles to successful tumor therapy. Thorough insights into the molecules and pathways signaling glioma cell invasion thus appear of major relevance for the development of targeted and individualized therapies. By miRNA expression profiling of microdissected human tumor biopsy specimens we identified miR-328 as one of the main miRNAs upregulated in invading glioma cells in vivo and further investigated its role in glioma pathogenesis. Methods We employed miRNA mimics and inhibitors to functionally characterize miR-328, 3' untranslated region luciferase assays, and T-cell factor/lymphoid enhancer factor reporter assays to pinpoint miR-328 targets and signaling pathways, and analyzed miR-328 expression in a large panel of gliomas. Results First, we corroborated the invasion-promoting role of miR-328 in A172 and TP365MG glioma cells. Secreted Frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signaling, was then pinpointed as a direct miR-328 target. SFRP1 expression is of prognostic relevance in gliomas with reduced expression, being associated with significantly lower overall patient survival in both the Repository of Molecular Brain Neoplasia Data (REMBRANDT) and The Cancer Genome Atlas. Of note, miR-328 regulated both SFRP1 protein expression levels and Wnt signaling pathway activity. Finally, in human glioma tissues miR-328 appeared to account for the downregulation of SFRP1 preferentially in lower-grade astrocytic gliomas and was inversely related to SFRP1 promoter hypermethylation. Conclusion Taken together, we report on a novel molecular miR-328-dependent mechanism that via SFRP1 inhibition and Wnt activation contributes to the infiltrative glioma phenotype at already early stages of glioma progression, with unfavorable prognostic implications for the final outcome of the disease. PMID:24305703

  1. Overexpression of CD99 Increases the Migration and Invasiveness of Human Malignant Glioma Cells.

    PubMed

    Seol, Ho Jun; Chang, Jong Hee; Yamamoto, Junkoh; Romagnuolo, Rocco; Suh, Youngchul; Weeks, Adrienne; Agnihotri, Sameer; Smith, Christian A; Rutka, James T

    2012-09-01

    The malignant glioma is the most common primary human brain tumor, and its migration and invasiveness away from the primary tumor mass are considered a leading cause of tumor recurrence and treatment failure. Recently, gene expression profiling revealed that the transmembrane glycoprotein CD99 is more highly expressed in malignant glioma than in normal brain. Although its function is not completely understood, CD99 is implicated in cell adhesion and migration in a variety of different cell types. CD99 has wild-type and splice variant isoforms. Previous studies have shown that wild-type CD99 may be an oncosuppressor in some tumors, distinct from the role of the splice variant isoform. In this study, our data reveal that only wild-type CD99 is expressed in human glioma cells and tissues. Using a tissue microarray, we validated that gliomas demonstrate higher expression of CD99 compared with nonneoplastic brain. To assess the role of CD99 in glioma migration and invasion, we inhibited CD99 expression by siRNA and demonstrated decreased glioma migration and invasion. In contrast, when CD99 was overexpressed in glioma cells, we observed enhancement of cell migration and invasiveness. An orthotopic brain tumor model demonstrates that CD99 overexpression significantly increases invasiveness and decreases survival rate. Interestingly, Rac activity was decreased and Rho activity was increased in CD99 overexpressing glioma cells, and the proportion of amoeboid cells to mesenchymal cells was significantly increased. Taken together, our findings suggest that CD99 may play an important role in the migration and invasion of human gliomas independent of Akt, ERK, or JNK signaling pathways. Moreover, CD99 might be involved in amoeboid-mesenchymal transition in glioma migration. CD99 may be an important future target to inhibit migration and invasion, especially in CD99-expressing gliomas. PMID:23486730

  2. L1CAM stimulates glioma cell motility and proliferation through the fibroblast growth factor receptor.

    PubMed

    Mohanan, Vishnu; Temburni, Murali K; Kappes, John C; Galileo, Deni S

    2013-04-01

    The L1CAM cell adhesion/recognition molecule (L1, CD171) and fibroblast growth factor receptor (FGFR) both are expressed by human high-grade glioma cells, but their potential actions in controlling cell behavior have not been linked. L1 actions in cancer cells have been attributed mainly to integrin receptors, and we demonstrated previously that L1-stimulated glioma cell migration correlates with integrin expression, increased focal adhesion kinase activation and focal complex turnover. Our analyses of datasets revealed FGFR is overexpressed in glioma regardless of grade, while ADAM10 metalloprotease expression increases with glioma grade. Here, we used dominant-negative and short hairpin RNA approaches to inhibit the activation of FGFR1 and expression of L1, respectively. An L1 peptide that inhibits L1-FGFR interaction and PD173074, a chemical inhibitor of FGFR1 activity, also were used to elucidate the involvement of L1-FGFR interactions on glioma cell behavior. Time-lapse cell motility studies and flow cytometry cell cycle analyses showed that L1 operates to increase glioma cell motility and proliferation through FGFR activation. Shutdown of both L1 expression and FGFR activity in glioma cells resulted in a complete termination of cell migration in vitro. These studies show for the first time that soluble L1 ectodomain (L1LE) acts on glioma cells through FGFRs, and that FGFRs are used by glioma cells for increasing motility as well as proliferation in response to activation by L1LE ligand. Thus, effective treatment of high-grade glioma may require simultaneous targeting of L1, FGFRs, and integrin receptors, which would reduce glioma cell motility as well as proliferation.

  3. Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk

    PubMed Central

    Safaeian, Mahboobeh; Rajaraman, Preetha; Hartge, Patricia; Yeager, Meredith; Linet, Martha; Butler, Mary Ann; Ruder, Avima M.; Purdue, Mark P.; Hsing, Ann; Beane-Freeman, Laura; Hoppin, Jane A.; Albanes, Demetrius; Weinstein, Stephanie J.; Inskip, Peter D.; Brenner, Alina; Rothman, Nathaniel; Chatterjee, Nilanjan; Gillanders, Elizabeth M.; Chanock, Stephen J.; Wang, Sophia S.

    2014-01-01

    Common variants in two of the five genetic regions recently identified from genome-wide association studies (GWAS) of risk of glioma were reported to interact with a history of allergic symptoms. In a pooled analysis of five epidemiologic studies, we evaluated the association between the five GWAS implicated gene variants and allergies and autoimmune conditions (AIC) on glioma risk (851 adult glioma cases and 3,977 controls). We further evaluated the joint effects between allergies and AIC and these gene variants on glioma risk. Risk estimates were calculated as odds ratios (OR) and 95 % confidence intervals (95 % CI), adjusted for age, gender, and study. Joint effects were evaluated by conducting stratified analyses whereby the risk associations (OR and 95 % CI) with the allergy or autoimmune conditions for glioma were evaluated by the presence or absence of the ‘at-risk’ variant, and estimated p interaction by fitting models with the main effects of allergy or autoimmune conditions and genotype and an interaction (product) term between them. Four of the five SNPs previously reported by others were statistically significantly associated with increased risk of glioma in our study (rs2736100, rs4295627, rs4977756, and rs6010620); rs498872 was not associated with glioma in our study. Reporting any allergies or AIC was associated with reduced risks of glioma (allergy: adjusted OR = 0.71, 95 % CI 0.55–0.91; AIC: adjusted OR = 0.65, 95 % CI 0.47–0.90). We did not observe differential association between allergic or autoimmune conditions and glioma by genotype, and there were no statistically significant p interactions. Stratified analysis by glioma grade (low and high grade) did not suggest risk differences by disease grade. Our results do not provide evidence that allergies or AIC modulate the association between the four GWAS-identified SNPs examined and risk of glioma. PMID:23903690

  4. Expression of p16 and Survivin in gliomas and their correlation with cell proliferation

    PubMed Central

    GAO, YANSHENG; LI, LINGZHEN; SONG, LAIJUN

    2015-01-01

    The survival rate of glioma patients is very low, and a lack of effective diagnostic techniques are available at present. The current study aimed to investigate the expression of p16 and Survivin and their association with proliferation and apoptosis in gliomas, as well as patient characteristics and prognosis. In total, 62 glioma specimens were surgically resected and pathologically confirmed at the Zhumadian Central Hospital (Zhumadian, China) between June 2008 and February 2014. Clinical data, including the gender and age of the patients, as well as the location, infiltration degree, size and pathological stage of the glioma, was collected. In order to evaluate the expression of p16 and Survivin in the gliomas, the Ki-67 labeling index was used to evaluate cell proliferation activity. The number of argyrophilic nucleolar organizer regions and the rate of cellular apoptosis was examined using the terminal deoxynucleotidyl transferase dUTP nick end labeling method. The results were analyzed using SPSS 14.0 statistical software. The positive rate of p16 gene expression in the gliomas was 46.77% (29 cases), and p16 gene expression was positively correlated with the differentiation status, tumor size and pre-operative symptoms. The positive rate of Survivin expression in the gliomas was 69.88% (58 cases), and Survivin expression was positively correlated with tumor size, differentiation status and clinical stage. The proliferation activity of the gliomas was enhanced with increasing p16 and Survivin expression, while apoptosis was inhibited. In conclusion, the overexpression of p16 and Survivin was closely associated with uncontrolled cell proliferation and the inhibition of apoptosis in gliomas. The combined analysis of the expression of p16 and Survivin in gliomas may provide guidance with respect to the clinical diagnosis, evaluation, treatment and prognosis of patients with glioma. PMID:26171019

  5. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

    PubMed Central

    Eckel-Passow, Jeanette E.; Lachance, Daniel H.; Molinaro, Annette M.; Walsh, Kyle M.; Decker, Paul A.; Sicotte, Hugues; Pekmezci, Melike; Rice, Terri; Kosel, Matt L.; Smirnov, Ivan V.; Sarkar, Gobinda; Caron, Alissa A.; Kollmeyer, Thomas M.; Praska, Corinne E.; Chada, Anisha R.; Halder, Chandralekha; Hansen, Helen M.; McCoy, Lucie S.; Bracci, Paige M.; Marshall, Roxanne; Zheng, Shichun; Reis, Gerald F.; Pico, Alexander R.; O’Neill, Brian P.; Buckner, Jan C.; Giannini, Caterina; Huse, Jason T.; Perry, Arie; Tihan, Tarik; Berger, Mitchell S.; Chang, Susan M.; Prados, Michael D.; Wiemels, Joseph; Wiencke, John K.; Wrensch, Margaret R.; Jenkins, Robert B.

    2015-01-01

    BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triplepositive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. PMID:26061753

  6. Boldine: a potential new antiproliferative drug against glioma cell lines.

    PubMed

    Gerhardt, Daniéli; Horn, Ana Paula; Gaelzer, Mariana Maier; Frozza, Rudimar Luiz; Delgado-Cañedo, Andrés; Pelegrini, Alessandra Luiza; Henriques, Amélia T; Lenz, Guido; Salbego, Christianne

    2009-12-01

    Malignant gliomas are the most common and devastating primary tumors of the central nervous system. Currently no efficient treatment is available. This study evaluated the effect and underlying mechanisms of boldine, an aporphine alkaloid of Peumus boldus, on glioma proliferation and cell death. Boldine decreased the cell number of U138-MG, U87-MG and C6 glioma lines at concentrations of 80, 250 and 500 muM. We observed that cell death caused by boldine was cell-type specific and dose-dependent. Exposure to boldine for 24 h did not activate key mediators of apoptosis. However, it induced alterations in the cell cycle suggesting a G(2)/M arrest in U138-MG cells. Boldine had no toxic effect on non-tumor cells when used at the same concentrations as those used on tumor cells. Based on these results, we speculate that boldine may be a promising compound for evaluation as an anti-cancer agent. PMID:19050827

  7. Bromelain reversibly inhibits invasive properties of glioma cells.

    PubMed

    Tysnes, B B; Maurer, H R; Porwol, T; Probst, B; Bjerkvig, R; Hoover, F

    2001-01-01

    Bromelain is an aqueous extract from pineapple stem that contains proteinases and exhibits pleiotropic therapeutic effects, i.e., antiedematous, antiinflammatory, antimetastatic, antithrombotic, and fibrinolytic activities. In this study, we tested bromelain's effects on glioma cells to assess whether bromelain could be a potential contributor to new antiinvasive strategies for gliomas. Several complementary assays demonstrated that bromelain significantly and reversibly reduced glioma cell adhesion, migration, and invasion without affecting cell viability, even after treatment periods extending over several months. Immunohistochemistry and immunoblotting experiments demonstrated that alpha3 and beta1 integrin subunits and hyaluronan receptor CD44 protein levels were reduced within 24 hours of bromelain treatment. These effects were not reflected at the RNA level because RNA profiling did not show any significant effects on gene expression. Interestingly, metabolic labelling with 35-S methionine demonstrated that de novo protein synthesis was greatly attenuated by bromelain, in a reversible manner. By using a transactivating signaling assay, we found that CRE-mediated signaling processes were suppressed. These results indicate that bromelain exerts its antiinvasive effects by proteolysis, signaling cascades, and translational attenuation.

  8. Stereotactic radiosurgery of deeply seated low grade gliomas.

    PubMed

    Barcia, J A; Barcia-Salorio, J L; Ferrer, C; Ferrer, E; Algás, R; Hernández, G

    1994-01-01

    The authors report the results of a series of 16 cases of low-grade gliomas in whom radiosurgery was performed. This series started in 1977. All the tumours received a single radiosurgical session (with a mean dose of 21.7 Gy, 5-10 mm. collimator; one patient received two sessions and in another patient two different targets were irradiated in the same session). Prior to radiosurgery, six patients received conventional external fractionated radiotherapy, with two lateral fields of up to 10 x 10 cm. and a mean dose of 55.1 Gy and another six patients with tumours less than 5 cm. in diameter, received stereotactic radiotherapy using four fields of up to 5 x 5 cm. and a mean dose of 53.1 Gy. In both cases, conventional fractionation was used, giving a dose of 1.8 to 2 Gy/day. The tumour disappeared in 8 cases (50%) and shunk or ceased its growth in 5 additional cases (31%). In 3 cases of brainstem gliomas in which the clinical condition was previously very poor there was no evolutional change and the patients eventually died. We conclude that radiosurgery is effective in the treatment of deeply seated low-grade gliomas, where it may become the treatment of choice in the absence of other more definitive choices.

  9. Atypical crossmodal emotional integration in patients with gliomas.

    PubMed

    Luherne-du Boullay, Viviane; Plaza, Monique; Perrault, Annabelle; Capelle, Laurent; Chaby, Laurence

    2014-11-01

    The relevance of emotional perception in interpersonal relationships and social cognition has been well documented. Although brain diseases might impair emotional processing, studies concerning emotional recognition in patients with brain tumours are relatively rare. The aim of this study was to explore emotional recognition in patients with gliomas in three conditions (visual, auditory and crossmodal) and to analyse how tumour-related variables (notably, tumour localisation) and patient-related variables influence emotion recognition. Twenty six patients with gliomas and 26 matched healthy controls were instructed to identify 5 basic emotions and a neutral expression, which were displayed through visual, auditory and crossmodal stimuli. Relative to the controls, recognition was weakly impaired in the patient group under both visual and auditory conditions, but the performances were comparable in the crossmodal condition. Additional analyses using the 'race model' suggest differences in multisensory emotional integration abilities across the groups, which were potentially correlated with the executive disorders observed in the patients. These observations support the view of compensatory mechanisms in the case of gliomas that might preserve the quality of life and help maintain the normal social and professional lives often observed in these patients.

