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Sample records for glioma bearer mouse

  1. Glioma

    MedlinePlus

    ... cells are called mixed gliomas. Tumors such as “optic nerve glioma” and “brain stem glioma” are named ... Oligodendroglioma: Click here to learn more about oligodendroglioma. Optic Glioma: These tumors may involve any part of ...

  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

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

    2012-03-30

    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.

  4. 31 CFR 358.8 - Are there fees for the conversion of bearer corpora or detached bearer coupons?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... bearer corpora or detached bearer coupons? 358.8 Section 358.8 Money and Finance: Treasury Regulations... DEBT REGULATIONS GOVERNING BOOK-ENTRY CONVERSION OF BEARER CORPORA AND DETACHED BEARER COUPONS § 358.8 Are there fees for the conversion of bearer corpora or detached bearer coupons? We do not charge...

  5. 31 CFR 358.3 - Are there any bearer corpora or detached bearer coupons that are not eligible for conversion?

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Are there any bearer corpora or... BUREAU OF THE PUBLIC DEBT REGULATIONS GOVERNING BOOK-ENTRY CONVERSION OF BEARER CORPORA AND DETACHED BEARER COUPONS § 358.3 Are there any bearer corpora or detached bearer coupons that are not eligible...

  6. 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

  7. 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.

  8. 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

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Which bearer corpora or detached... CORPORA AND DETACHED BEARER COUPONS § 358.5 Which bearer corpora or detached bearer coupons are eligible... associated with the corpus are not submitted with the corpus, the corpus will be converted to a...

  9. 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

    ... 31 Money and Finance: Treasury 2 2010-07-01 2010-07-01 false Which bearer corpora or detached... CORPORA AND DETACHED BEARER COUPONS § 358.4 Which bearer corpora or detached bearer coupons are eligible for conversion to transferable BECCS or CUBES securities? (a) For a callable corpus to be eligible...

  10. 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...

  11. 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

    ... 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. 3-D imaging mass spectrometry of protein distributions in mouse Neurofibromatosis 1 (NF1)-associated optic glioma.

    PubMed

    Anderson, David M G; Van de Plas, Raf; Rose, Kristie L; Hill, Salisha; Schey, Kevin L; Solga, Anne C; Gutmann, David H; Caprioli, Richard M

    2016-10-21

    Neurofibromatosis type 1 (NF1) is a common neurogenetic disorder, in which affected individuals develop tumors of the nervous system. Children with NF1 are particularly prone to brain tumors (gliomas) involving the optic pathway that can result in impaired vision. Since tumor formation and expansion requires a cooperative tumor microenvironment, it is important to identify the cellular and acellular components associated with glioma development and growth. In this study, we used 3-D matrix assisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to measure the distributions of multiple molecular species throughout optic nerve tissue in mice with and without glioma, and to explore their spatial relationships within the 3-D volume of the optic nerve and chiasm. 3-D IMS studies often involve extensive workflows due to the high volume of sections required to generate high quality 3-D images. Herein, we present a workflow for 3-D data acquisition and volume reconstruction using mouse optic nerve tissue. The resulting 3-D IMS data yield both molecular similarities and differences between glioma-bearing and wild-type (WT) tissues, including protein distributions localizing to different anatomical subregions.

  13. Characterisation of a new mouse monoclonal antibody (ONS-M21) reactive with both medulloblastomas and gliomas.

    PubMed Central

    Moriuchi, S.; Shimizu, K.; Miyao, Y.; Hayakawa, T.

    1993-01-01

    We developed an IgG1 mouse monoclonal antibody (ONS-M21) directed against a cell surface antigen of medulloblastomas and gliomas in immunisation of mice with the ONS-76 medulloblastoma cell line. The antibody specifically reacted with medulloblastomas, supratentorial primitive neuroectodermal tumours (SPNETs) and gliomas, but not with other neuroectodermally derived tumours (neuroblastoma and melanoma) or with other kinds of tumours (meningioma, neurinoma, leukaemia, and small cell lung cancer). No reactivity was identified with normal body tissues, including peripheral blood cells. Characterisation of the ONS-M21 antigen showed that it was a trypsin-sensitive glycoprotein with a molecular weight of 80 kDa on SDS-PAGE. The pattern of reactivity and the biochemical properties of this antigen were different from those of other markers of medulloblastoma. These results indicate that ONS-M21 detects a new tumour-associated cell surface antigen specifically expressed by medulloblastomas, SPNETs, and gliomas. This is the first report that medulloblastomas may share common cell surface antigens with gliomas, although most studies have concluded that medulloblastoma has a predominantly neuronal phenotype. The lack of reactivity with normal tissue implies that ONS-M21 has potential applications as both a diagnostic tool and a therapeutic agent. Images Figure 1 Figure 3 Figure 4 Figure 6 PMID:8217597

  14. 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 ...

  15. Potent tumor tropism of induced pluripotent stem cells and induced pluripotent stem cell-derived neural stem cells in the mouse intracerebral glioma model.

    PubMed

    Yamazoe, Tomohiro; Koizumi, Shinichiro; Yamasaki, Tomohiro; Amano, Shinji; Tokuyama, Tsutomu; Namba, Hiroki

    2015-01-01

    Although neural and mesenchymal stem cells have been well-known to have a strong glioma tropism, this activity in induced pluripotent stem cells (iPSCs) has not yet been fully studied. In the present study, we tested tumor tropic activity of mouse iPSCs and neural stem cells derived from the iPSC (iPS-NSCs) using in vitro Matrigel invasion chamber assay and in vivo mouse intracranial tumor model. Both iPSC and iPS-NSC had a similar potent in vitro tropism for glioma conditioned media. The migrated iPSCs to the gliomas kept expressing Nanog-GFP gene, suggesting no neuronal or glial differentiation. iPSCs or iPS-NSCs labeled with 5-bromo-2-deoxyuridine were intracranially implanted in the contralateral hemisphere to the GL261 glioma cell implantation in the allogeneic C57BL/6 mouse. Active migration of both stem cells was observed 7 days after implantation. Again, the iPSCs located in the tumor area expressed Nanog-GFP gene, suggesting that the migrated cells were still iPSCs. These findings demonstrated that both iPSCs and iPS-NSCs had potent glioma tropism and could be candidates as vehicles in stem cell-based glioma therapy.

  16. 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

  17. 31 CFR 358.7 - Where do I send my bearer corpora and detached bearer coupons to be converted?

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... detached bearer coupons to be converted to: Bureau of the Fiscal Service, Division of Customer Service, P... Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE FISCAL SERVICE REGULATIONS GOVERNING BOOK-ENTRY CONVERSION OF BEARER CORPORA AND DETACHED BEARER COUPONS §...

  18. Monitoring of tumor growth and post-irradiation recurrence in a diffuse intrinsic pontine glioma mouse model.

    PubMed

    Caretti, Viola; Zondervan, Ilse; Meijer, Dimphna H; Idema, Sander; Vos, Wim; Hamans, Bob; Bugiani, Marianna; Hulleman, Esther; Wesseling, Pieter; Vandertop, W Peter; Noske, David P; Kaspers, Gertjan; Molthoff, Carla F M; Wurdinger, Thomas

    2011-07-01

    Diffuse intrinsic pontine glioma (DIPG) is a fatal malignancy because of its diffuse infiltrative growth pattern. Translational research suffers from the lack of a representative DIPG animal model. Hence, human E98 glioma cells were stereotactically injected into the pons of nude mice. The E98 DIPG tumors presented a strikingly similar histhopathology to autopsy material of a DIPG patient, including diffuse and perivascular growth, brainstem- and supratentorial invasiveness and leptomeningeal growth. Magnetic resonance imaging (MRI) was effectively employed to image the E98 DIPG tumor. [(18) F] 3'-deoxy-3'-[(18) F]fluorothymidine (FLT) positron emission tomography (PET) imaging was applied to assess the subcutaneous (s.c.) E98 tumor proliferation status but no orthotopic DIPG activity could be visualized. Next, E98 cells were cultured in vitro and engineered to express firefly luciferase and mCherry (E98-Fluc-mCherry). These cultured E98-Fluc-mCherry cells developed focal pontine glioma when injected into the pons directly. However, the diffuse E98 DIPG infiltrative phenotype was restored when cells were injected into the pons immediately after an intermediate s.c. passage. The diffuse E98-Fluc-mCherry model was subsequently used to test escalating doses of irradiation, applying the bioluminescent Fluc signal to monitor tumor recurrence over time. Altogether, we here describe an accurate DIPG mouse model that can be of clinical relevance for testing experimental therapeutics in vivo.

  19. DICER governs characteristics of glioma stem cells and the resulting tumors in xenograft mouse models of glioblastoma

    PubMed Central

    Alamsahebpour, Amir; Burrell, Kelly; Li, Mira; Karabork, Merve; Ekinci, Can; Koch, Elizabeth; Solaroglu, Ihsan; Chang, Jeffery T.; Wouters, Bradly; Aldape, Kenneth; Zadeh, Gelareh

    2016-01-01

    The RNAse III endonuclease DICER is a key regulator of microRNA (miRNA) biogenesis and is frequently decreased in a variety of malignancies. We characterized the role of DICER in glioblastoma (GB), specifically demonstrating its effects on the ability of glioma stem-like cells (GSCs) to form tumors in a mouse model of GB. DICER silencing in GSCs reduced their stem cell characteristics, while tumors arising from these cells were more aggressive, larger in volume, and displayed a higher proliferation index and lineage differentiation. The resulting tumors, however, were more sensitive to radiation treatment. Our results demonstrate that DICER silencing enhances the tumorigenic potential of GSCs, providing a platform for analysis of specific relevant miRNAs and development of potentially novel therapies against GB. PMID:27421140

  20. Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

    DTIC Science & Technology

    2012-09-01

    CONTRACTING ORGANIZATION: Duke University REPORT DATE: TYPE OF REPORT: PREPARED FOR: U.S. Army Medical Research and Materiel...display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT DATE 2. REPORT TYPE Annual 3. DATES...ABSTRACT Diffuse Intrinsic Pontine Gliomas or DIPG, is a type of brain tumor that afflicts children and is the leading cause of death in pediatric

  1. 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

  2. Induction of the fibrinolytic system by cartilage extract mediates its antiangiogenic effect in mouse glioma.

    PubMed

    Simard, Bryan; Bouamrani, Ali; Jourdes, Peggy; Pernod, Gilles; Dimitriadou, Violetta; Berger, François

    2011-07-01

    Both the antiangiogenic and antitumoral activity of shark cartilage extracts (SCE) have been demonstrated in animal models and clinical trials. Studies reported that SCE induces the expression of tissue plasminogen activator gene (PLAT) in endothelial cells and increases the activity of the protein (t-PA) in vitro. The aim of this study was to demonstrate the crucial role of t-PA induction in the antiangiogenic and antitumor activity of SCE in experimental glioma. This study showed antiangiogenic and antitumoral effects of SCE in three mice glioma models (C6, HGD and GL26). Histological examination suggested perivascular proteolysis and edema as well as important intratumoral necrosis, which artefactually increased the tumor volume at high doses. Thus, the antiangiogenic effect of SCE correlated with the presence of t-PA and angiostatin in degenerating vessels. Functional in vivo experiments were conducted to modulate the plasminogen pathway. No antiangiogenic effect was observed on tumors overexpressing the plasminogen activator inhibitor-1 (PAI-1). Moreover, therapeutical effects were neutralized in mice that were cotreated with ε-aminocaproic acid (EACA, 120 mg/kg p.o.), an inhibitor that blocks the high-affinity lysine binding sites of both plasminogen and plasmin. In contrast, cotreatment with N-acetylcysteine (NAC, 7,5mg/kg i.p.), a sulfhydril donor that reduces plasmin into angiostatin or other antiangiogenic fragments, increased the benefit of SCE on mice survival. In subcutaneous models, NAC prevented the increase in tumor volume caused by high doses of cartilage extract. In conclusion, this study indicates that induction of t-PA by shark cartilage extract plays an essential role in its antiangiogenic activity, but that control of excessive proteolysis by a plasmin reductor could prevent edema and uncover the full benefit of shark cartilage extract in the treatment of intracranial tumors.

  3. 31 CFR 358.7 - Where do I send my bearer corpora and detached bearer coupons to be converted?

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... detached bearer coupons to be converted to: Bureau of the Public Debt, Division of Customer Service, P. O... Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE...

  4. 31 CFR 358.7 - Where do I send my bearer corpora and detached bearer coupons to be converted?

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... detached bearer coupons to be converted to: Bureau of the Public Debt, Division of Customer Service, P. O... Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE...