  10. Second Surgery in Insular Low-Grade Gliomas

    PubMed Central

    Ius, Tamara; Pauletto, Giada; Cesselli, Daniela; Isola, Miriam; Turella, Luca; Budai, Riccardo; DeMaglio, Giovanna; Eleopra, Roberto; Fadiga, Luciano; Lettieri, Christian; Pizzolitto, Stefano; Beltrami, Carlo Alberto; Skrap, Miran

    2015-01-01

    Background. Given the technical difficulties, a limited number of works have been published on insular gliomas surgery and risk factors for tumor recurrence (TR) are poorly documented. Objective. The aim of the study was to determine TR in adult patients with initial diagnosis of insular Low-Grade Gliomas (LGGs) that subsequently underwent second surgery. Methods. A consecutive series of 53 patients with insular LGGs was retrospectively reviewed; 23 patients had two operations for TR. Results. At the time of second surgery, almost half of the patients had experienced progression into high-grade gliomas (HGGs). Univariate analysis showed that TR is influenced by the following: extent of resection (EOR) (P < 0.002), ΔVT2T1 value (P < 0.001), histological diagnosis of oligodendroglioma (P = 0.017), and mutation of IDH1 (P = 0.022). The multivariate analysis showed that EOR at first surgery was the independent predictor for TR (P < 0.001). Conclusions. In patients with insular LGG the EOR at first surgery represents the major predictive factor for TR. At time of TR, more than 50% of cases had progressed in HGG, raising the question of the oncological management after the first surgery. PMID:26539503

  11. Fluorescence and image guided resection in high grade glioma.

    PubMed

    Panciani, Pier Paolo; Fontanella, Marco; Schatlo, Bawarjan; Garbossa, Diego; Agnoletti, Alessandro; Ducati, Alessandro; Lanotte, Michele

    2012-01-01

    The extent of resection in high grade glioma is increasingly been shown to positively effect survival. Nevertheless, heterogeneity and migratory behavior of glioma cells make gross total resection very challenging. Several techniques were used in order to improve the detection of residual tumor. Aim of this study was to analyze advantages and limitations of fluorescence and image guided resection. A multicentric prospective study was designed to evaluate the accuracy of each method. Furthermore, the role of 5-aminolevulinc acid and neuronavigation were reviewed. Twenty-three patients harboring suspected high grade glioma, amenable to complete resection, were enrolled. Fluorescence and image guides were used to perform surgery. Multiple samples were obtained from the resection cavity of each lesion according to 5-ALA staining positivity and boundaries as delineated by neuronavigation. All samples were analyzed by a pathologist blinded to the intra-operative labeling. Decision-making based on fluorescence showed a sensitivity of 91.1% and a specificity of 89.4% (p<0.001). On the other hand, the image-guided resection accuracy was low (sensitivity: 57.8%; specificity: 57.4%; p=0.346). We observed that the sensitivity of 5-ALA can be improved by the combined use of neuronavigation, but this leads to a significant reduction in specificity. Thus, the use of auxiliary techniques should always be subject to critical skills of the surgeon. We advocate a large-scale study to further improve the assessment of multimodal approaches.

  12. Doxorubicin-mediated Apoptosis in Glioma Cells Requires NFAT3

    PubMed Central

    Gopinath, Sreelatha; Vanamala, Sravan K.; Gujrati, Meena; Klopfenstein, Jeffrey D.; Dinh, Dzung H.; Rao, Jasti S.

    2009-01-01

    Nuclear Factor of Activated T cells (NFAT), a family of transcription factors, has been implicated in many cellular processes, including some cancers. For the first time, the present study characterizes the role of NFAT3 in doxorubicin (DOX) mediated apoptosis, migration, and invasion in SNB19 and U87 glioma cells. This study demonstrates specific knockdown of NFAT3 results in a dramatic inhibition of the apoptotic effect, induced by DOX, and favors cell survival. Inhibition of NFAT3 activation by shNFAT3 (shNF3) significantly downregulated TNF-α induction, its receptor TNFR1, caspase 10, caspase 3 and PARP, abrogating DOX-mediated apoptosis in glioma cells. DOX treatment resulted in NFAT3 translocation to the nucleus. Similarly, shNF3 treatment in SNB19 and U87 cells reversed DOX-induced inhibition of cell migration and invasion as determined by wound healing and matrigel invasion assays. Taken together, these results indicate that NFAT3 is a prerequisite for the induction of DOX-mediated apoptosis in glioma cells. PMID:19784808

  13. Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy.

    PubMed

    Floyd, J Alaina; Galperin, Anna; Ratner, Buddy D

    2016-02-01

    The grim prognosis for patients diagnosed with malignant gliomas necessitates the development of new therapeutic strategies for localized and sustained drug delivery to combat tumor drug resistance and regrowth. Here we introduce drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy (DREAM BIG therapy). DREAM BIG therapy is envisioned to deliver three chemotherapeutics, temporally staged over one year, via a bioadhesive, biodegradable spray directly to the brain surgical site after tumor excision. In this proof-of-principle article exploring key components of the DREAM BIG therapy prototype, rhodamine B (RB) encapsulated poly(lactic-co-glycolic acid) and immunoglobulin G (IgG) encapsulated poly(lactic acid) microspheres were formulated and characterized. The encapsulation efficiency of RB and IgG and the release kinetics of the model drugs from the microspheres were elucidated in addition to the release kinetics of RB from poly(lactic-co-glycolic acid) microspheres formulated in a degradable poly(N-isopropylacrylamide) solution. The successful aerosolized application onto brain tissue ex-vivo demonstrated the conformal adhesion of the RB encapsulated poly(lactic-co-glycolic acid) microspheres to the convoluted brain surface mediated by the thermoresponsive carrier, poly(N-isopropylacrylamide). These preliminary results suggest the potential of the DREAM BIG therapy for future use with multiple chemotherapeutics and microsphere types to combat gliomas at a localized site. PMID:26238392

  14. Quantum dot-labeled aptamer nanoprobes specifically targeting glioma cells

    NASA Astrophysics Data System (ADS)

    Chen, Xue-Chai; Deng, Yu-Lin; Lin, Yi; Pang, Dai-Wen; Qing, Hong; Qu, Feng; Xie, Hai-Yan

    2008-06-01

    Two new techniques, aptamer-based specific recognition and quantum dot (QD)-based fluorescence labeling, are becoming increasingly important in biosensing. In this study, these two techniques have been coupled together to construct a new kind of fluorescent QD-labeled aptamer (QD-Apt) nanoprobe by conjugating GBI-10 aptamer to the QD surface. GBI-10 is a single-stranded DNA (ssDNA) aptamer for tenascin-C, which distributes on the surface of glioma cells as a dominant extracellular matrix protein. The QD-Apt nanoprobe can recognize the tenascin-C on the human glioma cell surface, which will be helpful for the development of new convenient and sensitive in vitro diagnostic assays for glioma. The QD-Apt nanoprobe has particular features such as strong fluorescence, stability, monodispersity and uniformity. In addition, this probe preparation method is universal, so it is expected to provide a new type of stable nanoprobe for high-throughput and fast biosensing detection and bioimaging. New methods for real-time and dynamic tracking and imaging can be accordingly developed.

  15. Bromelain Reversibly Inhibits Invasive Properties of Glioma Cells

    PubMed Central

    Tysnes, Berit B; Maurer, H Rainer; Porwol, Torsten; Probst, Beatrice; Bjerkvig, Rolf; Hoover, Frank

    2001-01-01

    Abstract Bromelain is an aqueous extract from pineapple stem that contains proteinases and exhibits pleiotropic therapeutic effects, i.e., antiedematous, antiinflammatory, antimetastatic, antithrombotic, and fibrinolytic activities. In this study, we tested bromelain's effects on glioma cells to assess whether bromelain could be a potential contributor to new antiinvasive strategies for gliomas. Several complementary assays demonstrated that bromelain significantly and reversibly reduced glioma cell adhesion, migration, and invasion without affecting cell viability, even after treatment periods extending over several months. Immunohistochemistry and immunoblotting experiments demonstrated that α3 and β1 integrin subunits and hyaluronan receptor CD44 protein levels were reduced within 24 hours of bromelain treatment. These effects were not reflected at the RNA level because RNA profiling did not show any significant effects on gene expression. Interestingly, metabolic labelling with 35-S methionine demonstrated that de novo protein synthesis was greatly attenuated by bromelain, in a reversible manner. By using a trans-activating signaling assay, we found that CRE-mediated signaling processes were suppressed. These results indicate that bromelain exerts its antiinvasive effects by proteolysis, signaling cascades, and translational attenuation. PMID:11774029

  16. Radiotherapeutic management of optic nerve gliomas in children

    SciTech Connect

    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 (i.e., chiasmal and/or hypothalamic involvement and progressive visual loss).

  17. Circular RNA profile in gliomas revealed by identification tool UROBORUS

    PubMed Central

    Song, Xiaofeng; Zhang, Naibo; Han, Ping; Moon, Byoung-San; Lai, Rose K.; Wang, Kai; Lu, Wange

    2016-01-01

    Recent evidence suggests that many endogenous circular RNAs (circRNAs) may play roles in biological processes. However, the expression patterns and functions of circRNAs in human diseases are not well understood. Computationally identifying circRNAs from total RNA-seq data is a primary step in studying their expression pattern and biological roles. In this work, we have developed a computational pipeline named UROBORUS to detect circRNAs in total RNA-seq data. By applying UROBORUS to RNA-seq data from 46 gliomas and normal brain samples, we detected thousands of circRNAs supported by at least two read counts, followed by successful experimental validation on 24 circRNAs from the randomly selected 27 circRNAs. UROBORUS is an efficient tool that can detect circRNAs with low expression levels in total RNA-seq without RNase R treatment. The circRNAs expression profiling revealed more than 476 circular RNAs differentially expressed in control brain tissues and gliomas. Together with parental gene expression, we found that circRNA and its parental gene have diversified expression patterns in gliomas and control brain tissues. This study establishes an efficient and sensitive approach for predicting circRNAs using total RNA-seq data. The UROBORUS pipeline can be accessed freely for non-commercial purposes at http://uroborus.openbioinformatics.org/. PMID:26873924

  18. Atypical crossmodal emotional integration in patients with gliomas.

    PubMed

    Luherne-du Boullay, Viviane; Plaza, Monique; Perrault, Annabelle; Capelle, Laurent; Chaby, Laurence

    2014-11-01

    The relevance of emotional perception in interpersonal relationships and social cognition has been well documented. Although brain diseases might impair emotional processing, studies concerning emotional recognition in patients with brain tumours are relatively rare. The aim of this study was to explore emotional recognition in patients with gliomas in three conditions (visual, auditory and crossmodal) and to analyse how tumour-related variables (notably, tumour localisation) and patient-related variables influence emotion recognition. Twenty six patients with gliomas and 26 matched healthy controls were instructed to identify 5 basic emotions and a neutral expression, which were displayed through visual, auditory and crossmodal stimuli. Relative to the controls, recognition was weakly impaired in the patient group under both visual and auditory conditions, but the performances were comparable in the crossmodal condition. Additional analyses using the 'race model' suggest differences in multisensory emotional integration abilities across the groups, which were potentially correlated with the executive disorders observed in the patients. These observations support the view of compensatory mechanisms in the case of gliomas that might preserve the quality of life and help maintain the normal social and professional lives often observed in these patients. PMID:25463143

  19. SET and MYND domain-containing protein 3 is overexpressed in human glioma and contributes to tumorigenicity.

    PubMed

    Dai, Bin; Wan, Weiqing; Zhang, Peng; Zhang, Yisong; Pan, Changcun; Meng, Guolu; Xiao, Xinru; Wu, Zhen; Jia, Wang; Zhang, Junting; Zhang, Liwei

    2015-11-01

    SET and MYND domain-containing protein 3 (SMYD3) is a histone H3 lysine 4 (H3K4) di- and tri-methyltransferase that forms a transcriptional complex with RNA polymerase II and plays an important role in early embryonic lineage commitment through the activation of lineage-specific genes. SMYD3 activates the transcription of oncogenes and cell cycle genes in gastric and breast cancer cells. However, the contribution of SMYD3 in glioma tumorigenesis remains unknown. Here, we determined the expression of SMYD3 and assessed its clinical significance in human glioma. We found that SMYD3 was overexpressed in human glioma but not in normal brain tissue. The level of SMYD3 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of SMYD3 protein expression in human glioma tissues was inversely correlated with patient survival. Enforced SMYD3 expression promoted glioma LN-18 cell proliferation. Inhibition of SMYD3 expression in glioma T98G cells suppressed their anchorage‑independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that SMYD3 regulated the expression of p53 protein, which is essential in SMYD3‑induced cell growth in glioma cells. These results showed that SMYD3 is overexpressed in human glioma and contributes to glioma tumorigenicity through p53. Therefore, SMYD3 may be a new potential therapeutic target for human malignant glioma. PMID:26328527

  20. SET and MYND domain-containing protein 3 is overexpressed in human glioma and contributes to tumorigenicity.

    PubMed

    Dai, Bin; Wan, Weiqing; Zhang, Peng; Zhang, Yisong; Pan, Changcun; Meng, Guolu; Xiao, Xinru; Wu, Zhen; Jia, Wang; Zhang, Junting; Zhang, Liwei

    2015-11-01

    SET and MYND domain-containing protein 3 (SMYD3) is a histone H3 lysine 4 (H3K4) di- and tri-methyltransferase that forms a transcriptional complex with RNA polymerase II and plays an important role in early embryonic lineage commitment through the activation of lineage-specific genes. SMYD3 activates the transcription of oncogenes and cell cycle genes in gastric and breast cancer cells. However, the contribution of SMYD3 in glioma tumorigenesis remains unknown. Here, we determined the expression of SMYD3 and assessed its clinical significance in human glioma. We found that SMYD3 was overexpressed in human glioma but not in normal brain tissue. The level of SMYD3 protein expression in human glioma tissues was directly correlated with the glioma grade. The level of SMYD3 protein expression in human glioma tissues was inversely correlated with patient survival. Enforced SMYD3 expression promoted glioma LN-18 cell proliferation. Inhibition of SMYD3 expression in glioma T98G cells suppressed their anchorage‑independent growth in vitro and tumorigenicity in vivo. Furthermore, we found that SMYD3 regulated the expression of p53 protein, which is essential in SMYD3‑induced cell growth in glioma cells. These results showed that SMYD3 is overexpressed in human glioma and contributes to glioma tumorigenicity through p53. Therefore, SMYD3 may be a new potential therapeutic target for human malignant glioma.

  1. Epigenetic silencing of KAZALD1 confers a better prognosis and is associated with malignant transformation/progression in glioma.

    PubMed

    Wang, Hongjun; Feng, Ying; Bao, Zhaoshi; Jiang, Chuanlu; Yan, Wei; Wang, Yongzhi; Zhang, Chuanbao; Liu, Yanwei; Zhang, Quangeng; Zhang, Wei; Jiang, Chuanlu

    2013-11-01

    In order to more thoroughly analyze aberrant DNA methylation in glioma, we applied a large cohort methylation microarray including 119 glioma samples. Six genes, ADCY1, KAZALD1, KLF4, SLMAP, TETRAN and TP53INP1, were screened out through significance analysis of microarray (SAM), survival Cox-regression and certain other pre-set conditions. We focused on the KAZALD1 oncogene. KAZALD1, also known as IGFBP-rP10, belongs to the IGFBP family. We found that KAZALD1 was hypomethylated in high-grade glioma (anaplastic gliomas and glioblastomas) compared to low-grade glioma (astrocytoma, oligodendrocytoma and oligoastrocytoma) using methylation microarrays (p<0.001). Immunohistochemistry (IHC) of 91 glioma samples showed that the KAZALD1 expression scores of high-grade glioma samples were higher compared to the scores of low-grade gliomas (p<0.001). In high-grade gliomas, overall survival (OS) was shorter for patients with KAZALD1 hypomethylation or overexpression compared to those without. Decreased KAZALD1 expression in glioma inhibited cell proliferation and invasion both in vitro and in vivo. On the basis of these observations and the results from subset analysis, it is reasonable to conclude that KAZALD1 promoter hypomethylation is an important prognostic biomarker in glioma. KAZALD1 promotes glioma malignant progression through invasion and proliferation. PMID:24002581

  2. Increasing the efficacy of antitumor glioma vaccines by photodynamic therapy and local injection of allogeneic glioma cells

    NASA Astrophysics Data System (ADS)

    Christie, Catherine E.; Peng, Qian; Madsen, Steen J.; Uzal, Francisco A.; Hirschberg, Henry

    2016-03-01

    Immunotherapy of brain tumors involves the stimulation of an antitumor immune response. This type of therapy can be targeted specifically to tumor cells thus sparing surrounding normal brain. Due to the presence of the blood-brain barrier, the brain is relatively isolated from the systemic circulation and, as such, the initiation of significant immune responses is more limited than other types of cancers. The purpose of this study was to show that the efficacy of tumor primed antigen presenting macrophage vaccines could be increased by: (1) PDT of the priming tumor cells, and (2) injection of allogeneic glioma cells directly into brain tumors. Experiments were conducted in an in vivo brain tumor model using Fisher rats and BT4C (allogeneic) and F98 (syngeneic) glioma cells. Preliminary results showed that vaccination alone had significantly less inhibitory effect on F98 tumor growth compared to the combination of vaccination and allogeneic cell (BT4C) injection.

  3. The epidemiology of glioma in adults: a “state of the science” review

    PubMed Central

    Ostrom, Quinn T.; Bauchet, Luc; Davis, Faith G.; Deltour, Isabelle; Fisher, James L.; Langer, Chelsea Eastman; Pekmezci, Melike; Schwartzbaum, Judith A.; Turner, Michelle C.; Walsh, Kyle M.; Wrensch, Margaret R.; Barnholtz-Sloan, Jill S.