  5. 31 CFR 358.7 - Where do I send my bearer corpora and detached bearer coupons to be converted?

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... detached bearer coupons to be converted to: Bureau of the Public Debt, Division of Customer Service, P. O... Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE...

  6. 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 to: Bureau of the Public Debt, Division of Customer Service, P. O... Relating to Money and Finance (Continued) FISCAL SERVICE, DEPARTMENT OF THE TREASURY BUREAU OF THE...

  7. 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

  8. Metallothinein 1E Enhances Glioma Invasion through Modulation Matrix Metalloproteinases-2 and 9 in U87MG Mouse Brain Tumor Model

    PubMed Central

    Hur, Hyuk; Ryu, Hyang-Hwa; Li, Chun-Hao; Kim, In Young; Jang, Woo-Youl

    2016-01-01

    Malignant glioma cells invading surrounding normal brain are inoperable and resistant to radio- and chemotherapy, and eventually lead to tumor regrowth. Identification of genes related to motility is important for understanding the molecular biological behavior of invasive gliomas. According to our previous studies, Metallothionein 1E (MT1E) was identified to enhance migration of human malignant glioma cells. The purpose of this study was to confirm that MT1E could modulate glioma invasion in vivo. Firstly we established 2 cell lines; MTS23, overexpressed by MT1E complementary DNA construct and pV12 as control. The expression of matrix metalloproteinases (MMP)-2, -9 and a disintegrin and metalloproteinase 17 were increased in MTS23 compared with pV12. Furthermore it was confirmed that MT1E could modulate MMPs secretion and translocation of NFkB p50 and B-cell lymphoma-3 through small interfering ribonucleic acid knocked U87MG cells. Then MTS23 and pV12 were injected into intracranial region of 5 week old male nude mouse. After 4 weeks, for brain tissues of these two groups, histological analysis, and immunohistochemical stain of MMP-2, 9 and Nestin were performed. As results, the group injected with MTS23 showed irregular margin and tumor cells infiltrating the surrounding normal brain, while that of pV12 (control) had round and clear margin. And regrowth of tumor cells in MTS23 group was observed in another site apart from tumor cell inoculation. MT1E could enhance tumor proliferation and invasion of malignant glioma through regulation of activation and expression of MMPs. PMID:27847566

  9. Resistance to oncolytic myxoma virus therapy in nf1(-/-)/trp53(-/-) syngeneic mouse glioma models is independent of anti-viral type-I interferon.

    PubMed

    Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing; Maxwell, Lori; Reilly, Karlyne M; McFadden, Grant; Yong, V Wee; Forsyth, Peter A

    2013-01-01

    Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1 (+/-) Trp53 (+/-) mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models.

  10. The PD-1/B7-H1 Pathway Modulates the Natural Killer Cells versus Mouse Glioma Stem Cells

    PubMed Central

    Zong, Wen Jing; Yu, Chun Jiang; Li, Jun Fa; Qu, Yan Ming; Han, Song

    2015-01-01

    Purpose Glioblastoma multiforme (GBM) is the most malignant primary type of brain tumor in adults. There has been increased focus on the immunotherapies to treat GBM patients, the therapeutic value of natural killer (NK) cells is still unknown. Programmed death-1 (PD-1) is a major immunological checkpoint that can negatively regulate the T-cell-mediated immune response. We tested the combination of the inhibiting the PD-1/B7H1 pathway with a NK-cell mediated immune response in an orthotopic mouse model of GBM. Methods and Materials Mouse glioma stem cells (GL261GSCs) and mouse NK cells were isolated and identified. A lactate dehydrogenase (LDH) assay was perfomed to detect the cytotoxicity of NK cells against GL261GSCs. GL261GSCs were intracranially implanted into mice, and the mice were stratified into 3 treatment groups: 1) control, 2) NK cells treatment, and 3) PD-1 inhibited NK cells treatment group. Overall survival was quantified, and animal magnetic resonance imaging (MRI) was performed to determine tumor growth. The brains were harvested after the mice were euthanized, and immunohistochemistry against CD45 and PCNA was performed. Results The mouse NK cells were identified as 90% CD3- NK1.1+CD335+ by flow cytometric analysis. In the LDH assay, the ratios of the damaged GL261GSCs, with the E:T ratios of 2.5:1, 5:1, and 10:1, were as follows: 1) non-inhibited group: 7.42%, 11.31%, and 15.1%, 2) B7H1 inhibited group: 14.75%, 18.25% and 29.1%, 3) PD-1 inhibited group: 15.53%, 19.21% and 29.93%, 4) double inhibited group: 33.24%, 42.86% and 54.91%. In the in vivo experiments, the mice in the PD-1 inhibited NK cells treatment group and IL-2-stimulated-NK cells treatment group displayed a slowest tumor growth (F = 308.5, P<0.01) and a slower tumor growth compared with control group (F = 118.9, P<0.01), respectively. The median survival of the mice in the three groups were as follows: 1) conrol group: 29 days, 2) NK cells treatment group: 35 days (P = 0.0012), 3) PD

  11. 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.

  12. Digital technologies as truth-bearers in health care.

    PubMed

    Bartlett, Ruth; Balmer, Andrew; Brannelly, Petula

    2017-01-01

    In this paper, we explore the idea of digital technologies as truth-bearers in health care and argue that devices like SenseCam, which facilitate reflection and memory recall, have a potentially vital role in healthcare situations when questions of veracity are at stake (e.g., when best interest decisions are being made). We discuss the role of digital technologies as truth-bearers in the context of nursing people with dementia, as this is one area of health care in which the topic of truth-telling has been hotly debated. People with dementia have been excluded from research studies and decisions that affect their lives because they are not regarded as truth-bearers-that is, as being capable of giving truthful accounts of their experiences. Also, considerable research has focused on the ethics of lying to and deceiving people with dementia. Given their increasing prominence in healthcare settings, there has been surprisingly little discussion of what role digital technologies might play in relation to these questions of truth and deception. Drawing on theories from science and technology studies (STS), we explore their possible future role in some of the truth-making processes of health care. In particular, we discuss the potential value of constraints on use of SenseCam to support the accounts of people with dementia as part of their care.

  13. Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model.

    PubMed

    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.