    2014-01-01

    Gliomas are the most common primary intracranial tumor, representing 81% of malignant brain tumors. Although relatively rare, they cause significant mortality and morbidity. Glioblastoma, the most common glioma histology (∼45% of all gliomas), has a 5-year relative survival of ∼5%. A small portion of these tumors are caused by Mendelian disorders, including neurofibromatosis, tuberous sclerosis, and Li-Fraumeni syndrome. Genomic analyses of glioma have also produced new evidence about risk and prognosis. Recently discovered biomarkers that indicate improved survival include O6-methylguanine-DNA methyltransferase methylation, isocitrate dehydrogenase mutation, and a glioma cytosine–phosphate–guanine island methylator phenotype. Genome-wide association studies have identified heritable risk alleles within 7 genes that are associated with increased risk of glioma. Many risk factors have been examined as potential contributors to glioma risk. Most significantly, these include an increase in risk by exposure to ionizing radiation and a decrease in risk by history of allergies or atopic disease(s). The potential influence of occupational exposures and cellular phones has also been examined, with inconclusive results. We provide a “state of the science” review of current research into causes and risk factors for gliomas in adults. PMID:24842956

  4. MicroRNA-141 inhibits glioma cells growth and metastasis by targeting TGF-β2

    PubMed Central

    Peng, Tao; Zhang, Shuyan; Li, Wenchen; Fu, Shuanglin; Luan, Yongxin; Zuo, Ling

    2016-01-01

    MicroRNA-141 (miR-141) has been reported to function as tumor suppressor in many types of cancer. However, the molecular function and underlying mechanisms of miR-141 in glioma is still unknown. The aims of this study were to investigate miR-141 expression and determine its biological function and underlying mechanism in glioma. In this study, we found that miR-141 expression levels, both in glioma cell lines and in tissues, were significantly lower than that in a normal human astrocyte cell line or adjacent non-cancerous tissues. Overexpression of miR-141 significantly inhibited glioma cell proliferation, colony formation, migration and invasion in vitro, as well as suppressed glioma tumor growth in vivo. In addition, transforming growth factor beta 2 (TGF-β2) was identified as a target of miR-141 in glioma cells. TGF-β2 expression was also found to be upregulated, and negatively associated with miR-141 in glioma tissues. TGF-β2 over-expression partly reversed the effect caused by transfection of miR-141 mimic. These findings together suggested that miR-141 functioned as tumor suppressor by targeting TGF-β2, and that miR-141 might be a promising therapeutic strategy for future treatment of glioma.

  5. MicroRNA-141 inhibits glioma cells growth and metastasis by targeting TGF-β2.

    PubMed

    Peng, Tao; Zhang, Shuyan; Li, Wenchen; Fu, Shuanglin; Luan, Yongxin; Zuo, Ling

    2016-01-01

    MicroRNA-141 (miR-141) has been reported to function as tumor suppressor in many types of cancer. However, the molecular function and underlying mechanisms of miR-141 in glioma is still unknown. The aims of this study were to investigate miR-141 expression and determine its biological function and underlying mechanism in glioma. In this study, we found that miR-141 expression levels, both in glioma cell lines and in tissues, were significantly lower than that in a normal human astrocyte cell line or adjacent non-cancerous tissues. Overexpression of miR-141 significantly inhibited glioma cell proliferation, colony formation, migration and invasion in vitro, as well as suppressed glioma tumor growth in vivo. In addition, transforming growth factor beta 2 (TGF-β2) was identified as a target of miR-141 in glioma cells. TGF-β2 expression was also found to be upregulated, and negatively associated with miR-141 in glioma tissues. TGF-β2 over-expression partly reversed the effect caused by transfection of miR-141 mimic. These findings together suggested that miR-141 functioned as tumor suppressor by targeting TGF-β2, and that miR-141 might be a promising therapeutic strategy for future treatment of glioma. PMID:27648141

  6. TM-15GLUTAMINE BASED PET IMAGING FACILITATES ENHANCED METABOLIC DETECTION OF GLIOMAS IN VIVO

    PubMed Central

    Venneti, Sriram; Dunphy, Mark; Zhang, Hanwen; Pitter, Kenneth; Campos, Carl; Carlin, Sean; Lyashchenko, Serge; Plöessl, Carl; Rohle, Daniel; Omuro, Antonio; Cross, Justin; Brennan, Cameron; Weber, Wolfgang; Holland, Eric; Mellinghoff, Ingo; Kung, Hank; Lewis, Jason; Thompson, Craig

    2014-01-01

    Glutamine is the most abundant plasma amino acid and many cancers show altered glutamine metabolism. We evaluated glutamine uptake and metabolism in gliomas using PET imaging and biochemical approaches. We demonstrate that glutamine is a key TCA cycle anaplerotic substrate and is metabolized to generate 2-HG in IDH1-mutant gliomas. PET imaging with18F-labeled glutamine (18F-FGln) showed high uptake in gliomas in vivo but low background uptake in the surrounding brain in RCAS-PDGF/PTEN null and IDH1-mutant glioma animal models, facilitating clear tumor delineation in contrast to that seen with 18F-FDG. We did not observe 18F-FGln uptake in animals with neuroinflammation or animals with a disrupted BBB. Further, 18F-FGln uptake was specifically reduced on chemo/radiation therapy. Finally, 18F-FGln showed high avidity in human glioma with low uptake in the surrounding brain. These data suggest that 18F-FGln is specifically taken up by gliomas, can be used to assess the metabolic state of gliomas in vivo and may serve as a valuable tool in the clinical management of gliomas.

  7. Recent advances in diagnosis and treatment of gliomas using chlorotoxin-based bioconjugates.

    PubMed

    Cheng, Yongjun; Zhao, Jinhua; Qiao, Wenli; Chen, Kai

    2014-01-01

    Malignant gliomas, especially glioblastoma multiforme, are the most widely distributed and deadliest brain tumors because of their resistance to surgical and medical treatment. Research of glioma-specific bioconjugates for diagnosis and therapy developed rapidly during the past several years. Many studies have demonstrated that chlorotoxin (CTX) and Buthus martensii Karsch chlorotoxin (BmK CT) specifically inhibited glioma cells growth and metastasis, and accelerated tumor apoptosis. The bioconjugates of CTX or BmK CT with other molecules have played an increasing role in diagnostic imaging and treatment of gliomas. To date, CTX-based bioconjugates have achieved great success in phase I/II clinical trials about safety profiles. Here, we will provide a review on the important role of ion channels in the underlying mechanisms of gliomas invasive growth and how CTX suppresses gliomas proliferation and migration. We will summarize the recent advances in the applications of CTX bioconjugates for gliomas diagnosis and treatment. In addition, we will review recent studies on BmK CT bioconjugates and compare their efficacies with CTX derivatives. Finally, we will address advantages and challenges in the use of CTX or BmK CT bioconjugates as specific agents for theranostic applications in gliomas.

  8. Alisertib and Fractionated Stereotactic Radiosurgery in Treating Patients With Recurrent High Grade Gliomas

    ClinicalTrials.gov

    2016-10-19

    Adult Anaplastic Astrocytoma; Adult Anaplastic Ependymoma; Adult Anaplastic Oligodendroglioma; Adult Brain Stem Glioma; Adult Diffuse Astrocytoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Mixed Glioma; Adult Oligodendroglioma; Adult Pilocytic Astrocytoma; Adult Pineal Gland Astrocytoma; Adult Subependymal Giant Cell Astrocytoma; Recurrent Adult Brain Tumor

  9. miR-101 inhibits glioma cell invasion via the downregulation of COX-2

    PubMed Central

    Ma, Chunyang; Zheng, Chuanyi; Bai, Enqi; Yang, Kun

    2016-01-01

    Glioma is the most common type of primary tumor of the central nervous system. The present study aimed to demonstrate the role of miR-101 and cyclooxygenase-2 (COX-2) in the initiation and development of glioma. The expression of miR-101 and COX-2 in normal and malignant human glial cells and tissues was determined by western blotting and quantitative polymerase chain reaction analysis. The role of miR-101 on COX-2 expression was evaluated by a dual-luciferase reporter assay. The effects of miR-101 and COX-2 in glioma cell proliferation and invasion was verified by CCK-8 test and Transwell assays, respectively. The present study demonstrated that miR-101 expression was downregulated while COX-2 was upregulated in glioma tissues and cells. Furthermore, transfection of miR-101 significantly downregulated COX-2 expression in both U373 and U87 glioma cells. In addition, further experiments revealed that overexpression of miR-101 resulted in significant inhibition of the in vitro proliferation and migration of glioma cells, and the in vivo growth of established tumors. Direct downregulation of COX-2 by transfection with corresponding small interfering RNA also inhibited the proliferation and invasion of glioma cells. These results indicate that downregulation of miR-101 is involved in the initiation and development of glioma via COX-2 upregulation.

  10. Transferrin modified PEG-PLA-resveratrol conjugates: in vitro and in vivo studies for glioma.

    PubMed

    Guo, Wanhua; Li, Aimei; Jia, Zhijun; Yuan, Yi; Dai, Haifeng; Li, Hongxiu

    2013-10-15

    Glioblastoma is one of the most malignant brain tumors with a poor prognosis. In this study, we examined the effects of transferrin (Tf)-modified poly ethyleneglycol-poly lactic acid (PEG-PLA) nanoparticles conjugated with resveratrol (Tf-PEG-PLA-RSV) to glioma therapy in vitro and in vivo. The cell viability of Tf-PEG-PLA-RSV on C6 and U87 glioma cells was determined by the MTT assay. In vivo biodistribution and antitumor activity were investigated in Brain glioma bearing rat model of C6 glioma by i.p. administration of RSV-polymer conjugates. We found that the average diameter of each Tf-PEG-PLA-RSV is around 150 nm with 32 molecules of Tf on surface. In vitro cytotoxicity of PEG-PLA-RSV against C6 and U87 cells was higher than that of free RSV, and further the modification of Tf enhanced the cytotoxicity of the RSV-polymer conjugates as a result of the increased cellular uptake of the RSV-modified conjugates by glioma cells. In comparison with free RSV, RSV conjugates could significantly decrease tumor volume and accumulate in brain tumor, which resulted in prolonging the survival of C6 glioma-bearing rats. These results suggest that Tf-NP-RSV had a potential of therapeutic effect to glioma both in vitro and in vivo and might be a potential candidate for targeted therapy of glioma and worthy of further investigation.

  11. Malignant glioma of the optic chiasm eight years after radiotherapy for prolactinoma

    SciTech Connect

    Hufnagel, T.J.; Kim, J.H.; Lesser, R.; Miller, J.M.; Abrahams, J.J.; Piepmeier, J.; Manuelidis, E.E.

    1988-12-01

    A 41-year-old man had rapidly progressive visual loss caused by a malignant glioma that developed in the optic chiasm eight years after radiation therapy for a recurrent prolactinoma. Radiation-induced glioma should be considered as a cause of progressive visual loss in patients who have received irradiation in the region of the sella turcica.

  12. Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study.

    PubMed

    Buck, Jason R; McKinley, Eliot T; Fu, Allie; Abel, Ty W; Thompson, Reid C; Chambless, Lola; Watchmaker, Jennifer M; Harty, James P; Cooper, Michael K; Manning, H Charles

    2015-01-01

    Current positron emission tomography (PET) imaging biomarkers for detection of infiltrating gliomas are limited. Translocator protein (TSPO) is a novel and promising biomarker for glioma PET imaging. To validate TSPO as a potential target for molecular imaging of glioma, TSPO expression was assayed in a tumor microarray containing 37 high-grade (III, IV) gliomas. TSPO staining was detected in all tumor specimens. Subsequently, PET imaging was performed with an aryloxyanilide-based TSPO ligand, [18F]PBR06, in primary orthotopic xenograft models of WHO grade III and IV gliomas. Selective uptake of [18F]PBR06 in engrafted tumor was measured. Furthermore, PET imaging with [18F]PBR06 demonstrated infiltrative glioma growth that was undetectable by traditional magnetic resonance imaging (MRI). Preliminary PET with [18F]PBR06 demonstrated a preferential tumor-to-normal background ratio in comparison to 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). These results suggest that TSPO PET imaging with such high-affinity radiotracers may represent a novel strategy to characterize distinct molecular features of glioma growth, as well as better define the extent of glioma infiltration for therapeutic purposes.

  13. miR-101 inhibits glioma cell invasion via the downregulation of COX-2

    PubMed Central

    Ma, Chunyang; Zheng, Chuanyi; Bai, Enqi; Yang, Kun

    2016-01-01

    Glioma is the most common type of primary tumor of the central nervous system. The present study aimed to demonstrate the role of miR-101 and cyclooxygenase-2 (COX-2) in the initiation and development of glioma. The expression of miR-101 and COX-2 in normal and malignant human glial cells and tissues was determined by western blotting and quantitative polymerase chain reaction analysis. The role of miR-101 on COX-2 expression was evaluated by a dual-luciferase reporter assay. The effects of miR-101 and COX-2 in glioma cell proliferation and invasion was verified by CCK-8 test and Transwell assays, respectively. The present study demonstrated that miR-101 expression was downregulated while COX-2 was upregulated in glioma tissues and cells. Furthermore, transfection of miR-101 significantly downregulated COX-2 expression in both U373 and U87 glioma cells. In addition, further experiments revealed that overexpression of miR-101 resulted in significant inhibition of the in vitro proliferation and migration of glioma cells, and the in vivo growth of established tumors. Direct downregulation of COX-2 by transfection with corresponding small interfering RNA also inhibited the proliferation and invasion of glioma cells. These results indicate that downregulation of miR-101 is involved in the initiation and development of glioma via COX-2 upregulation. PMID:27698824

  14. A complex mechanism for HDGF-mediated cell growth, migration, invasion, and TMZ chemosensitivity in glioma.

    PubMed

    Song, Ye; Hu, Zheng; Long, Hao; Peng, Yuping; Zhang, Xi'an; Que, Tianshi; Zheng, Shihao; Li, Zhiyong; Wang, Gang; Yi, Liu; Liu, Zhen; Fang, Weiyi; Qi, Songtao

    2014-09-01

    HDGF is overexpressed in gliomas as compared to normal brain. We therefore analyzed the molecular mechanisms of HDGF action in gliomas. HDGF was downregulated in normal brain tissue as compared to glioma specimens at both the mRNA and the protein levels. In glioma samples, increased HDGF expression was associated with disease progression. Knocking down HDGF expression not only significantly decreased cellular proliferation, migration, invasion, and tumorigenesis, but also markedly enhanced TMZ-induced cytotoxicity and apoptosis in glioma cells. Mechanistic analyses revealed that CCND1, c-myc, and TGF-β were downregulated after stable HDGF knockdown in the U251 and U87 glioma cells. HDGF knockdown restored E-cadherin expression and suppressed mesenchymal cell markers such as vimentin, β-catenin, and N-cadherin. The expression of cleaved caspase-3 increased, while Bcl-2 decreased in each cell line following treatment with shHDGF and TMZ, as compared to TMZ alone. Furthermore, RNAi-based knockdown study revealed that HDGF is probably involved in the activation of both the PI3K/Akt and the TGF-β signaling pathways. Together, our data suggested that HDGF regulates glioma cell growth, apoptosis and epithelial-mesenchymal transition (EMT) probably through the Akt and the TGF-β signaling pathways. These results provide evidence that targeting HDGF or its downstream targets may lead to novel therapies for gliomas.

  15. MicroRNA-141 inhibits glioma cells growth and metastasis by targeting TGF-β2

    PubMed Central

    Peng, Tao; Zhang, Shuyan; Li, Wenchen; Fu, Shuanglin; Luan, Yongxin; Zuo, Ling

    2016-01-01

    MicroRNA-141 (miR-141) has been reported to function as tumor suppressor in many types of cancer. However, the molecular function and underlying mechanisms of miR-141 in glioma is still unknown. The aims of this study were to investigate miR-141 expression and determine its biological function and underlying mechanism in glioma. In this study, we found that miR-141 expression levels, both in glioma cell lines and in tissues, were significantly lower than that in a normal human astrocyte cell line or adjacent non-cancerous tissues. Overexpression of miR-141 significantly inhibited glioma cell proliferation, colony formation, migration and invasion in vitro, as well as suppressed glioma tumor growth in vivo. In addition, transforming growth factor beta 2 (TGF-β2) was identified as a target of miR-141 in glioma cells. TGF-β2 expression was also found to be upregulated, and negatively associated with miR-141 in glioma tissues. TGF-β2 over-expression partly reversed the effect caused by transfection of miR-141 mimic. These findings together suggested that miR-141 functioned as tumor suppressor by targeting TGF-β2, and that miR-141 might be a promising therapeutic strategy for future treatment of glioma. PMID:27648141

  16. Recent advances in diagnosis and treatment of gliomas using chlorotoxin-based bioconjugates

    PubMed Central

    Cheng, Yongjun; Zhao, Jinhua; Qiao, Wenli; Chen, Kai

    2014-01-01

    Malignant gliomas, especially glioblastoma multiforme, are the most widely distributed and deadliest brain tumors because of their resistance to surgical and medical treatment. Research of glioma-specific bioconjugates for diagnosis and therapy developed rapidly during the past several years. Many studies have demonstrated that chlorotoxin (CTX) and Buthus martensii Karsch chlorotoxin (BmK CT) specifically inhibited glioma cells growth and metastasis, and accelerated tumor apoptosis. The bioconjugates of CTX or BmK CT with other molecules have played an increasing role in diagnostic imaging and treatment of gliomas. To date, CTX-based bioconjugates have achieved great success in phase I/II clinical trials about safety profiles. Here, we will provide a review on the important role of ion channels in the underlying mechanisms of gliomas invasive growth and how CTX suppresses gliomas proliferation and migration. We will summarize the recent advances in the applications of CTX bioconjugates for gliomas diagnosis and treatment. In addition, we will review recent studies on BmK CT bioconjugates and compare their efficacies with CTX derivatives. Finally, we will address advantages and challenges in the use of CTX or BmK CT bioconjugates as specific agents for theranostic applications in gliomas. PMID:25143859

  17. Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas

    PubMed Central

    Halani, Sameer H; Adamson, D Cory

    2016-01-01

    Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas.