  14. 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

  15. Resistance to Oncolytic Myxoma Virus Therapy in Nf1−/−/Trp53−/− Syngeneic Mouse Glioma Models Is Independent of Anti-Viral Type-I Interferon

    PubMed Central

    Zemp, Franz J.; McKenzie, Brienne A.; Lun, Xueqing; Maxwell, Lori; Reilly, Karlyne M.; McFadden, Grant; Yong, V. Wee; Forsyth, Peter A.

    2013-01-01

    Despite promising preclinical studies, oncolytic viral therapy for malignant gliomas has resulted in variable, but underwhelming results in clinical evaluations. Of concern are the low levels of tumour infection and viral replication within the tumour. This discrepancy between the laboratory and the clinic could result from the disparity of xenograft versus syngeneic models in determining in vivo viral infection, replication and treatment efficacy. Here we describe a panel of primary mouse glioma lines derived from Nf1+/−Trp53+/− mice in the C57Bl/6J background for use in the preclinical testing of the oncolytic virus Myxoma (MYXV). These lines show a range of susceptibility to MYXV replication in vitro, but all succumb to viral-mediated cell death. Two of these lines orthotopically grafted produced aggressive gliomas. Intracranial injection of MYXV failed to result in sustained viral replication or treatment efficacy, with minimal tumour infection that was completely resolved by 7 days post-infection. We hypothesized that the stromal production of Type-I interferons (IFNα/β) could explain the resistance seen in these models; however, we found that neither the cell lines in vitro nor the tumours in vivo produce any IFNα/β in response to MYXV infection. To confirm IFNα/β did not play a role in this resistance, we ablated the ability of tumours to respond to IFNα/β via IRF9 knockdown, and generated identical results. Our studies demonstrate that these syngeneic cell lines are relevant preclinical models for testing experimental glioma treatments, and show that IFNα/β is not responsible for the MYXV treatment resistance seen in syngeneic glioma models. PMID:23762429

  16. ET-39REPEATED PHARMACOLOGICAL DOSES OF ASCORBATE PROTECTS TUMOURS FROM RADIATION DAMAGE IN AN INTRACRANIAL MOUSE GLIOMA MODEL

    PubMed Central

    McConnell, Melanie; Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah; Castro, Leticia; Schleich, Nanette; Herst, Patries

    2014-01-01

    High dose ascorbate is used as an anti-cancer treatment by complementary and alternative medicine. In the acidic, metal-rich tumour environment ascorbate acts as a pro-oxidant, generating free radicals and DNA damage, similar to ionising radiation. We showed that addition of high-dose ascorbate to radiation blocked repair of radiation-induced DNA damage in primary GBM cell lines, effectively radio-sensitising. We examined the effect of ascorbate and radiation on the murine glioma GL261 in vitro, and combined with intra-peritoneal ascorbate in an intra-cranial GL261 model. As previously seen, high dose ascorbate radio-sensitized GL261 cells in a clonogenicity assay. Tumour-bearing mice were treated with: 4.5Gy to the brain 8 days post-implantation; repeated high-dose ascorbate from day 8-45; both treatments; or no treatment. While radiation increased survival, intraperitoneal ascorbate alone had no effect. In contrast with in vitro data, tumour-bearing mice treated with radiation and daily ascorbate had poorer survival than those treated with radiation alone. Histological analysis of the tumours showed less necrosis and bleeding within tumours treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. While the mechanism of protection is not yet defined, this finding might have important clinical implications for combining high-dose ascorbate with radiation therapy.

  17. 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

  18. 18F-AFETP, 18F-FET, and 18F-FDG Imaging of Mouse DBT Gliomas

    PubMed Central

    Sai, Kiran Kumar Solingapuram; Huang, Chaofeng; Yuan, Liya; Zhou, Dong; Piwnica-Worms, David; Garbow, Joel R.; Engelbach, John A.; Mach, Robert H.; Rich, Keith M.; McConathy, Jonathan

    2013-01-01

    The goal of this study was to evaluate the 18F-labeled nonnatural amino acid (S)-2-amino-3-[1-(2-18F-fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (18F-AFETP) as a PET imaging agent for brain tumors and to compare its effectiveness with the more-established tracers O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) and 18F-FDG in a murine model of glioblastoma. The tracer 18F-AFETP is a structural analog of histidine and is a lead compound for imaging cationic amino acid transport, a relatively unexplored target for oncologic imaging. Methods 18F-AFETP was prepared using the click reaction. BALB/c mice with intracranially implanted delayed brain tumor (DBT) gliomas (n = 4) underwent biodistribution and dynamic small-animal PET imaging for 60 min after intravenous injection of 18F-AFETP. Tumor and brain uptake of 18F-AFETP were compared with those of 18F-FDG and 18F-FET through small-animal PET analyses. Results 18F-AFETP demonstrated focally increased uptake in tumors with good visualization. Peak tumor uptake occurred within 10 min of injection, with stable or gradual decrease over time. All 3 tracers demonstrated relatively high uptake in the DBTs throughout the study. At late time points (47.5–57.5 min after injection), the average standardized uptake value with 18F-FDG (1.9 ± 0.1) was significantly greater than with 18F-FET (1.1 ± 0.1) and 18F-AFETP (0.7 ± 0.2). The uptake also differed substantially in normal brain, with significant differences in the standardized uptake values at late times among 18F-FDG (1.5 ± 0.2), 18F-FET (0.5 ± 0.05), and 18F-AFETP (0.1 ± 0.04). The resulting average tumor-to-brain ratio at the late time points was significantly higher for 18F-AFETP (7.5 ± 0.1) than for 18F-FDG (1.3 ± 0.1) and 18F-FET (2.0 ± 0.3). Conclusion 18F-AFETP is a promising brain tumor imaging agent, providing rapid and persistent tumor visualization, with good tumor–to–normal-brain ratios in the DBT glioma model. High tumor-to-brain, tumor

  19. 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

  20. 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

  1. 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

  2. MEF promotes stemness in the pathogenesis of gliomas.

    PubMed

    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

    2012-12-07

    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 gliomas. We found that MEF is highly expressed in both human and mouse glioblastomas 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 that promotes stem cell characteristics through Sox2 activation.