  18. Application of iron oxide nanoparticles in glioma imaging and therapy: from bench to bedside

    NASA Astrophysics Data System (ADS)

    Liu, Heng; Zhang, Jun; Chen, Xiao; Du, Xue-Song; Zhang, Jin-Long; Liu, Gang; Zhang, Wei-Guo

    2016-04-01

    Gliomas are the most common primary brain tumors and have a very dismal prognosis. However, recent advancements in nanomedicine and nanotechnology provide opportunities for personalized treatment regimens to improve the poor prognosis of patients suffering from glioma. This comprehensive review starts with an outline of the current status facing glioma. It then provides an overview of the state-of-the-art applications of iron oxide nanoparticles (IONPs) to glioma diagnostics and therapeutics, including MR contrast enhancement, drug delivery, cell labeling and tracking, magnetic hyperthermia treatment and magnetic particle imaging. It also addresses current challenges associated with the biological barriers and IONP design with an emphasis on recent advances and innovative approaches for glioma targeting strategies. Opportunities for future development are highlighted.

  19. Matrine inhibits the invasive properties of human glioma cells by regulating epithelial‑to‑mesenchymal transition.

    PubMed

    Wang, Zhongwei; Wu, Yi; Wang, Yali; Jin, Yingying; Ma, Xiulong; Zhang, Yang; Ren, Hongtao

    2015-05-01

    Matrine is reported to be effective in tumor therapies; however, the anti‑metastatic effect and molecular mechanism(s) of matrine on glioma remain poorly understood. Therefore, the purpose of this study was to assess the effects of matrine on glioma and the associated mechanism(s). In the study, we demonstrated that matrine inhibited the proliferation of glioma cells. We also observed that matrine inhibited the migration and invasion of glioma cells at non‑toxic concentrations. Matrine also decreased the expression of E‑cadherin and increased the expression of N‑cadherin. These results suggest that the anti‑metastatic effect of matrine may be correlated with epithelial‑to‑mesenchymal transition (EMT). Moreover, matrine could reduce the phosphorylation levels of p38 and AKT proteins. In conclusion, these results suggest matrine may be a potential alternative against invasive glioma cells via the p38 MAPK and AKT signaling‑dependent inhibition of EMT.

  20. Securin promotes migration and invasion via matrix metalloproteinases in glioma cells

    PubMed Central

    YAN, HAICHENG; WANG, WEI; DOU, CHANGWU; TIAN, FUMING; QI, SONGTAO

    2015-01-01

    Human securin, encoded by pituitary tumor transforming gene 1, is implicated in several oncogenic processes in the pathogenesis of brain tumors, including glioma. The aim of the present study was to examine the effect of securin on the migration and invasion of glioma cells. The results revealed that the overexpression of securin in glioma LN-229 cells significantly increased the invasion and transmigration abilities. By contrast, these abilities were significantly reduced by the downregulation of securin in glioma U373 cells. Furthermore, the results demonstrated that securin overexpression and downregulation significantly increased and decreased the levels of matrix metalloproteinase 2 and 9, respectively. These findings indicate a promotive role for securin in glioma migration and invasion, which may involve the action of matrix metalloproteinases. PMID:26137166

  1. Compound 331 selectively induces glioma cell death by upregulating miR-494 and downregulating CDC20.

    PubMed

    Zhang, Lei; Niu, Tianhui; Huang, Yafei; Zhu, Haichuan; Zhong, Wu; Lin, Jian; Zhang, Yan

    2015-01-01

    Malignant gliomas are the most common malignant tumors in the central nervous system (CNS). Up to date, the prognosis of glioma is still very poor, effective therapy with less side-effect is very necessary. Herein, we identify a compound named as "331" selectively induced cell death in glioma cells but not in astrocytes. Compound 331 upregulated miR-494 and downregulated CDC20 in glioma cells but not in astrocytes. These results suggest that compound 331 could be a potential drug selectively targeting glioma cells through upregulating miR-494 and downregulating CDC20. PMID:26153143

  2. Compound 331 selectively induces glioma cell death by upregulating miR-494 and downregulating CDC20

    PubMed Central

    Zhang, Lei; Niu, Tianhui; Huang, Yafei; Zhu, Haichuan; Zhong, Wu; Lin, Jian; Zhang, Yan

    2015-01-01

    Malignant gliomas are the most common malignant tumors in the central nervous system (CNS). Up to date, the prognosis of glioma is still very poor, effective therapy with less side-effect is very necessary. Herein, we identify a compound named as “331” selectively induced cell death in glioma cells but not in astrocytes. Compound 331 upregulated miR-494 and downregulated CDC20 in glioma cells but not in astrocytes. These results suggest that compound 331 could be a potential drug selectively targeting glioma cells through upregulating miR-494 and downregulating CDC20. PMID:26153143

  3. Expression of ADP-ribosyltransferase 1 Is Associated with Poor Prognosis of Glioma Patients.

    PubMed

    Li, Zhen; Yan, Xinling; Sun, Yuyan; Yang, Xiaoqing

    2016-01-01

    Glioma has a poor prognosis due to its rapid overgrowth, diffuse invasion, and chemotherapy resistance. The improvements in clinical outcome are still limited and the identification of novel biomarkers involved in the progression of gliomas is still under critical demands. Amino acid ADP-ribosyltransferase 1 (ART1) is an enzyme that catalyzes the mono-ADP-ribosylation, a reversible post-translational modification. For example, the mono-ADP-ribosylation of transcription factors can affect their binding to target gene promoters. However, the functional significance of ART1 in glioma has not been reported. We collected 107 glioma cases from Qianfoshan Hospital and Yidu Central Hospital of Weifang between April 2008 and September 2015 to analyze the prognosis value of ART1 in gliomas. RT-qPCR analysis showed that the expression level of ART1 mRNA in glioma tissues was 4-fold higher than that in normal brain tissues. According to the immunohistochemical staining results, 44 patients (41.1%) were categorized as ART1 positive (≥ 20% of stained glioma cells), while the other 63 patients (58.9%) categorized as ART1 negative (< 20% of stained glioma cells). Moreover, the mean percentage of ART1-positive cells was 43.7%, 53.6% and 64.2% in WHO grade II, III and IV specimens, respectively. Through univariate and multivariate analyses, we identified ART1 as an independent prognostic factor. We also found that ART1 overexpression in U251 glioblastoma cells could significantly decrease the susceptibility to vincristine, one of tubulin-targeted drugs, which is widely used in clinical treatment for glioma. Taken together, we propose that up-regulation of ART1 expression is associated with the aggressiveness of glioma. PMID:27466078

  4. Melatonergic system-based two-gene index is prognostic in human gliomas.

    PubMed

    Kinker, Gabriela S; Oba-Shinjo, Sueli M; Carvalho-Sousa, Claudia E; Muxel, Sandra M; Marie, Suely K N; Markus, Regina P; Fernandes, Pedro A

    2016-01-01

    Gliomas, the most common primary brain tumors in adults, are classified into four malignancy grades according to morphological features. Recent studies have shown that melatonin treatment induces cytotoxicity in glioma-initiating cells and reduces the invasion and migration of glioma cell lines, inhibiting the nuclear factor κB (NFκB) oncopathway. Given that C6 rat glioma cells produce melatonin, we investigated the correlation between the capacity of gliomas to synthesize/metabolize melatonin and their overall malignancy. We first characterized the melatonergic system of human gliomas cell lines with different grades of aggressiveness (HOG, T98G, and U87MG) and demonstrated that glioma-synthesized melatonin exerts an autocrine antiproliferative effect. Accordingly, the sensitivity to exogenous melatonin was higher for the most aggressive cell line, U87MG, which synthesized/accumulated less melatonin. Using The Cancer Genome Atlas RNAseq data of 351 glioma patients, we designed a predictive model of the content of melatonin in the tumor microenvironment, the ASMT:CYP1B1 index, combining the gene expression levels of melatonin synthesis and metabolism enzymes. The ASMT:CYP1B1 index negatively correlated with tumor grade, as well as with the expression of pro-proliferation and anti-apoptotic NFκB target genes. More importantly, the index was a grade- and histological type-independent prognostic factor. Even when considering only high-grade glioma patients, a low ASMT:CYP1B1 value, which suggests decreased melatonin and enhanced aggressiveness, was strongly associated with poor survival. Overall, our data reveal the prognostic value of the melatonergic system of gliomas and provide insights into the therapeutic role of melatonin. PMID:26510398

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

    SciTech Connect

    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

    2011-07-01

    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{sup +} 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.

  6. Loss of Diacylglycerol Kinase-Ζ Inhibits Cell Proliferation and Survival in Human Gliomas.

    PubMed

    Diao, Jinfu; Wu, Chunyong; Zhang, Junying; Liu, Jialin; Zhang, Xinwu; Hao, Pengcheng; Zhao, Shanmin; Zhang, Zhiwen

    2016-10-01

    Diacylglycerol kinases ζ (DGKζ) is a critical lipid kinase which is involved in phosphatidic acid (PA) generation via diacylglycerol (DAG) phosphorylation. DGKζ is highly expressed in central nervous system and essential for brain development. Studies have indicated that DGKζ is associated with colon cancer invasion and metastasis. However, the involvement of DGKζ in human glioma development remains elusive. Here, we explored the impact and possible mechanisms of DGKζ knockdown on the proliferation and survival of glioma cells. The relationship between DGKζ expression status and human glioma stages was explored in 111 specimens of human gliomas via immunohistochemistry technology. Then the impact of DGKζ on cell proliferation, cell cycle, survival, and colony formation ability was determined in U-87 MG glioma cell lines via lentiviral-mediated small interfering (shRNA) strategy. The influence of DGKζ knockdown on global gene expression in U-87 MGglioma cell lines was further analyzed by microarray platform to reveal the possible molecular mechanisms underlying DGKζ-mediated glioma development and progression. Immunohistochemistry analysis revealed that DGKζ expression is positively correlated with human gliomagrade. Lentiviral-mediated small interfering (shRNA) strategyefficiently reduced DGKζ expression and DGKζ knockdown impaired cell proliferation, inhibited colony formation ability, and induced cell cycle arrest and cell apoptosis in U-87 MG glioma cells. Finally, microarray analysis revealed that multiple cancer-associated pathways and oncogenes were regulated by DGKζ knockdown, which provides insights into underlying mechansims of DGKζ-associated glioma development and progression. Our results established the positive correlation between DGKζ expression and gliomagrade. Furthermore, DGKζ knockdown in human glioma cell lines U-87 MG impaired cell proliferation, inhibited colony formation ability, and induced cell cycle arrest and apoptosis

  7. (68)Ga-PRGD2 PET/CT in the evaluation of Glioma: a prospective study.

    PubMed

    Li, Deling; Zhao, Xiaobin; Zhang, Liwei; Li, Fang; Ji, Nan; Gao, Zhixian; Wang, Jisheng; Kang, Peng; Liu, Zhaofei; Shi, Jiyun; Chen, Xiaoyuan; Zhu, Zhaohui

    2014-11-01

    Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate (68)gallium-BNOTA-PRGD2 ((68)Ga-PRGD2) as a new reagent for noninvasive integrin αvβ3 imaging in glioma patients. With informed consent, 12 patients with suspicious brain glioma, as diagnosed by enhanced magnetic resonance imaging (MRI) scanning, were enrolled to undergo (68)Ga-PRGD2 PET/CT and (18)F-FDG PET/CT scans before surgery. The preoperative images were compared and correlated with the pathologically determined WHO grade. Next, the expression of integrin αvβ3, CD34, and Ki-67 were determined by immunohistochemical staining of the resected brain tumor tissue. Our findings demonstrated that (68)Ga-PRGD2 specifically accumulated in the brain tumors that were rich of integrin αvβ3 and other neovasculature markers, but not in the brain parenchyma other than the choroid plexus. Therefore, (68)Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than (18)F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of (68)Ga-PRGD2, rather than those of (18)F-FDG, were significantly correlated with the glioma grading. The maximum tumor-to-brain ratios (TBRmax) of both tracers were significantly correlated with glioma grading, whereas (68)Ga-PRGD2 seemed to be more superior to (18)F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, (68)Ga-PRGD2 PET/CT showed different accumulation patterns for HGG of WHO grades III and IV. This is the first noninvasive integrin imaging study, to the best of our knowledge, conducted in preoperative patients with different grades of glioma, and it preliminarily indicated the effectiveness of this novel method for evaluating glioma grading and demarcation.

  8. Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models.

    PubMed

    Jansen, Marc H A; Lagerweij, Tonny; Sewing, A Charlotte P; Vugts, Danielle J; van Vuurden, Dannis G; Molthoff, Carla F M; Caretti, Viola; Veringa, Susanna J E; Petersen, Naomi; Carcaboso, Angel M; Noske, David P; Vandertop, W Peter; Wesseling, Pieter; van Dongen, Guus A M S; Kaspers, Gertjan J L; Hulleman, Esther

    2016-09-01

    The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ((89)Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after (89)Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant (89)Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of (89)Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of (89)Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by (89)Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166-74. ©2016 AACR. PMID:27325687

  9. Germline rearrangements in families with strong family history of glioma and malignant melanoma, colon, and breast cancer

    PubMed Central

    Andersson, Ulrika; Wibom, Carl; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Armstrong, Georgina N.; Shete, Sanjay; Lau, Ching C.; Bainbridge, Matthew N.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Lai, Rose; Il'yasova, Dora; Houlston, Richard S.; Schildkraut, Joellen; Bernstein, Jonine L.; Olson, Sara H.; Jenkins, Robert B.; Lachance, Daniel H.; Wrensch, Margaret; Davis, Faith G.; Merrell, Ryan; Johansen, Christoffer; Sadetzki, Siegal; Bondy, Melissa L.; Melin, Beatrice S.; Adatto, Phyllis; Morice, Fabian; Payen, Sam; McQuinn, Lacey; McGaha, Rebecca; Guerra, Sandra; Paith, Leslie; Roth, Katherine; Zeng, Dong; Zhang, Hui; Yung, Alfred; Aldape, Kenneth; Gilbert, Mark; Weinberger, Jeffrey; Colman, Howard; Conrad, Charles; de Groot, John; Forman, Arthur; Groves, Morris; Levin, Victor; Loghin, Monica; Puduvalli, Vinay; Sawaya, Raymond; Heimberger, Amy; Lang, Frederick; Levine, Nicholas; Tolentino, Lori; Saunders, Kate; Thach, Thu-Trang; Iacono, Donna Dello; Sloan, Andrew; Gerson, Stanton; Selman, Warren; Bambakidis, Nicholas; Hart, David; Miller, Jonathan; Hoffer, Alan; Cohen, Mark; Rogers, Lisa; Nock, Charles J; Wolinsky, Yingli; Devine, Karen; Fulop, Jordonna; Barrett, Wendi; Shimmel, Kristen; Ostrom, Quinn; Barnett, Gene; Rosenfeld, Steven; Vogelbaum, Michael; Weil, Robert; Ahluwalia, Manmeet; Peereboom, David; Staugaitis, Susan; Schilero, Cathy; Brewer, Cathy; Smolenski, Kathy; McGraw, Mary; Naska, Theresa; Rosenfeld, Steven; Ram, Zvi; Blumenthal, Deborah T.; Bokstein, Felix; Umansky, Felix; Zaaroor, Menashe; Cohen, Avi; Tzuk-Shina, Tzeela; Voldby, Bo; Laursen, René; Andersen, Claus; Brennum, Jannick; Henriksen, Matilde Bille; Marzouk, Maya; Davis, Mary Elizabeth; Boland, Eamon; Smith, Marcel; Eze, Ogechukwu; Way, Mahalia; Lada, Pat; Miedzianowski, Nancy; Frechette, Michelle; Paleologos, Nina; Byström, Gudrun; Svedberg, Eva; Huggert, Sara; Kimdal, Mikael; Sandström, Monica; Brännström, Nikolina; Hayat, Amina; Tihan, Tarik; Zheng, Shichun; Berger, Mitchel; Butowski, Nicholas; Chang, Susan; Clarke, Jennifer; Prados, Michael; Rice, Terri; Sison, Jeannette; Kivett, Valerie; Duo, Xiaoqin; Hansen, Helen; Hsuang, George; Lamela, Rosito; Ramos, Christian; Patoka, Joe; Wagenman, Katherine; Zhou, Mi; Klein, Adam; McGee, Nora; Pfefferle, Jon; Wilson, Callie; Morris, Pagan; Hughes, Mary; Britt-Williams, Marlin; Foft, Jessica; Madsen, Julia; Polony, Csaba; McCarthy, Bridget; Zahora, Candice; Villano, John; Engelhard, Herbert; Borg, Ake; Chanock, Stephen K; Collins, Peter; Elston, Robert; Kleihues, Paul; Kruchko, Carol; Petersen, Gloria; Plon, Sharon; Thompson, Patricia; Johansen, C.; Sadetzki, S.; Melin, B.; Bondy, Melissa L.; Lau, Ching C.; Scheurer, Michael E.; Armstrong, Georgina N.; Liu, Yanhong; Shete, Sanjay; Yu, Robert K.; Aldape, Kenneth D.; Gilbert, Mark R.; Weinberg, Jeffrey; Houlston, Richard S.; Hosking, Fay J.; Robertson, Lindsay; Papaemmanuil, Elli; Claus, Elizabeth B.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill; Sloan, Andrew E.; Barnett, Gene; Devine, Karen; Wolinsky, Yingli; Lai, Rose; McKean-Cowdin, Roberta; Il'yasova, Dora; Schildkraut, Joellen; Sadetzki, Siegal; Yechezkel, Galit Hirsh; Bruchim, Revital Bar-Sade; Aslanov, Lili; Sadetzki, Siegal; Johansen, Christoffer; Kosteljanetz, Michael; Broholm, Helle; Bernstein, Jonine L.; Olson, Sara H.; Schubert, Erica; DeAngelis, Lisa; Jenkins, Robert B.; Yang, Ping; Rynearson, Amanda; Andersson, Ulrika; Wibom, Carl; Henriksson, Roger; Melin, Beatrice S.; Cederquist, Kristina; Aradottir, Steina; Borg, Åke; Merrell, Ryan; Lada, Patricia; Wrensch, Margaret; Wiencke, John; Wiemels, Joe; McCoy, Lucie; McCarthy, Bridget J.; Davis, Faith G.

    2014-01-01

    Background Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer.The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes. PMID:24723567

  10. Irradiation and Bevacizumab in High-Grade Glioma Retreatment Settings

    SciTech Connect

    Niyazi, Maximilian; Ganswindt, Ute; Schwarz, Silke Birgit; Kreth, Friedrich-Wilhelm; Tonn, Joerg-Christian; Geisler, Julia; Fougere, Christian la; Ertl, Lorenz; Linn, Jennifer; Siefert, Axel; Belka, Claus

    2012-01-01

    Purpose: Reirradiation is a treatment option for recurrent high-grade glioma with proven but limited effectiveness. Therapies directed against vascular endothelial growth factor have been shown to exert certain efficacy in combination with chemotherapy and have been safely tested in combination with radiotherapy in a small cohort of patients. To study the feasibility of reirradiation combined with bevacizumab treatment, the toxicity and treatment outcomes of this approach were analyzed retrospectively. Patients and Methods: After previous treatment with standard radiotherapy (with or without temozolomide) patients with recurrent malignant glioma received bevacizumab (10 mg/kg intravenous) on Day 1 and Day 15 during radiotherapy. Maintenance therapy was selected based on individual considerations, and mainly bevacizumab-containing regimens were chosen. Patients received 36 Gy in 18 fractions. Results: The data of the medical charts of the 30 patients were analyzed retrospectively. All were irradiated in a single institution and received either bevacizumab (n = 20), no additional substance (n = 7), or temozolomide (n = 3). Reirradiation was tolerated well, regardless of the added drug. In 1 patient treated with bevacizumab, a wound dehiscence occurred. Overall survival was significantly better in patients receiving bevacizumab (p = 0.03, log-rank test). In a multivariate proportional hazards Cox model, bevacizumab, Karnovsky performance status, and World Health Organization grade at relapse turned out to be the most important predictors for overall survival. Conclusion: Reirradiation with bevacizumab is a feasible and effective treatment for patients with recurrent high-grade gliomas. A randomized trial is warranted to finally answer the question whether bevacizumab adds substantial benefit to a radiotherapeutic retreatment setting.

  11. Endothelial Cell Implantation and Survival within Experimental Gliomas

    NASA Astrophysics Data System (ADS)

    Lal, Bachchu; Indurti, Ravi R.; Couraud, Pierre-Olivier; Goldstein, Gary W.; Laterra, John

    1994-10-01

    The delivery of therapeutic genes to primary brain neoplasms opens new opportunities for treating these frequently fatal tumors. Efficient gene delivery to tissues remains an important obstacle to therapy, and this problem has unique characteristics in brain tumors due to the blood-brain and blood-tumor barriers. The presence of endothelial mitogens and vessel proliferation within solid tumors suggests that genetically modified endothelial cells might efficiently transplant to brain tumors. Rat brain endothelial cells immortalized with the adenovirus E1A gene and further modified to express the β-galactosidase reporter were examined for their ability to survive implantation to experimental rat gliomas. Rats received 9L, F98, or C6 glioma cells in combination with endothelial cells intracranially to caudate/putamen or subcutaneously to flank. Implanted endothelial cells were identified by β-galactosidase histochemistry or by polymerase chain reaction in all tumors up to 35 days postimplantation, the latest time examined. Implanted endothelial cells appeared to cooperate in tumor vessel formation and expressed the brain-specific endothelial glucose transporter type 1 as identified by immunohistochemistry. The proliferation of implanted endothelial cells was supported by their increased number within tumors between postimplantation days 14 and 21 (P = 0.015) and by their expression of the proliferation antigen Ki67. These findings establish that genetically modified endothelial cells can be stably engrafted to growing gliomas and suggest that endothelial cell implantation may provide a means of delivering therapeutic genes to brain neoplasms and other solid tumors. In addition, endothelial implantation to brain may be useful for defining mechanisms of brain-specific endothelial differentiation.

  12. A New Epigenetic Mechanism of Temozolomide Action in Glioma Cells

    PubMed Central

    Barciszewska, Anna-Maria; Gurda, Dorota; Głodowicz, Paweł; Nowak, Stanisław; Naskręt-Barciszewska, Mirosława Z

    2015-01-01

    Temozolomide (TMZ) is an oral alkylating chemotherapeutic agent that prolongs the survival of patients with glioblastoma (GBM). Despite that high TMZ potential, progression of disease and recurrence are still observed. Therefore a better understanding of the mechanism of action of this drug is necessary and may allow more durable benefit from its anti-glioma properties. Using nucleotide post-labelling method and separation on thin-layer chromatography we measured of global changes of 5-methylcytosine (m5C) in DNA of glioma cells treated with TMZ. Although m5C is not a product of TMZ methylation reaction of DNA, we analysed the effects of the drug action on different glioma cell lines through global changes at the level of the DNA main epigenetic mark. The first effect of TMZ action we observed is DNA hypermethylation followed by global demethylation. Therefore an increase of DNA methylation and down regulation of some genes expression can be ascribed to activation of DNA methyltransferases (DNMTs). On the other hand hypomethylation is induced by oxidative stress and causes uncontrolled expression of pathologic protein genes. The results of brain tumours treatment with TMZ suggest the new mechanism of modulation epigenetic marker in cancer cells. A high TMZ concentration induced a significant increase of m5C content in DNA in the short time, but a low TMZ concentration at longer time hypomethylation is observed for whole range of TMZ concentrations. Therefore TMZ administration with low doses of the drug and short time should be considered as optimal therapy. PMID:26309255

  13. Treatment of Glioma Using neuroArm Surgical System

    PubMed Central

    2016-01-01

    The use of robotic technology in the surgical treatment of brain tumour promises increased precision and accuracy in the performance of surgery. Robotic manipulators may allow superior access to narrow surgical corridors compared to freehand or conventional neurosurgery. This paper reports values and ranges of tool-tissue interaction forces during the performance of glioma surgery using an MR compatible, image-guided neurosurgical robot called neuroArm. The system, capable of microsurgery and stereotaxy, was used in the surgical resection of glioma in seven cases. neuroArm is equipped with force sensors at the end-effector allowing quantification of tool-tissue interaction forces and transmits force of dissection to the surgeon sited at a remote workstation that includes a haptic interface. Interaction forces between the tool tips and the brain tissue were measured for each procedure, and the peak forces were quantified. Results showed maximum and minimum peak force values of 2.89 N (anaplastic astrocytoma, WHO grade III) and 0.50 N (anaplastic oligodendroglioma, WHO grade III), respectively, with the mean of peak forces varying from case to case, depending on type of the glioma. Mean values of the peak forces varied in range of 1.27 N (anaplastic astrocytoma, WHO grade III) to 1.89 N (glioblastoma with oligodendroglial component, WHO grade IV). In some cases, ANOVA test failed to reject the null hypothesis of equality in means of the peak forces measured. However, we could not find a relationship between forces exerted to the pathological tissue and its size, type, or location. PMID:27314044

  14. Photochemical internalization for the treatment of malignant gliomas

    NASA Astrophysics Data System (ADS)

    Madsen, Steen J.; Kharkhuu, Khishigzaya; Berg, Kristian; Hirschberg, Henry

    2007-02-01

    Photochemical internalization (PCI) is a technique to improve the utilization of macromolecules (e.g. chemotherapeutic agents) in cancer therapy in a site-specific manner. The concept is based on the use of specially designed photosensitizers which localize preferentially in the membranes of endocytic vesicles. Upon exposure to light the photosensitizers induce the formation of reactive oxygen species such as singlet molecular oxygen. The photooxidation of the endocytic membranes leads to the release of the contents of the vesicles into the cytosol. In this way, macromolecules encapsulated by the vesicles will reach the cytosol and exert their biological activity instead of being degraded by lysosomal hydrolases. The utility of PCI for the treatment of malignant gliomas was investigated in vitro using an F98 rat glioma cell line. The cytotoxicity of 5-aminolevulinic acid (ALA) based PCI of bleomycin was compared to: (1) ALA-PDT, and (2) bleomycin. In all cases, monolayers were incubated in ALA, bleomycin, or ALA + bleomycin for 4 hours and were subsequently exposed to 635 nm light. Toxicity was evaluated using colony formation assays. F98 rat glioma cells in monolayer were found to be susceptible to the effects of both ALA-PDT and bleomycin. ALA-PDT was found to be particularly effective when light was delivered at a low irradiance of 5 mW cm -2. In this case, a radiant exposure of 20 J cm -2 resulted in only 4% survival. Bleomycin was found to be toxic at relatively low concentrations, incubation of F98 cells in 10 μg ml -1 for 4 hours resulted in 1% survival. The PCI effect was found to be negligible for the parameters investigated in the F98 cell line suggesting that: (1) the incubation time was sub-optimal and/or (2) ALA was inappropriate for this application.

  15. The management of lomustine overdose in malignant glioma patients

    PubMed Central

    Wirsching, Hans-Georg; Tritschler, Isabel; Palla, Antonella; Renner, Christoph; Weller, Michael; Tabatabai, Ghazaleh

    2014-01-01

    Lomustine is an oral alkylating drug commonly used for brain tumor patients. Recently, the lomustine-containing PCV polychemotherapy regime (procarbazine, CCNU/lomustine, and vincristine) in combination with radiotherapy has become the standard of care for anaplastic oligodendroglioma with 1p/19q codeletion and high-risk low-grade glioma. Here, we review the literature of all reported cases of lomustine overdose, highlight complications by exemplifying a case of inadvertent lomustine overdose, and outline the management of this potential complication of outpatient PCV therapy. PMID:26034630

  16. Hypothalamic Glioma in a Patient With Sturge-Weber Syndrome.

    PubMed

    Cohen, Julia W; Walter, Andrew W

    2016-01-01

    Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by vascular malformations involving brain, skin, and occasionally eyes. There is no recognized tumor predisposition in patients with SWS as there is with some other phakomatoses. We present a patient with SWS who developed a low-grade glioma (LGG). We hypothesize that there could be an association between SWS and LGG formation, noting that GNAQ mutations have been implicated in the underlying biology of both SWS and a subset of pediatric LGG. It is suggested that SWS may be a cancer predisposition syndrome. PMID:26422287

  17. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

    PubMed

    Grasso, Catherine S; Tang, Yujie; Truffaux, Nathalene; Berlow, Noah E; Liu, Lining; Debily, Marie-Anne; Quist, Michael J; Davis, Lara E; Huang, Elaine C; Woo, Pamelyn J; Ponnuswami, Anitha; Chen, Spenser; Johung, Tessa B; Sun, Wenchao; Kogiso, Mari; Du, Yuchen; Qi, Lin; Huang, Yulun; Hütt-Cabezas, Marianne; Warren, Katherine E; Le Dret, Ludivine; Meltzer, Paul S; Mao, Hua; Quezado, Martha; van Vuurden, Dannis G; Abraham, Jinu; Fouladi, Maryam; Svalina, Matthew N; Wang, Nicholas; Hawkins, Cynthia; Nazarian, Javad; Alonso, Marta M; Raabe, Eric H; Hulleman, Esther; Spellman, Paul T; Li, Xiao-Nan; Keller, Charles; Pal, Ranadip; Grill, Jacques; Monje, Michelle

    2015-06-01

    Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

  18. Incidental Diagnosis of Diffuse Intrinsic Pontine Glioma in Children

    PubMed Central

    Wright, K. D.; Sabin, N. D.; Cheuk, D.; McNall-Knapp, R. Y.; Shurtleff, S. A.; Gajjar, A.; Broniscer, A.

    2014-01-01

    Children with diffuse intrinsic pontine glioma (DIPG) have a short onset, rapidly progressive neurologic decline before diagnosis. Therefore, incidental diagnosis of such an aggressive cancer is counterintuitive, yet our experience shows DIPG may occur as part of a spectrum of incidentally diagnosed pediatric brain cancers. Although children with incidentally diagnosed DIPG may experience a longer survival, it remains a potentially deadly cancer despite treatment with radiotherapy. Histologic confirmation is warranted when feasible in such patients to confirm diagnosis. Moreover, recent advances in genome-wide analyses may suggest incidentally diagnosed DIPGs are biologically distinct from the majority of these cancers. PMID:25598012

  19. Experimental approaches for the treatment of malignant gliomas

    PubMed Central

    Arko, Leopold; Katsyv, Igor; Park, Grace E.; Luan, William Patrick; Park, John K.