  3. Genetics of adult glioma.

    PubMed

    Goodenberger, McKinsey L; Jenkins, Robert B

    2012-12-01

    Gliomas make up approximately 30% of all brain and central nervous system tumors and 80% of all malignant brain tumors. Despite the frequency of gliomas, the etiology of these tumors remains largely unknown. Diffuse gliomas, including astrocytomas and oligodendrogliomas, belong to a single pathologic class but have very different histologies and molecular etiologies. Recent genomic studies have identified separate molecular subtypes within the glioma classification that appear to correlate with biological etiology, prognosis, and response to therapy. The discovery of these subtypes suggests that molecular genetic tests are and will be useful, beyond classical histology, for the clinical classification of gliomas. While a familial susceptibility to glioma has been identified, only a small percentage of gliomas are thought to be due to single-gene hereditary cancer syndromes. Through the use of linkage studies and genome-wide association studies, multiple germline variants have been identified that are beginning to define the genetic susceptibility to glioma.

  4. Endogenous GABAA receptor activity suppresses glioma growth.

    PubMed

    Blanchart, A; Fernando, R; Häring, M; Assaife-Lopes, N; Romanov, R A; Andäng, M; Harkany, T; Ernfors, P

    2017-02-09

    Although genome alterations driving glioma by fueling cell malignancy have largely been resolved, less is known of the impact of tumor environment on disease progression. Here, we demonstrate functional GABAA receptor-activated currents in human glioblastoma cells and show the existence of a continuous GABA signaling within the tumor cell mass that significantly affects tumor growth and survival expectancy in mouse models. Endogenous GABA released by tumor cells, attenuates proliferation of the glioma cells with enriched expression of stem/progenitor markers and with competence to seed growth of new tumors. Our results suggest that GABA levels rapidly increase in tumors impeding further growth. Thus, shunting chloride ions by a maintained local GABAA receptor activity within glioma cells has a significant impact on tumor development by attenuating proliferation, reducing tumor growth and prolonging survival, a mechanism that may have important impact on therapy resistance and recurrence following tumor resection.

  5. Epidemiology of gliomas.

    PubMed

    Ostrom, Quinn T; Gittleman, Haley; Stetson, Lindsay; Virk, Selene M; Barnholtz-Sloan, Jill S

    2015-01-01

    Gliomas are the most common type of primary intracranial tumors. Some glioma subtypes cause significant mortality and morbidity that are disproportionate to their relatively rare incidence. A very small proportion of glioma cases can be attributed to inherited genetic disorders. Many potential risk factors for glioma have been studied to date, but few provide explanation for the number of brain tumors identified. The most significant of these factors includes increased risk due to exposure to ionizing radiation, and decreased risk with history of allergy or atopic disease. The potential effect of exposure to cellular phones has been studied extensively, but the results remain inconclusive. Recent genomic analyses, using the genome-wide association study (GWAS) design, have identified several inherited risk variants that are associated with increased glioma risk. The following chapter provides an overview of the current state of research in the epidemiology of intracranial glioma.

  6. Antitumor activity of (R,R')-4-methoxy-1-naphthylfenoterol in a rat C6 glioma xenograft model in the mouse.

    PubMed

    Bernier, Michel; Paul, Rajib K; Dossou, Katina S S; Wnorowski, Artur; Ramamoorthy, Anuradha; Paris, Arnaud; Moaddel, Ruin; Cloix, Jean-François; Wainer, Irving W

    2013-12-01

    (R,R')-4-methoxy-1-naphthylfenoterol (MNF) inhibits cancer cell proliferation in vitro through cell-type specific modulation of β2-adrenergic receptor and/or cannabinoid receptor function. Here, we report an investigation into antitumor activity of MNF in rat C6 glioma cells. The potent antiproliferative action of MNF in these cells (IC50 of ∼1 nmol/L) was refractory to pharmacological inhibition of β2-adrenergic receptor while a synthetic inverse agonist of cannabinoid receptor 1 significantly blocked MNF activity. The antitumor activity of MNF was then assessed in a C6 glioblastoma xenograft model in mice. Three days after subcutaneous implantation of C6 cells into the lower flank of nude mice, these animals were subjected to i.p. injections of saline or MNF (2 mg/kg) for 19 days and tumor volumes were measured over the course of the experiment. Gene expression analysis, quantitative RT-PCR and immunoblot assays were performed on the tumors after treatment. Significant reduction in mean tumor volumes was observed in mice receiving MNF when compared with the saline-treated group. We identified clusters in expression of genes involved in cellular proliferation, as well as molecular markers for glioblastoma that were significantly downregulated in tumors of MNF-treated mice as compared to saline-injected controls. The efficacy of MNF against C6 glioma cell proliferation in vivo and in vitro was accompanied by marked reduction in the expression of cell cycle regulator proteins. This study is the first demonstration of MNF-dependent chemoprevention of a glioblastoma xenograft model and may offer a potential mechanism for its anticancer action in vivo.

  7. Antitumor activity of (R,R’)-4-methoxy-1-naphthylfenoterol in a rat C6 glioma xenograft model in the mouse

    PubMed Central

    Bernier, Michel; Paul, Rajib K; Dossou, Katina S S; Wnorowski, Artur; Ramamoorthy, Anuradha; Paris, Arnaud; Moaddel, Ruin; Cloix, Jean-François; Wainer, Irving W

    2013-01-01

    (R,R’)-4-methoxy-1-naphthylfenoterol (MNF) inhibits cancer cell proliferation in vitro through cell-type specific modulation of β2-adrenergic receptor and/or cannabinoid receptor function. Here, we report an investigation into antitumor activity of MNF in rat C6 glioma cells. The potent antiproliferative action of MNF in these cells (IC50 of ∼1 nmol/L) was refractory to pharmacological inhibition of β2-adrenergic receptor while a synthetic inverse agonist of cannabinoid receptor 1 significantly blocked MNF activity. The antitumor activity of MNF was then assessed in a C6 glioblastoma xenograft model in mice. Three days after subcutaneous implantation of C6 cells into the lower flank of nude mice, these animals were subjected to i.p. injections of saline or MNF (2 mg/kg) for 19 days and tumor volumes were measured over the course of the experiment. Gene expression analysis, quantitative RT-PCR and immunoblot assays were performed on the tumors after treatment. Significant reduction in mean tumor volumes was observed in mice receiving MNF when compared with the saline-treated group. We identified clusters in expression of genes involved in cellular proliferation, as well as molecular markers for glioblastoma that were significantly downregulated in tumors of MNF-treated mice as compared to saline-injected controls. The efficacy of MNF against C6 glioma cell proliferation in vivo and in vitro was accompanied by marked reduction in the expression of cell cycle regulator proteins. This study is the first demonstration of MNF-dependent chemoprevention of a glioblastoma xenograft model and may offer a potential mechanism for its anticancer action in vivo. PMID:25505565