    2010-01-01

    Malignant gliomas, which include glioblastomas and anaplastic astrocytomas, are the most common primary tumors of the brain. Over the past 30 years, the standard treatment for these tumors has evolved to include maximal safe surgical resection, radiation therapy and temozolomide chemotherapy. While the median survival of patients with glioblastomas has improved from 6 months to 14.6 months, these tumors continue to be lethal for the vast majority of patients. There has, however, been recent substantial progress in our mechanistic understanding of tumor development and growth. The translation of these genetic, epigenetic and biochemical findings into therapies that have been tested in clinical trials is the subject of this review. PMID:20546782

  20. Pseudoprogression in boron neutron capture therapy for malignant gliomas and meningiomas

    PubMed Central

    Miyatake, Shin-Ichi; Kawabata, Shinji; Nonoguchi, Naosuke; Yokoyama, Kunio; Kuroiwa, Toshihiko; Matsui, Hideki; Ono, Koji

    2009-01-01

    Pseudoprogression has been recognized and widely accepted in the treatment of malignant gliomas, as transient increases in the volume of the enhanced area just after chemoradiotherapy, especially using temozolomide. We experienced a similar phenomenon in the treatment of malignant gliomas and meningiomas using boron neutron capture therapy (BNCT), a cell-selective form of particle radiation. Here, we introduce representative cases and analyze the pathogenesis. Fifty-two cases of malignant glioma and 13 cases of malignant meningioma who were treated by BNCT were reviewed retrospectively mainly via MR images. Eleven of 52 malignant gliomas and 3 of 13 malignant meningiomas showed transient increases of enhanced volume in MR images within 3 months after BNCT. Among these cases, five patients with glioma underwent surgery because of suspicion of relapse. In histology, most of the specimens showed necrosis with small amounts of residual tumor cells. Ki-67 labeling showed decreased positivity compared with previous samples from the individuals. Fluoride-labeled boronophenylalanine PET was applied in four and two cases of malignant gliomas and meningiomas, respectively, at the time of transient increase of lesions. These PET scans showed decreased lesion:normal brain ratios in all cases compared with scans obtained prior to BNCT. With or without surgery, all lesions were decreased or stable in size during observation. Transient increases in enhanced volume in malignant gliomas and meningiomas immediately after BNCT seemed to be pseudoprogression. This pathogenesis was considered as treatment-related intratumoral necrosis in the subacute phase after BNCT. PMID:19289492

  1. Effect of treatment with baicalein on the intracerebral tumor growth and survival of orthotopic glioma models.

    PubMed

    Wang, Fu-Rong; Jiang, Yong-Sheng

    2015-08-01

    Baicalein, a widely used Chinese herbal medicine, has been proved as a promising chemopreventive compound for many cancers. The aim of this work was to assess the anti-tumor effect of baicalein in the orthotopic glioma models. It was found that treatment of mice with U87 gliomas with baicalein (20 and 40 mg/kg/day, i.p.) significantly inhibited the intracerebral tumor growth and prolonged the survival. Furthermore, treatment with baicalein suppressed cell proliferation, promoted apoptosis, and arrested cell cycle in U87 gliomas. In addition, treatment with baicalein reduced tumor permeability, attenuated edema of tumors and brains, and improved tight junctions in gliomas. Finally, treatment with baicalein reduced the expression of HIF-1α, VEGF, and VEGFR2 in U87 gliomas. In addition, treatment with baicalein also markedly suppressed tumor growth and prolonged the survival of rats with 9L gliomas. In conclusion, baicalein has an obvious anti-tumor activity in the orthotopic glioma models. Our results suggested that treatment with baicalein might be an effective therapy for recurrent malignant brain cancers through suppressing tumor growth and alleviating edema.

  2. miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis.

    PubMed

    Xue, Jianfei; Zhou, Aidong; Wu, Yamei; Morris, Saint-Aaron; Lin, Kangyu; Amin, Samirkumar; Verhaak, Roeland; Fuller, Gregory; Xie, Keping; Heimberger, Amy B; Huang, Suyun

    2016-07-15

    Malignant glioma is an often fatal type of cancer. Aberrant activation of STAT3 leads to glioma tumorigenesis. STAT3-induced transcription of protein-coding genes has been extensively studied; however, little is known about STAT3-regulated miRNA gene transcription in glioma tumorigenesis. In this study, we found that abnormal activation or decreased expression of STAT3 promotes or inhibits the expression of miR-182-5p, respectively. Bioinformatics analyses determined that tumor suppressor protocadherin-8 (PCDH8) is a candidate target gene of miR-182-5p. miR-182-5p negatively regulated PCDH8 expression by directly targeting its 3'-untranslated region. PCDH8 knockdown induced the proliferative and invasive capacities of glioma cells. Silencing of PCDH8 or miR-182-5p mimics could reverse the inhibitory effect of WP1066, a STAT3 inhibitor, or STAT3 knockdown in vitro and in vivo on glioma progression. Clinically, expression levels of PCDH8 were inversely correlated with those of p-STAT3 or miR-182-5p in glioblastoma tissues. These findings reveal that the STAT3/miR-182-5p/PCDH8 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioma. Cancer Res; 76(14); 4293-304. ©2016 AACR. PMID:27246830

  3. Chloride channel-mediated brain glioma targeting of chlorotoxin-modified doxorubicine-loaded liposomes.

    PubMed

    Xiang, Yu; Liang, Liang; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Zhang, Qiang

    2011-06-30

    The chlorotoxin (ClTx), a scorpion-derived peptide, binding to gliomas with high specificity, was firstly applied to establish the ClTx-modified doxorubicin (DOX)-loaded liposome delivery system for targeting the brain glioma and improving the anticancer efficacy. In vitro physicochemical characterization of the novel liposome system presented satisfactory size of 100 nm with uniform distribution, high encapsulation efficiency and adequate loading capacity of both fluorescent probe and anticancer drug. It was demonstrated quantitatively by the spectrophotofluorometry and flow cytometry and qualitatively by the confocal microscopy that ClTx highly facilitated the uptake of liposomes by three glioma cell lines and one endothelial cell line. In vitro cytotoxicity studies proved that the presence of ClTx increased the cytotoxicity against glioma cells and endothelial cells with various levels for different cell lines. In BALB/c mice bearing U87 tumor xenografts, biodistribution of DiR-loaded liposomes by body imaging and anti-glioma pharmacodynamics of DOX-loaded liposomes were investigated. The ClTx-modified liposomes showed more accumulation in the subcutaneous and intracranial tumors, higher tumor growth inhibition and lower blood toxicity in the armpit tumor model. The in vitro and in vivo results exhibited good correlation of glioma targeting of the ClTx-modified liposomes. Significantly, with the ClTx as the targeting ligand, the liposomes might serve as an applicable delivery system for brain glioma therapy or imaging.

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

    SciTech Connect

    Barbarin, Alice; Séité, Paule; Godet, Julie; Bensalma, Souheyla; Muller, Jean-Marc; Chadéneau, Corinne

    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.

  5. Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process.

    PubMed

    Galvao, Rui Pedro; Kasina, Anita; McNeill, Robert S; Harbin, Jordan E; Foreman, Oded; Verhaak, Roel G W; Nishiyama, Akiko; Miller, C Ryan; Zong, Hui

    2014-10-01

    How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.

  6. Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process.

    PubMed

    Galvao, Rui Pedro; Kasina, Anita; McNeill, Robert S; Harbin, Jordan E; Foreman, Oded; Verhaak, Roel G W; Nishiyama, Akiko; Miller, C Ryan; Zong, Hui

    2014-10-01

    How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas. PMID:25246577

  7. GSK621 Targets Glioma Cells via Activating AMP-Activated Protein Kinase Signalings

    PubMed Central

    Jiang, Hong; Liu, Wei; Zhan, Shi-Kun; Pan, Yi-Xin; Bian, Liu-Guan; Sun, Bomin; Sun, Qing-Fang; Pan, Si-Jian

    2016-01-01

    Here, we studied the anti-glioma cell activity by a novel AMP-activated protein kinase (AMPK) activator GSK621. We showed that GSK621 was cytotoxic to human glioma cells (U87MG and U251MG lines), possibly via provoking caspase-dependent apoptotic cell death. Its cytotoxicity was alleviated by caspase inhibitors. GSK621 activated AMPK to inhibit mammalian target of rapamycin (mTOR) and downregulate Tetraspanin 8 (Tspan8) in glioma cells. AMPK inhibition, through shRNA knockdown of AMPKα or introduction of a dominant negative (T172A) AMPKα, almost reversed GSK621-induced AMPK activation, mTOR inhibition and Tspan8 degradation. Consequently, GSK621’s cytotoxicity in glioma cells was also significantly attenuated by AMPKα knockdown or mutation. Further studies showed that GSK621, at a relatively low concentration, significantly potentiated temozolomide (TMZ)’s sensitivity and lethality against glioma cells. We summarized that GSK621 inhibits human glioma cells possibly via activating AMPK signaling. This novel AMPK activator could be a novel and promising anti-glioma cell agent. PMID:27532105

  8. Use of tricyclic antidepressants and risk of glioma: a nationwide case–control study

    PubMed Central

    Pottegård, Anton; García Rodríguez, Luis Alberto; Rasmussen, Lotte; Damkier, Per; Friis, Søren; Gaist, David

    2016-01-01

    Background: A protective effect of tricyclic antidepressants (TCAs) against gliomas has been suggested by a small number of studies. We investigated this putative association in a nationwide setting. Methods: Using a case–control design, we identified all patients with histologically verified glioma (cases) in Denmark between 2000 and 2012 and matched these 1 : 20 to population controls. Conditional logistic regression was used to estimate adjusted odds ratios (ORs) for glioma associated with long-term (⩾3 years) use of TCAs. Similar analyses were performed for selective serotonin reuptake inhibitors (SSRIs). Results: We identified 3767 glioma cases and 75 340 population controls. Long-term use of TCAs was inversely associated with risk of glioma (OR 0.72, 95% CI: 0.41–1.25). Long-term SSRI use was not associated with glioma risk (OR 0.93, 95% CI: 0.75–1.16). Conclusions: Our study indicated that long-term use of TCAs may be associated with a reduced risk of glioma, however, the statistical precision was limited. A similar pattern was not observed for use of SSRIs. PMID:27115466

  9. Temozolomide/PLGA microparticles plus vatalanib inhibits tumor growth and angiogenesis in an orthotopic glioma model.

    PubMed

    Zhang, Yu-Hui; Yue, Zhi-Jian; Zhang, He; Tang, Gu-Sheng; Wang, Yang; Liu, Jian-Min

    2010-11-01

    Temozolomide (TM) has anti-tumor activity in patients with malignant glioma. Implantable poly (D,L-lactide-co-glycolide) (PLGA) microparticles of TM (TM-MS) have been developed, enhancing the cytotoxicity of TM to Glioma C6 cells. Vatalanib, as anti-angiogenic agent, has also shown anti-tumor activity with malignant gliomas. We examined the combined effects of TM-MS and vatalanib in a rat orthotopic glioma model and found TM-MS offered a greater tumor inhibition than TM, and combination treatment with both of them improved the survival time versus single agent therapy. The combination treatment also demonstrated an inhibition to rat glioma tumors, a significant decrease in cell proliferation, an increase in apoptosis, and a lower microvessel density within the glioma tumors. The results suggest that TM-MS can more effectively inhibit tumor than TM, and combination treatment with TM-MS and vatalanib inhibits tumor growth and angiogenesis and may prove to be a promising therapy for malignant gliomas. PMID:20816959

  10. Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice

    PubMed Central

    Auffinger, Brenda; Ahmed, Atique U.; Lesniak, Maciej S.

    2013-01-01

    Glioblastoma multiforme, one of the most common and aggressive brain tumors in adults, is highly resistant to currently available therapies and often recurs. Due to its poor prognosis and difficult management, there is an urgent need for the development and translation of new anti-glioma therapeutic approaches into the clinic. In this context, oncolytic virotherapy arises as an exciting treatment option for glioma patients. These natural or genetically engineered viruses are able to effectively infect cancer cells, inducing a specific anti-tumor cytotoxic effect. In addition, some viruses have been redesigned to modulate glioma microenvironment, to express cytokines to boost a systemic anti-glioma immune response and to incorporate angiostatic genes to decrease glioma vasculature. Although recent clinical trials have confirmed the safety of oncolytic virotherapies in the brain, their moderate clinical efficacy has not yet matched the encouraging preclinical laboratory results. In this review, we will discuss the leading anti-glioma virotherapy approaches that are presently under preclinical and clinical evaluation. We will also review different delivery methods, in vivo virus behavior, fate, replication, intratumoral spread, activation of anti-tumor immune response, and targeting of glioma stem cells. We will focus on the advantages and limitations of each therapeutic approach and how to overcome these hurdles to effectively translate exciting laboratory results into promising clinical trials. PMID:23443138

  11. Modulation of glioma risk and progression by dietary nutrients and anti-inflammatory agents

    PubMed Central

    Kyritsis, Athanassios P.; Bondy, Melissa L.; Levin, Victor A.

    2011-01-01

    Gliomas are tumors of glial origin formed in the central nervous system and exhibit profound morphological and genetic heterogeneity. The etiology of this heterogeneity involves an interaction between genetic alterations and environmental risk factors. Scientific evidence suggests that certain natural dietary components, such as phytoestrogens, flavonoids, polyunsaturated fatty acids and vitamins may exert a protective effect against gliomas by changing the nature of the interaction between genetics and environment. Similarly, certain anti-inflammatory drugs and dietary modifications, such as methionine restriction and the adoption of low-calorie or ketogenic diets, may take advantage of glioma and normal glial cells’ differential requirements for glucose, methionine, and ketone bodies and may therefore be effective as part of preventive or treatment strategies for gliomas. Treatment trials of glioma patients and chemoprevention trials of individuals with a known genetic predisposition to glioma using the most promising of these agents, such as the anti-inflammatory drugs curcumin and gamma-linolenic acid, are needed to validate or refute these agents’ putative role in gliomas. PMID:21302177

  12. Anti-EGFR function of EFEMP1 in glioma cells and patient prognosis

    PubMed Central

    Hu, Yuanjie; Gao, Hengjun; Vo, Christopher; Ke, Chao; Pan, Francine; Yu, Liping; Siegel, Eric; Hess, Kenneth R.; Linskey, Mark E.; Zhou, Yi-Hong

    2014-01-01

    EGFR is one of the key oncogenes subjected to targeted therapy for several cancers, as it is known to be amplified and/or mutated in up to 40% of malignant gliomas. EFEMP1, a fibulin-like extracellular protein, exerts both tumor suppressive and oncogenic effects in various cancers and glioma cell models. Although EFEMP1's anti-cancer activity has most commonly been attributed to its anti-angiogenic effects, we showed for gliomas that EFEMP1's binding to EGFR accounts for its suppression of the intracranial tumorigenicity of glioma cells expressing high levels of EGFR. In gliomas where EFEMP1 expression, and thus the anti-EGFR effect of EFEMP1, was suppressed, heightened levels of EGFR expression were associated with unfavorable patient outcomes in prognostic models. Results from the current study clearly demonstrate the impact that the anti-EGFR function of EFEMP1 has on the expression of EGFR and patient prognosis. A glioma prognostic model also suggests EFEMP1's context-dependent oncogenic function in gliomas expressing low levels of EGFR. Hence the level of EFEMP1 expression may have a predictive value for choosing patients for anti-EGFR therapy. PMID:25594013

  13. Mouse Curve Biometrics

    SciTech Connect

    Schulz, Douglas A.

    2007-10-08

    A biometric system suitable for validating user identity using only mouse movements and no specialized equipment is presented. Mouse curves (mouse movements with little or no pause between them) are individually classied and used to develop classication histograms, which are representative of an individual's typical mouse use. These classication histograms can then be compared to validate identity. This classication approach is suitable for providing continuous identity validation during an entire user session.

  14. Metabolomics profiling in plasma samples from glioma patients correlates with tumor phenotypes

    PubMed Central

    Zhao, Hua; Heimberger, Amy B.; Lu, Zhimin; Wu, Xifeng; Hodges, Tiffany R.; Song, Renduo; Shen, Jie

    2016-01-01

    Background Tumor-based molecular biomarkers have redefined in the classification gliomas. However, the association of systemic metabolomics with glioma phenotype has not been explored yet. Methods In this study, we conducted two-step (discovery and validation) metabolomic profiling in plasma samples from 87 glioma patients. The metabolomics data were tested for correlation with glioma grade (high vs low), glioblastoma (GBM) versus malignant gliomas, and IDH mutation status. Results Five metabolites, namely uracil, arginine, lactate, cystamine, and ornithine, significantly differed between high- and low-grade glioma patients in both the discovery and validation cohorts. When the discovery and validation cohorts were combined, we identified 29 significant metabolites with 18 remaining significant after adjusting for multiple comparisons. Those 18 significant metabolites separated high- from low-grade glioma patients with 91.1% accuracy. In the pathway analysis, a total of 18 significantly metabolic pathways were identified. Similarly, we identified 2 and 6 metabolites that significantly differed between GBM and non-GBM, and IDH mutation positive and negative patients after multiple comparison adjusting. Those 6 significant metabolites separated IDH1 mutation positive from negative glioma patients with 94.4% accuracy. Three pathways were identified to be associated with IDH mutation status. Within arginine and proline metabolism, levels of intermediate metabolites in creatine pathway were all significantly lower in IDH mutation positive than in negative patients, suggesting an increased activity of creatine pathway in IDH mutation positive tumors. Conclusion Our findings identified metabolites and metabolic pathways that differentiated tumor phenotypes. These may be useful as host biomarker candidates to further help glioma molecular classification. PMID:26967252

  15. Over-expression of tetraspanin 8 in malignant glioma regulates tumor cell progression

    SciTech Connect

    Pan, Si-Jian; Wu, Yue-Bing; Cai, Shang; Pan, Yi-Xin; Liu, Wei; Bian, Liu-Guan; Sun, Bomin; Sun, Qing-Fang

    2015-03-13

    Tumor cell invasion and proliferation remain the overwhelming causes of death for malignant glioma patients. To establish effective therapeutic methods, new targets implied in these processes have to be identified. Tetraspanin 8 (Tspn8) forms complexes with a large variety of trans-membrane and/or cytosolic proteins to regulate several important cellular functions. In the current study, we found that Tspn8 was over-expressed in multiple clinical malignant glioma tissues, and its expression level correlated with the grade of tumors. Tspn8 expression in malignant glioma cells (U251MG and U87MG lines) is important for cell proliferation and migration. siRNA-mediated knockdown of Tspn8 markedly reduced in vitro proliferation and migration of U251MG and U87MG cells. Meanwhile, Tspn8 silencing also increased the sensitivity of temozolomide (TMZ), and significantly increased U251MG or U87MG cell death and apoptosis by TMZ were achieved with Tspn8 knockdown. We observed that Tspn8 formed a complex with activated focal adhesion kinase (FAK) in both human malignant glioma tissues and in above glioma cells. This complexation appeared required for FAK activation, since Tspn8 knockdown inhibited FAK activation in U251MG and U87MG cells. These results provide evidence that Tspn8 contributes to the pathogenesis of glioblastoma probably by promoting proliferation, migration and TMZ-resistance of glioma cells. Therefore, targeting Tspn8 may provide a potential therapeutic intervention for malignant glioma. - Highlights: • Tspn8 is over-expressed in multiple clinical malignant glioma tissues. • Tspn8 expression is correlated with the grade of malignant gliomas. • Tspn8 knockdown suppresses U251MG/U87MG proliferation and in vitro migration. • Tspn8 knockdown significantly increases TMZ sensitivity in U251MG/U87MG cells. • Tspn8 forms a complex with FAK, required for FAK activation.

  16. Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells

    SciTech Connect

    Yuan, Xiaopeng; Du, Jie; Hua, Song; Zhang, Haowen; Gu, Cheng; Wang, Jie; Yang, Lei; Huang, Jianfeng; Yu, Jiahua Liu, Fenju

    2015-01-15

    Radiotherapy is an essential component of the standard therapy for newly diagnosed glioblastoma. To increase the radiosensitivity of glioma cells is a feasible solution to improve the therapeutic effects. It has been suggested that inhibition of signal transducer and activator of transcription 3 (STAT3) can radiosensitize glioma cells, probably via the activation of mitochondrial apoptotic pathway. In this study, human malignant glioma cells, U251 and A172, were treated with an STAT3 inhibitor, WP1066, or a short hairpin RNA plasmid targeting STAT3 to suppress the activation of STAT3 signaling. The radiosensitizing effects of STAT3 inhibition were confirmed in glioma cells. Intriguingly, combination of ionizing radiation exposure and STAT3 inhibition triggered a pronounced increase of autophagy flux. To explore the role of autophagy, glioma cells were treated with 3-methyladenine or siRNA for autophagy-related gene 5, and it was demonstrated that inhibition of autophagy further strengthened the radiosensitizing effects of STAT3 inhibition. Accordingly, more apoptotic cells were induced by the dual inhibition of autophagy and STAT3 signaling. In conclusion, our data revealed a protective role of autophagy in the radiosensitizing effects of STAT3 inhibition, and inhibition of both autophagy and STAT3 might be a potential therapeutic strategy to increase the radiosensitivity of glioma cells. - Highlights: • Inactivation of STAT3 signaling radiosensitizes malignant glioma cells. • STAT3 inhibition triggers a significant increase of autophagy flux induced by ionizing radiation in glioma cells. • Suppression of autophagy further strengthens the radiosensitizing effects of STAT3 inhibition in glioma cells. • Dual inhibition of autophagy and STAT3 induce massive apoptotic cells upon exposure to ionizing radiation.

  17. MAGI3 negatively regulates Wnt/β-catenin signaling and suppresses malignant phenotypes of glioma cells

    PubMed Central

    Zheng, Shuai; Meng, Ran; Fa, Pengyan; Zhao, Chunjuan; Liu, Hua; Song, Ran; Tao, Tao; Yang, Longyan; Dai, Jie; Wang, Songlin; Jiang, Wen G.; He, Junqi

    2015-01-01

    Gliomas are the most common primary brain malignancies and are associated with a poor prognosis. Here, we showed that the PDZ domain-containing protein membrane-associated guanylate kinase inverted 3 (MAGI3) was downregulated at the both mRNA and protein levels in human glioma samples. MAGI3 inhibited proliferation, migration, and cell cycle progression of glioma cells in its overexpression and knockdown studies. By using GST pull-down and co-immunoprecipitation assays, we found that MAGI3 bound to β-catenin through its PDZ domains and the PDZ-binding motif of β-catenin. MAGI3 overexpression inhibited β-catenin transcriptional activity via its interaction with β-catenin. Consistently, MAGI3 overexpression in glioma cells C6 suppressed expression of β-catenin target genes including Cyclin D1 and Axin2, whereas MAGI3 knockdown in glioma cells U373 and LN229 enhanced their expression. MAGI3 overexpression decreased growth of C6 subcutaneous tumors in mice, and inhibited expression of β-catenin target genes in xenograft tumors. Furthermore, analysis based on the Gene Expression Omnibus (GEO) glioma dataset showed association of MAGI3 expression with overall survival and tumor grade. Finally, we demonstrated negative correlation between MAGI3 expression and activity of Wnt/β-catenin signaling through GSEA of three public glioma datasets and immunohistochemical staining of clinical glioma samples. Taken together, these results identify MAGI3 as a novel tumor suppressor and provide insight into the pathogenesis of glioma. PMID:26452219

  18. Association between regulator of telomere elongation helicase 1 polymorphism and susceptibility to glioma

    PubMed Central

    Pei, Shujun; Zhao, Feng; Liu, Junle; Fu, Qiang; Shang, Peizhong

    2015-01-01

    Background: Glioma is the most devastating type of malignant brain tumors in adults. Genetic factors play important roles in the pathogenesis of glioma. In recent years, some studies found that there were significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility, however, the results were controversial. The aim of this study was to obtain a more exact estimation of the association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma through a meta-analysis. Methods: The meta-analysis included 19 published case-control studies involving 8541 cases and 14226 controls. The included papers were searched from PubMed and Embase database. Odds ratio (OR) with 95% confidence interval (95% CI) were used to evaluate the association of regulator of telomere elongation helicase 1 rs6010620 polymorphism with glioma. Results: A significant association between regulator of telomere elongation helicase 1 rs6010620 polymorphism and glioma susceptibility was observed for GG vs. AA+AG (OR=1.28, 95% CI=1.14-1.43) and G vs. A (OR=1.07, 95% CI=1.03-1.10). Further subgroup analysis based on ethnicity showed similar results in Asians and Caucasians. In the subgroup analysis of source of control, a significant association between the G allele and glioma susceptibility were found in population-based group and hospital-based group. Conclusions: The meta-analysis suggested that regulator of telomere elongation helicase 1 rs6010620 polymorphism was a risk factor for glioma. And this study also suggested that rs6010620 GG genotype and G allele may be indicators for the risk of glioma. PMID:25785045

  19. Targeting Ras-RAF-ERK and its Interactive Pathways as a Novel Therapy for Malignant Gliomas

    PubMed Central

    Lo, H.-W.

    2013-01-01

    Malignant gliomas are the most common and the deadliest brain malignancies in adults. Despite the lack of a complete understanding of the biology of these tumors, significant advances have been made in the past decades. One of the key discoveries made in the area of malignant gliomas is that these tumors can be induced and maintained by aberrant signaling networks. In this context, the Ras pathway has been extensively exploited, from both basic and translational perspectives. Although somatic oncogenic mutations of Ras genes are frequent in several cancer types, early investigations on gliomas revealed disappointing facts that the Ras mutations are nearly absent in malignant gliomas and that the BRAF mutations are present in a very small percentage of gliomas. Therefore, the observed deregulation of the Ras-RAF-ERK signaling pathway in gliomas is attributed to its upstream positive regulators, including, EGFR and PDGFR known to be highly active in the majority of malignant gliomas. In contrast to the initial negative results on the somatic mutations of H-Ras, K-Ras and BRAF, recent breakthrough studies on pediatric low-grade astrocytomas uncovered genetic alterations of the BRAF gene involving copy number gains and rearrangements. The 7q34 rearrangements result in a novel in-frame KIAA1549:BRAF fusion gene that possesses constitutive BRAF kinase activity resembling oncogenic BRAF (V600E). In light of the earlier findings and recent breakthroughs, this review summarizes our current understanding of the Ras-RAF-ERK signaling pathway in gliomas and the outcome of preclinical and clinical studies that evaluated the efficacy of Ras-targeted therapy in malignant gliomas. PMID:20718706

  20. Human and rat glioma growth, invasion, and vascularization in a novel chick embryo brain tumor model.

    PubMed

    Cretu, Alexandra; Fotos, Joseph S; Little, Brian W; Galileo, Deni S

    2005-01-01

    The mechanisms that control the insidiously invasive nature of malignant gliomas are poorly understood, and their study would be facilitated by an in vivo model that is easy to manipulate and inexpensive. The developing chick embryo brain was assessed as a new xenograft model for the production, growth, and study of human and rat glioma cell lines. Three established glioma lines (U-87 MG, C6, and 9L) were injected into chick embryo brain ventricles on embryonic day (E) 5 and brains were examined after several days to two weeks after injection. All glioma lines survived, produced vascularized intraventricular tumors, and invaded the brain in a manner similar to that in rodents. Rat C6 glioma cells spread along vasculature and also invaded the neural tissue. Human U-87 glioma cells migrated along vasculature and exhibited slight invasion of neural tissue. Rat 9L gliosarcoma cells were highly motile, but migrated only along the vasculature. A derivative of 9L cells that stably expressed the cell surface adhesion molecule NgCAM/L1 was produced and also injected into chick embryo brain ventricles to see if this protein could facilitate tumor cell migration away from the vasculature into areas such as axonal tracts. 9L/NgCAM cells, however, did not migrate away from the vasculature and, thus, this protein alone cannot be responsible for diffuse invasiveness of some gliomas. 9L/NgCAM cell motility was assessed in vitro using sophisticated time-lapse microscopy and quantitative analysis, and was significantly altered compared to parental 9L cells. These studies demonstrate that the chick embryo brain is a successful and novel xenograft model for mammalian gliomas and demonstrate the potential usefulness of this new model for studying glioma tumor cell growth, vascularization, and invasiveness.

  1. Polymorphism in the IL4R gene and clinical features are associated with glioma prognosis

    PubMed Central

    Jin, Tian bo; Du, Shuli; Zhu, Xi kai; Li, Gang; Ouyang, Yongri; He, Na; Zhang, Zhiying; Zhang, Yuan; Kang, Longli; Yuan, Dongya

    2016-01-01

    Abstract Inflammatory gene polymorphisms may be associated with glioma risk. The purpose of this study was to analyze effects of certain inflammatory gene and some clinical factors on patient survival. The clinical information of 269 glioma patients conceived operation from September 2010 to May 2014 to decide the 1-, 3-year survival rates according to follow-up results and analyze age, gender, the WHO classification, extent of surgical resection, radiotherapy and chemotherapy factors effects on prognosis. Survival distributions were estimated by using the Kaplan–Meier method and difference in the survival was tested using the log-rank test. To estimate the association between the IL4, IL13, IL10, IL4R SNPs, and PFS and OS in glioma, the HR and 95% CI were calculated by univariate Cox proportional hazards model. Multivariate Cox model were performed to compute adjusted HR and 95% CI. All data was analyzed with SPSS17.0 package. Extent of surgical resection, chemotherapy, and age are an important factor in glioma overall survival and progression-free survival overall. Extent of surgery and chemotherapy are important factors in astrocytoma overall survival. Univariate analysis showed that IL4R rs1801275 was significantly associated with overall survival of glioma and astrocytoma patients (P < 0.05). Multivariate Cox regression analysis showed that IL4R rs1801275 GG genotype could increase the death risk of glioma and astrocytoma patients (Glioma: hazard ratio [HR]: 4.897, 95% confidence limits [95% CI]: 1.962–12.222, P = 0.001; Astrocytoma: HR: 15.944, 95% CI: 4.019–63.253, P < 0.05). Our research results showed that extent of surgical resection, age, and chemotherapy affect the prognosis of glioma. The IL4R gene may affect the survival of glioma patients. PMID:27495027

  2. Building a Brainier Mouse.

    ERIC Educational Resources Information Center

    Tsien, Joe Z.

    2000-01-01

    Describes a genetic engineering project to build an intelligent mouse. Cites understanding the molecular basis of learning and memory as a very important step. Concludes that while science will never create a genius mouse that plays the stock market, it can turn a mouse into a quick learner with a better memory. (YDS)

  3. Unlocking the promise of oncolytic virotherapy in glioma: combination with chemotherapy to enhance efficacy

    PubMed Central

    Spencer, Drew A; Young, Jacob S; Kanojia, Deepak; Kim, Julius W; Polster, Sean P; Murphy, Jason P; Lesniak, Maciej S

    2015-01-01

    Malignant glioma is a relentless burden to both patients and clinicians, and calls for innovation to overcome the limitations in current management. Glioma therapy using viruses has been investigated to accentuate the nature of a virus, killing a host tumor cell during its replication. As virus mediated approaches progress with promising therapeutic advantages, combination therapy with chemotherapy and oncolytic viruses has emerged as a more synergistic and possibly efficacious therapy. Here, we will review malignant glioma as well as prior experience with oncolytic viruses, chemotherapy and combination of the two, examining how the combination can be optimized in the future. PMID:25996044

  4. RTEL1 tagging SNPs and haplotypes were associated with glioma development

    PubMed Central

    2013-01-01

    Abstract 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. Virtual slides The virtual slides for this article

  5. Glioma cells enhance endothelial progenitor cell angiogenesis via VEGFR-2, not VEGFR-1.

    PubMed

    Zhang, Junxia; Zhao, Peng; Fu, Zhen; Chen, Xiaolei; Liu, Ning; Lu, Ailin; Li, Rui; Shi, Lei; Pu, Peiyu; Kang, Chunsheng; You, Yongping

    2008-12-01

    Although potential contribution of endothelial progenitor cells (EPCs) to angiogenesis in glioma has been proposed, the molecular mechanisms of EPCs recruitment to vasculature have not been fully elucidated. Here, we show that the supernatant from glioma cells promotes EPCs angiogenesis via VEGFR-2, not VEGFR-1. Moreover, VEGFR-2 siRNA inhibits VEGFR-2 expression in EPCs, tube formation on matrigel and cell migration. MMP-9 activity and expression and the Akt and ERK phosphorylations are decreased by VEGFR-2 siRNA. Thus, these results indicate that glioma cells enhance EPC angiogenesis via VEGFR-2, not VEGFR-1, mediated by the MMP-9, Akt and ERK signal pathways.

  6. Imaging Biomarker Dynamics in an Intracranial Murine Glioma Study of Radiation and Antiangiogenic Therapy

    SciTech Connect

    Chung, Caroline; Jalali, Shahrzad; Foltz, Warren; Burrell, Kelly; Wildgoose, Petra; Lindsay, Patricia; Graves, Christian; Camphausen, Kevin; Milosevic, Michael; Jaffray, David; Zadeh, Gelareh; Ménard, Cynthia

    2013-03-01

    Purpose: There is a growing need for noninvasive biomarkers to guide individualized spatiotemporal delivery of radiation therapy (RT) and antiangiogenic (AA) therapy for brain tumors. This study explored early biomarkers of response to RT and the AA agent sunitinib (SU), in a murine intracranial glioma model, using serial magnetic resonance imaging (MRI). Methods and Materials: Mice with MRI-visible tumors were stratified by tumor size into 4 therapy arms: control, RT, SU, and SU plus RT (SURT). Single-fraction conformal RT was delivered using MRI and on-line cone beam computed tomography (CT) guidance. Serial MR images (T2-weighted, diffusion, dynamic contrast-enhanced and gadolinium-enhanced T1-weighted scans) were acquired biweekly to evaluate tumor volume, apparent diffusion coefficient (ADC), and tumor perfusion and permeability responses (K{sub trans}, K{sub ep}). Results: Mice in all treatment arms survived longer than those in control, with a median survival of 35 days for SURT (P<.0001) and 30 days for RT (P=.009) and SU (P=.01) mice vs 26 days for control mice. At Day 3, ADC rise was greater with RT than without (P=.002). Sunitinib treatment reduced tumor perfusion/permeability values with mean K{sub trans} reduction of 27.6% for SU (P=.04) and 26.3% for SURT (P=.04) mice and mean K{sub ep} reduction of 38.1% for SU (P=.01) and 27.3% for SURT (P=.02) mice. The magnitude of individual mouse ADC responses at Days 3 and 7 correlated with subsequent tumor growth rate R values of −0.878 (P=.002) and −0.80 (P=.01), respectively. Conclusions: Early quantitative changes in diffusion and perfusion MRI measures reflect treatment responses soon after starting therapy and thereby raise the potential for these imaging biomarkers to guide adaptive and potentially individualized therapy approaches in the future.