  8. A glioma classification scheme based on coexpression modules of EGFR and PDGFRA.

    PubMed

    Sun, Yingyu; Zhang, Wei; Chen, Dongfeng; Lv, Yuhong; Zheng, Junxiong; Lilljebjörn, Henrik; Ran, Liang; Bao, Zhaoshi; Soneson, Charlotte; Sjögren, Hans Olov; Salford, Leif G; Ji, Jianguang; French, Pim J; Fioretos, Thoas; Jiang, Tao; Fan, Xiaolong

    2014-03-04

    We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM(low)PM(low) gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM(low)PM(low) gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM(low)PM(low) gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtype-specific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

  9. Glioma associated microglial MMP9 expression is up regulated by TLR2 signalling and sensitive to minocycline

    PubMed Central

    Hu, Feng; Ku, Min-Chi; Markovic, Darko; Dzaye, Omar Dildar a; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne A.; Kettenmann, Helmut

    2014-01-01

    The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix-metalloprotease 2, matrix-metalloprotease 9 and membrane-type 1 matrix metalloprotease. In this work we demonstrate that, matrix-metalloprotease 9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of matrix-metalloprotease 9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signalling pathway for the glioma induced upregulation of microglial matrix-metalloprotease 9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial matrix-metalloprotease 9. Moreover, glioma supernatant triggered an upregulation of Toll-like receptor 2 expression in microglia. Both, the upregulation of matrix-metalloprotease 9 and Toll-like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signalling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy. PMID:24752463

  10. Molecular neuropathology of gliomas.

    PubMed

    Riemenschneider, Markus J; Reifenberger, Guido

    2009-01-01

    Gliomas are the most common primary human brain tumors. They comprise a heterogeneous group of benign and malignant neoplasms that are histologically classified according to the World Health Organization (WHO) classification of tumors of the nervous system. Over the past 20 years the cytogenetic and molecular genetic alterations associated with glioma formation and progression have been intensely studied and genetic profiles as additional aids to the definition of brain tumors have been incorporated in the WHO classification. In fact, first steps have been undertaken in supplementing classical histopathological diagnosis by the use of molecular tests, such as MGMT promoter hypermethylation in glioblastomas or detection of losses of chromosome arms 1p and 19q in oligodendroglial tumors. The tremendous progress that has been made in the use of array-based profiling techniques will likely contribute to a further molecular refinement of glioma classification and lead to the identification of glioma core pathways that can be specifically targeted by more individualized glioma therapies.

  11. 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.

  12. Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells

    PubMed Central

    Lin, Hua; Patel, Shaan; Affleck, Valerie S.; Wilson, Ian; Turnbull, Douglass M.; Joshi, Abhijit R.; Maxwell, Ross

    2017-01-01

    Background. Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells. Methods. We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention. Results. We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma. Conclusions. Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice. PMID:27365097

  13. 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.

  14. 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.

  15. 31 CFR 358.19 - Who is responsible for any loss resulting from the conversion of a bearer corpus missing callable...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... resulting from the conversion of a bearer corpus missing callable coupons? 358.19 Section 358.19 Money and... TREASURY BUREAU OF THE PUBLIC DEBT REGULATIONS GOVERNING BOOK-ENTRY CONVERSION OF BEARER CORPORA AND... corpus missing callable coupons? The submitting depository institution shall indemnify the United...

  16. Radiation-induced gliomas

    PubMed Central

    Prasad, Gautam; Haas-Kogan, Daphne A.

    2013-01-01

    Radiation-induced gliomas represent a relatively rare but well-characterized entity in the neuro-oncologic literature. Extensive retrospective cohort data in pediatric populations after therapeutic intracranial radiation show a clearly increased risk in glioma incidence that is both patient age- and radiation dose/volume-dependent. Data in adults are more limited but show heightened risk in certain groups exposed to radiation. In both populations, there is no evidence linking increased risk associated with routine exposure to diagnostic radiation. At the molecular level, recent studies have found distinct genetic differences between radiation-induced gliomas and their spontaneously-occurring counterparts. Clinically, there is understandable reluctance on the part of clinicians to re-treat patients due to concern for cumulative neurotoxicity. However, available data suggest that aggressive intervention can lead to improved outcomes in patients with radiation-induced gliomas. PMID:19831840

  17. 48 CFR 252.247-7003 - Pass-Through of Motor Carrier Fuel Surcharge Adjustment To The Cost Bearer.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 3 2010-10-01 2010-10-01 false Pass-Through of Motor... SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions And Clauses 252.247-7003 Pass-Through of Motor...: PASS-THROUGH OF MOTOR CARRIER FUEL SURCHARGE ADJUSTMENT TO THE COST BEARER (SEP 2010) (a) This...

  18. 31 CFR 306.27 - Redemption of bearer securities at maturity, upon prior call, or for advance refunding or...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... maturity, upon prior call, or for advance refunding or prerefunding. 306.27 Section 306.27 Money and... § 306.27 Redemption of bearer securities at maturity, upon prior call, or for advance refunding or prerefunding. All interest coupons due and payable on or before the date of maturity or date fixed in the...

  19. Expression of TIP-1 Confers Radioresistance of Malignant Glioma Cells

    PubMed Central

    Han, Miaojun; Wang, Hailun; Zhang, Hua-Tang; Han, Zhaozhong

    2012-01-01

    Background Malignant gliomas represent one group of tumors that poorly respond to ionizing radiation (IR) alone or combined with chemotherapeutic agents because of the intrinsic or acquired resistance. In this study, TIP-1 was identified as one novel protein that confers resistance of glioma cells to IR. Methodology/Principal Findings Meta-analysis indicated that high TIP-1 expression levels correlate with the poor prognosis of human malignant gliomas after radiotherapy. Studies with established human glioma cell lines demonstrated that TIP-1 depletion with specific shRNAs sensitized the cells to IR, whereas an ectopic expression of TIP-1 protected the glioma cells from the IR-induced DNA damage and cell death. Biochemical studies indicated that TIP-1 protein promoted p53 ubiquitination and resulted in a reduced p53 protein level. Furthermore, p53 and its ubiquitination are required for the TIP-1 regulated cellular response to IR. A yeast two-hybrid screening identified that TIP-1, through its single PDZ domain, binds to the carboxyl terminus of LZAP that has been studied as one tumor suppressor functioning through ARF binding and p53 activation. It was revealed that the presence of TIP-1 enhances the protein association between LZAP and ARF and modulates the functionality of ARF/HDM2 toward multi-ubiquitination of p53, while depleting TIP-1 rescued p53 from polyubiquitination and degradation in the irradiated glioma cells. Studies with a mouse xenograft model indicated that depleting TIP-1 within D54 cells improved the tumor growth control with IR. Conclusions/Significance This study provided the first evidence showing that TIP-1 modulates p53 protein stability and is involved in the radioresistance of malignant gliomas, suggesting that antagonizing TIP-1 might be one novel approach to sensitize malignant gliomas to radiotherapy. PMID:23028987

  20. 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.