  7. Phosphoribosylpyrophosphate Synthetase 1 Knockdown Suppresses Tumor Formation of Glioma CD133+ Cells Through Upregulating Cell Apoptosis.

    PubMed

    Li, Chen; Yan, Zhongjie; Cao, Xuhua; Zhang, Xiaowei; Yang, Liang

    2016-10-01

    Relapse is the main cause of mortality in patients with glioblastoma multiforme (GBM). Treatment options involve surgical resection followed by a combination of radiotheraphy and chemotherapy with temozolomide. Several genes and genetic pathways have been identified to contribute to therapeutic resistance, giving rise to recurrence of the malignancy. In the last decades, glioma stem cells (GSCs) with the capacity of self-renewal have been demonstrated to maintain tumor propagation and treatment resistance. Here, we isolated CD133-positive (CD133+) and CD133-negative (CD133-) cells from glioblastoma U98G and U87MG cell lines. The role of phosphoribosylpyrophosphate synthetase 1 (PRPS1), which catalyzes the first step of the synthesis of nucleotide, in proliferation and apoptosis was investigated. We found that PRPS1 had a remarkable effect on cell proliferation and sphere formation in both CD133+ and CD133- cells. Compared to CD133- cells, CD133+ cells exhibited more significant results in cell apoptosis assay. CD133+ T98G and U87MG cells were used in xenograft mouse model of tumor formation. Interestingly, the mice implanted with PRPS1 knockdown T98G or U87MG stem cells exhibited prolonged survival time and reduced tumor volume. By immunostaining caspase-3 in tumor tissues of these mice, we demonstrated that the apoptotic activities in tumor cells were positively correlated to the survival time but negatively correlated to PRPS1 expression. Our results indicate that PRPS1 plays an important role in proliferation and apoptosis in GSCs and provide new clues for potential PRPS1-targeted therapy in GBM treatment. PMID:27343059

  8. Radiation dosimetry of 131I-chlorotoxin for targeted radiotherapy in glioma-bearing mice.

    PubMed

    Shen, Sui; Khazaeli, M B; Gillespie, G Yancey; Alvarez, Vernon L

    2005-01-01

    Chlorotoxin, or TM-601, is a peptide derived from the venom of the scorpionLeiurus Quinquestriatus that specifically binds to malignant brain tumors, but not to normal tissues. Targeted radiotherapy using 131I-Chlorotoxin is promising for post-surgery treatment of brain tumors. This study reports dosimetry results of 131I-Chlorotoxin in athymic nude mice with intracranially implanted human glioma xenografts and projected radiation doses in patients receiving 370 MBq of 131I-Chlorotoxin. 125I/131I-Chlorotoxin were injected into the right brain where D54 MG xenografts were implanted. Mice were sacrificed 24-96 h later. The blood, normal organs, and tumors were weighed and counted to determine 131I-Chlorotoxin concentration. The radiation dose from 131I was calculated based on non-penetrating radiation in the mouse model. Assuming similar tissue uptake in mice and patients, radiation doses for patients were extrapolated. Distributions of 125I/131I-Chlorotoxin were only significant in tumor, stomach, kidneys, and brain (injection site), reflecting non-specific uptake of Chlorotoxin in normal tissues. Mean radiation dose (cGy/37 kBq) was 58.2 for tumor, 17.9 for brains, 1.8 for marrow, 27.1 for stomach, 16.0 for kidneys in mice. For intracranial injection of 370 MBq 131I-Chlorotoxin in patients, extrapolated patient dose (cGy) was 70 for brains, 6 for marrow, 35 for stomach, 60 to kidneys, 227 to tumor, suggesting that 3.7 GBq of 131I-Chlorotoxin can be safely administrated to patients. These promising results demonstrated potential in improving patient survival using this novel targeting agent.

  9. Methylation of the miR-126 gene associated with glioma progression.

    PubMed

    Cui, Hongwei; Mu, Yongping; Yu, Lei; Xi, Ya-guang; Matthiesen, Rune; Su, Xiulan; Sun, Wenjie

    2016-04-01

    Gliomas are the most common and the most malignant brain tumors, accouting for 45-55% of all intracranial tumors. The incidence of glioma worldwide is about 6-12 per 100,000. Recently, several studies showed that the activation of the oncogenes and the inactivation and/or loss of the tumor suppressor genes, especially for miRNA-21, let-7 and so on, are the most primary molecule event in gliomas. MicroRNAs (miRNAs) are a class of endogenously expressed small noncoding RNAs which are usually 21-23 nucleotides long. miRNAs regulate gene expression and play important roles in a variety of physiological and pathological processes, such as cell proliferation, differentiation and apoptosis. To date, Growing evidence has shown that mi RNAs are frequently dysregulated in human cancers and can act as both tumor suppressors and oncogenes. Along with the discovery of micro RNA, more and more research focusing on its relationship with glioma was carried out to investigate the biological features of glioma and to provide experimental evidence for glioma mechanism. In the present study, we aimed to verify the miRNA-126 down-regulation which showed in the results of glioma tissue miRNAs chip and discuss the miRNA-126 methylation in patients with glioma. A total of 50 samples from patients with glioma and 20 control samples from patients with cerebral trauma were included in this study. The expression levels of the miR-126 gene were detected using quantitative polymerase chain reaction (PCR), and the methylation status of miR-126 was examined using methylation-specific PCR-denaturing high-performance liquid chromatography (MSP-DHPLC). The expression level of miRNA-126 was found to be significantly higher in the control group (0.6134 ± 0.1214) than in the glioma group (0.2771 ± 0.1529; P < 0.05). The expression was also significantly elevated in low-grade gliomas (0.3117 ± 0.1474) compared with high-grade gliomas (0.1582 ± 0.1345; P < 0.05). In addition, increased methylation of

  10. Resveratrol Represses Pokemon Expression in Human Glioma Cells.

    PubMed

    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. PMID:25875864

  11. Application of nanoparticles on diagnosis and therapy in gliomas.

    PubMed

    Hernández-Pedro, Norma Y; Rangel-López, Edgar; Magaña-Maldonado, Roxana; de la Cruz, Verónica Pérez; del Angel, Abel Santamaría; Pineda, Benjamín; Sotelo, Julio

    2013-01-01

    Glioblastoma multiforme (GBM) is one of the most deadly diseases that affect humans, and it is characterized by high resistance to chemotherapy and radiotherapy. Its median survival is only fourteen months, and this dramatic prognosis has stilled without changes during the last two decades; consequently GBM remains as an unsolved clinical problem. Therefore, alternative diagnostic and therapeutic approaches are needed for gliomas. Nanoparticles represent an innovative tool in research and therapies in GBM due to their capacity of self-assembly, small size, increased stability, biocompatibility, tumor-specific targeting using antibodies or ligands, encapsulation and delivery of antineoplastic drugs, and increasing the contact surface between cells and nanomaterials. The active targeting of nanoparticles through conjugation with cell surface markers could enhance the efficacy of nanoparticles for delivering several agents into the tumoral area while significantly reducing toxicity in living systems. Nanoparticles can exploit some biological pathways to achieve specific delivery to cellular and intracellular targets, including transport across the blood-brain barrier, which many anticancer drugs cannot bypass. This review addresses the advancements of nanoparticles in drug delivery, imaging, diagnosis, and therapy in gliomas. The mechanisms of action, potential effects, and therapeutic results of these systems and their future applications in GBM are discussed.

  12. Analysis of SOX2-Regulated Transcriptome in Glioma Stem Cells

    PubMed Central

    Acanda de la Rocha, Arlet M.; López-Bertoni, Hernando; Guruceaga, Elizabeth; González-Huarriz, Marisol; Martínez-Vélez, Naiara; Xipell, Enric; Fueyo, Juan; Gomez-Manzano, Candelaria

    2016-01-01

    Introduction Glioblastoma is the most malignant brain tumor in adults and is associated with poor survival despite multimodal treatments. Glioma stem-like cells (GSCs) are cells functionally defined by their self-renewal potential and the ability to reconstitute the original tumor upon orthotopic implantation. They have been postulated to be the culprit of glioma chemo- and radio-resistance ultimately leading to relapse. Understanding the molecular circuits governing the GSC compartment is essential. SOX2, a critical transcription regulator of embryonic and neural stem cell function, is deregulated in GSCs however; the precise molecular pathways regulated by this gene in GSCs remain poorly understood. Results We performed a genome-wide analysis of SOX2-regulated transcripts in GSCs, using a microarray. We identified a total of 2048 differentially expressed coding transcripts and 261 non-coding transcripts. Cell adhesion and cell-cell signaling are among the most enriched terms using Gene Ontology (GO) classification. The pathways altered after SOX2 down-modulation includes multiple cellular processes such as amino-acid metabolism and intercellular signaling cascades. We also defined and classified the set of non-coding transcripts differentially expressed regulated by SOX2 in GSCs, and validated two of them. Conclusions We present a comprehensive analysis of the transcriptome controlled by SOX2 in GSCs, gaining insights in the understanding of the potential roles of SOX2 in glioblastoma. PMID:27669421

  13. Application of Nanoparticles on Diagnosis and Therapy in Gliomas

    PubMed Central

    Hernández-Pedro, Norma Y.; Rangel-López, Edgar; Magaña-Maldonado, Roxana; de la Cruz, Verónica Pérez; Santamaría del Angel, Abel; Pineda, Benjamín; Sotelo, Julio

    2013-01-01

    Glioblastoma multiforme (GBM) is one of the most deadly diseases that affect humans, and it is characterized by high resistance to chemotherapy and radiotherapy. Its median survival is only fourteen months, and this dramatic prognosis has stilled without changes during the last two decades; consequently GBM remains as an unsolved clinical problem. Therefore, alternative diagnostic and therapeutic approaches are needed for gliomas. Nanoparticles represent an innovative tool in research and therapies in GBM due to their capacity of self-assembly, small size, increased stability, biocompatibility, tumor-specific targeting using antibodies or ligands, encapsulation and delivery of antineoplastic drugs, and increasing the contact surface between cells and nanomaterials. The active targeting of nanoparticles through conjugation with cell surface markers could enhance the efficacy of nanoparticles for delivering several agents into the tumoral area while significantly reducing toxicity in living systems. Nanoparticles can exploit some biological pathways to achieve specific delivery to cellular and intracellular targets, including transport across the blood-brain barrier, which many anticancer drugs cannot bypass. This review addresses the advancements of nanoparticles in drug delivery, imaging, diagnosis, and therapy in gliomas. The mechanisms of action, potential effects, and therapeutic results of these systems and their future applications in GBM are discussed. PMID:23691498

  14. IGFBP2 promotes glioma tumor stem cell expansion and survival

    SciTech Connect

    Hsieh, David; Hsieh, Antony; Stea, Baldassarre; Ellsworth, Ron

    2010-06-25

    IGFBP2 is overexpressed in the most common brain tumor, glioblastoma (GBM), and its expression is inversely correlated to GBM patient survival. Previous reports have demonstrated a role for IGFBP2 in glioma cell invasion and astrocytoma development. However, the function of IGFBP2 in the restricted, self-renewing, and tumorigenic GBM cell population comprised of tumor-initiating stem cells has yet to be determined. Herein we demonstrate that IGFBP2 is overexpressed within the stem cell compartment of GBMs and is integral for the clonal expansion and proliferative properties of glioma stem cells (GSCs). In addition, IGFBP2 inhibition reduced Akt-dependent GSC genotoxic and drug resistance. These results suggest that IGFBP2 is a selective malignant factor that may contribute significantly to GBM pathogenesis by enriching for GSCs and mediating their survival. Given the current dearth of selective molecular targets against GSCs, we anticipate our results to be of high therapeutic relevance in combating the rapid and lethal course of GBM.

  15. Molecularly targeted therapies for malignant glioma: rationale for combinatorial strategies

    PubMed Central

    Thaker, Nikhil G; Pollack, Ian F

    2010-01-01

    Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient’s tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG. PMID:19951140

  16. Resveratrol Represses Pokemon Expression in Human Glioma Cells.

    PubMed

    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.

  17. Methods to Differentiate Radiation Necrosis and Recurrent Disease in Gliomas

    NASA Astrophysics Data System (ADS)

    Ewell, Lars

    2007-03-01

    Given the difficulty in differentiating Radiation Induced Necrosis (RIN) and recurrent disease in glioma patients using conventional techniques (CT scans, MRI scans), researchers have looked for different imaging modalities. Among these different modalities are Diffusion Weighted Magnetic Resonance Imaging (DWMRI) and Magnetic Resonance Spectroscopy (MRS). In DWMRI, an Apparent Diffusion Coefficient (ADC) is calculated for a Region Of Interest (ROI), and then monitored over time (longitudinally). In the brain, different anatomical features can complicate the interpretation of ADCs. In particular, the density and spatial variation of the cerebral spinal fluid filled fissures known as sulci can influence how a change in an ADC is explained. We have used the covariance of pixel intensity in T1 weighted MRI scans to study how intra-patient and inter-patient sulci density varies, and will present these results. MRS uses the shift in the MR signal due to the local chemical environment to determine the concentration of brain metabolites like choline and creatin. The ratio of metabolites such as these has been shown to have the power to discriminate between RIN and recurrent disease in glioma patients. At our institution, we have initiated a protocol whereby we will use DWMRI and MRS to study how best to utilize these complimentary forms of imaging.

  18. Effects of radiotherapy after hyperbaric oxygenation on malignant gliomas

    PubMed Central

    Kohshi, K; Kinoshita, Y; Imada, H; Kunugita, N; Abe, H; Terashima, H; Tokui, N; Uemura, S

    1999-01-01

    The purpose of this non-randomized trial was to evaluate the efficacy of radiotherapy combined with hyperbaric oxygen (HBO) in patients with malignant glioma. Between 1987 and 1997, 29 patients in whom computerized tomography (CT) or magnetic resonance imaging (MRI) scans showed post-operative residual tumours were locally irradiated with nitrosourea-based chemotherapy. Treatments were consecutively combined with HBO at two institutions since 1991 and 1993. Fifteen patients were irradiated daily after HBO, and the periods of time from decompression to irradiation were within 15 and 30 min in 11 and four patients respectively. Fourteen other patients were treated without HBO. Tumour responses were assessed by CT or MRI scans and survival times were compared between the treated groups. In the HBO group, 11 of 15 patients (73%) showed ≥ 50% tumour regression. All responders were irradiated within 15 min after decompression. In the non-HBO group, four of 14 patients (29%) showed tumour regression. The median survivals in patients with and without HBO were 24 and 12 months, respectively, and were significantly different (P < 0.05). No serious side-effects were observed in the HBO patients. In conclusion, irradiation after HBO seems to be a useful form of treatment for malignant gliomas, but irradiation should be administered immediately after decompression. © 1999 Cancer Research Campaign PMID:10390002

  19. Neutron interstitial brachytherapy for malignant gliomas: a pilot study

    SciTech Connect

    Patchell, R.A.; Maruyama, Y.; Tibbs, P.A.; Beach, J.L.; Kryscio, R.J.; Young, A.B.

    1988-01-01

    Fifty-six patients with malignant glioma were treated with implantation of the neutron-emitting element californium-252 (/sup 252/Cf) within 2 weeks after surgical debulking of the tumor. Implantation was performed using computerized tomography-guided placement of afterloading catheters, and the /sup 252/Cf sources were removed after approximately 300 neutron rads were delivered. Patients then received 6000 to 7000 conventional photon rads by external beam. The total photon-equivalent dose to the tumor ranged from 8100 to 9100 rads. The median survival time was 10 months, with 18-and 24-month survival rates of 28% and 19%, respectively. The results of reoperation or autopsy showed that patients had recurrence of the tumor but that radiation necrosis was restricted to the area of the original tumor. Serious complications occurred in five patients (9%) and consisted of wound infections in three, cerebral edema in one, and radiation necrosis beyond the original tumor margin in one. Previous studies using external-beam neutron radiation have shown that neutrons are capable of totally eradicating malignant gliomas; however, in most cases, unacceptable widespread radiation necrosis has resulted. Neutron implants are a logical way to increase the dose to the tumor and decrease the dose to normal brain. Interstitial neutron radiation can be given safely with /sup 252/Cf, and the survival results achieved by radiation alone using relatively low doses of interstitial neutron radiation from /sup 252/Cf implants plus conventional photon radiation were equal to the results attained with any currently available conventional therapy.

  20. Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

    PubMed

    Venkatesh, Humsa S; Johung, Tessa B; Caretti, Viola; Noll, Alyssa; Tang, Yujie; Nagaraja, Surya; Gibson, Erin M; Mount, Christopher W; Polepalli, Jai; Mitra, Siddhartha S; Woo, Pamelyn J; Malenka, Robert C; Vogel, Hannes; Bredel, Markus; Mallick, Parag; Monje, Michelle

    2015-05-01

    Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.