  1. Smoking and Glioma Risk

    PubMed Central

    Shao, Chuan; Zhao, Wei; Qi, Zhenyu; He, Jiaquan

    2016-01-01

    Abstract To systematically assess the relationship between smoking and glioma risk. A dose–response meta-analysis of case–control and cohort studies was performed. Pertinent studies were identified by searching database and reference lists. Random-effects model was employed to pool the estimates of the relative risks (RRs) with corresponding 95% confidence intervals (CIs). A total of 19 case–control and 6 cohort studies were included. Overall, compared with those who never smoked, the pooled RR and 95% CI was 0.98 (0.92–1.05) for ever smoker. The subgroups were not significantly different regarding risk of glioma except the group of age at start smoking (RR = 1.17, 95% CI: 0.93–1.48 for age < 20; RR = 1.25, 95% CI: 1.02–1.52 for age ≥ 20). Dose–response analysis also suggested no significant association between smoking and the risk of glioma, although some evidence for a linear relationship between smoking and glioma risk was observed. In conclusion, this meta-analysis provides little support for a causal relationship between smoking and risk of glioma. PMID:26765433

  2. 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

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

    ClinicalTrials.gov

    2017-01-30

    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

  4. Pten signaling in gliomas.

    PubMed Central

    Knobbe, Christiane B.; Merlo, Adrian; Reifenberger, Guido

    2002-01-01

    In 1997, the PTEN gene (phosphatase and tensin homolog deleted on chromosome 10) was identified as a tumor suppressor gene on the long arm of chromosome 10. Since then, important progress has been made with respect to the understanding of the role of the Pten protein in the normal development of the brain as well as in the molecular pathogenesis of human gliomas. This review summarizes the current state of the art concerning the involvement of aberrant Pten function in the development of different biologic features of malignant gliomas, such as loss of cell-cycle control and uncontrolled cell proliferation, escape from apoptosis, brain invasion, and aberrant neoangiogenesis. Most of the tumor-suppressive properties of Pten are dependent on its lipid phosphatase activity, which inhibits the phosphatidylinositol-3'-kinase (PI3K)/Akt signaling pathway through dephosphorylation of phosphatidylinositol-(3,4,5)-triphosphate. The additional function of Pten as a dual-specificity protein phosphatase may also play a role in glioma pathogenesis. Besides the wealth of data elucidating the functional roles of Pten, recent studies suggest a diagnostic significance of PTEN gene alterations as a molecular marker for poor prognosis in anaplastic astrocytomas and anaplastic oligodendrogliomas. Furthermore, the possibility of selective targeting of PTEN mutant tumor cells by specific pharmacologic inhibitors of members of the Pten/PI3K/Akt pathway opens up new perspectives for a targeted molecular therapy of malignant gliomas. PMID:12084351

  5. 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

  6. Anti-tumor activity of phenoxybenzamine hydrochloride on malignant glioma cells.

    PubMed

    Lin, Xian-Bin; Jiang, Lei; Ding, Mao-Hua; Chen, Zhen-Hua; Bao, Yi; Chen, Yi; Sun, Wei; Zhang, Chen-Ran; Hu, Hong-Kang; Cai, Zhen; Lu, Cheng-Yin; Zhou, Jue-Yu; Qian, Jun; Wu, Xiao-Jun; Jin, Wei-Lin; Hu, Guo-Han

    2016-03-01

    Phenoxybenzamine hydrochloride (PHEN) is a selective antagonist of both α-adrenoceptor and calmodulin that exhibits anticancer properties. The aim of this study was to explore the anti-tumor function of PHEN in glioma. Cell proliferation assay was used to assess glioma cell growth. Migration and invasion capacity of glioma cells was monitored by wound-healing and transwell assay, respectively. Neurosphere formation test was adopted for the tumorigenesis of glioma cells, which was also confirmed by soft agar cloning formation test in vitro and a nude mouse model in vivo. Finally, we explored the potential pathway utilized by PHEN using Western blot and immunofluoresce staining. PHEN exhibited a significant inhibitory effect on the proliferation of both U251 and U87MG glioma cell lines in a positive dose-dependent manner. PHEN apparently attenuated the malignancy of glioma in terms of migration and invasion and also suppressed the tumorigenic capacity both in vitro and in vivo. Mechanism study showed that PHEN promoted tumor suppression by inhibiting the TrkB-Akt pathway. The results of the present study demonstrated that PHEN suppressed the proliferation, migration, invasion, and tumorigenesis of glioma cells, induced LINGO-1 expression, and inhibited the TrkB-Akt pathway, which may prove to be the mechanisms underlying the anti-tumor effect of PHEN on glioma cells.

  7. Mechanisms of Glioma Formation: Iterative Perivascular Glioma Growth and Invasion Leads to Tumor Progression, VEGF-Independent Vascularization, and Resistance to Antiangiogenic Therapy12

    PubMed Central

    Baker, Gregory J.; Yadav, Viveka Nand; Motsch, Sebastien; Koschmann, Carl; Calinescu, Anda-Alexandra; Mineharu, Yohei; Camelo-Piragua, Sandra Ines; Orringer, Daniel; Bannykh, Serguei; Nichols, Wesley S.; deCarvalho, Ana C.; Mikkelsen, Tom; Castro, Maria G.; Lowenstein, Pedro R.

    2014-01-01

    As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain. Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients. PMID:25117977

  8. Akt- or MEK-mediated mTOR inhibition suppresses Nf1 optic glioma growth

    PubMed Central

    Kaul, Aparna; Toonen, Joseph A.; Cimino, Patrick J.; Gianino, Scott M.; Gutmann, David H.

    2015-01-01

    Background Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. Methods Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma–bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. Results Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma–associated retinal ganglion cell loss and nerve fiber layer thinning. Conclusion These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1–optic pathway glioma clinical trials. PMID:25534823

  9. 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

  10. Inherited predisposition to glioma

    PubMed Central

    Kyritsis, Athanassios P.; Bondy, Melissa L.; Rao, Jasti S.; Sioka, Chrissa

    2010-01-01

    In gliomas, germline gene alterations play a significant role during malignant transformation of progenitor glial cells, at least for families with occurrence of multiple cancers or with specific hereditary cancer syndromes. Scientific evidence during the last few years has revealed several constitutive genetic abnormalities that may influence glioma formation. These germline abnormalities are manifested as either gene polymorphisms or hemizygous mutations of key regulatory genes that are involved either in DNA repair or in apoptosis. Such changes, among others, include hemizygous alterations of the neurofibromatosis 1 (NF1) and p53 genes that are involved in apoptotic pathways, and alterations in multiple DNA repair genes such as mismatch repair (MMR) genes, x-ray cross-complementary genes (XRCC), and O6-methylguanine-DNA methyltransferase (MGMT) genes. Subsequent cellular changes include somatic mutations in cell cycle regulatory genes and genes involved in angiogenesis and invasion, leading eventually to tumor formation in various stages. Future molecular diagnosis may identify new genomic regions that could harbor genes important for glioma predisposition and aid in the early diagnosis of these patients and genetic counseling of their families. PMID:20150373

  11. Canine spinal cord glioma.

    PubMed

    Rissi, Daniel R; Barber, Renee; Burnum, Annabelle; Miller, Andrew D

    2017-01-01

    Spinal cord glioma is uncommonly reported in dogs. We describe the clinicopathologic and diagnostic features of 7 cases of canine spinal cord glioma and briefly review the veterinary literature on this topic. The median age at presentation was 7.2 y. Six females and 1 male were affected and 4 dogs were brachycephalic. The clinical course lasted from 3 d to 12 wk, and clinical signs were progressive and associated with multiple suspected neuroanatomic locations in the spinal cord. Magnetic resonance imaging of 6 cases revealed T2-weighted hyperintense lesions with variable contrast enhancement in the spinal cord. All dogs had a presumptive clinical diagnosis of intraparenchymal neoplasia or myelitis based on history, advanced imaging, and cerebrospinal fluid analysis. Euthanasia was elected in all cases because of poor outcome despite anti-inflammatory or immunosuppressive treatment or because of poor prognosis at the time of diagnosis. Tumor location during autopsy ranged from C1 to L6, with no clear predilection for a specific spinal cord segment. The diagnosis was based on histopathology and the immunohistochemistry expression of glial fibrillary acidic protein, oligodendrocyte lineage transcription factor 2, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, neuron-specific enolase, synaptophysin, and Ki-67. Diagnoses consisted of 4 cases of oligodendroglioma, 2 cases of gliomatosis cerebri, and 1 astrocytoma. This case series further defines the clinicopathologic features of canine spinal glioma and highlights the need for comprehensive immunohistochemistry in addition to routine histopathology to confirm the diagnosis of these tumors.

  12. 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.

  13. Microscopic DTI accurately identifies early glioma cell migration: correlation with multimodal imaging in a new glioma stem cell model.

    PubMed

    Gimenez, Ulysse; Perles-Barbacaru, Adriana-T; Millet, Arnaud; Appaix, Florence; El-Atifi, Michele; Pernet-Gallay, Karin; van der Sanden, Boudewijn; Berger, François; Lahrech, Hana

    2016-11-01

    Monitoring glioma cell infiltration in the brain is critical for diagnosis and therapy. Using a new glioma Glio6 mouse model derived from human stem cells we show how diffusion tensor imaging (DTI) may predict glioma cell migration/invasion. In vivo multiparametric MRI was performed at one, two and three months of Glio6 glioma growth (Glio6 (n = 6), sham (n = 3)). This longitudinal study reveals the existence of a time window to study glioma cell/migration/invasion selectively. Indeed, at two months only Glio6 cell invasion was detected, while tumor mass formation, edema, blood-brain barrier leakage and tumor angiogenesis were detected later, at three months. To robustly confirm the potential of DTI for detecting glioma cell migration/invasion, a microscopic 3D-DTI (80 μm isotropic spatial resolution) technique was developed and applied to fixed mouse brains (Glio6 (n = 6), sham (n = 3)). DTI changes were predominant in the corpus callosum (CC), a known path of cell migration. Fractional anisotropy (FA) and perpendicular diffusivity (D⊥ ) changes derived from ex vivo microscopic 3D-DTI were significant at two months of tumor growth. In the caudate putamen an FA increase of +38% (p < 0.001) was observed, while in the CC a - 28% decrease in FA (p < 0.005) and a + 95% increase in D⊥ (p < 0.005) were observed. In the CC, DTI changes and fluorescent Glio6 cell density obtained by two-photon microscopy in the same brains were correlated (p < 0.001, r = 0.69), validating FA and D⊥ as early quantitative biomarkers to detect glioma cell migration/invasion. The origin of DTI changes was assessed by electron microscopy of the same tract, showing axon bundle disorganization. During the first two months, Glio6 cells display a migratory phenotype without being associated with the constitution of a brain tumor mass. This offers a unique opportunity to apply microscopic 3D-DTI and to validate DTI parameters FA and D⊥ as biomarkers for glioma cell

  14. 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.

  15. Cellular factors promoting resistance to effective treatment of glioma with oncolytic myxoma virus.

    PubMed

    Zemp, Franz J; McKenzie, Brienne A; Lun, Xueqing; Reilly, Karlyne M; McFadden, Grant; Yong, V Wee; Forsyth, Peter A

    2014-12-15

    Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.

  16. 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

  17. 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.

  18. A dual PI3K/mTOR inhibitor, PI-103, cooperates with stem cell-delivered TRAIL in experimental glioma models.

    PubMed

    Bagci-Onder, Tugba; Wakimoto, Hiroaki; Anderegg, Maarten; Cameron, Cody; Shah, Khalid

    2011-01-01

    The resistance of glioma cells to a number of antitumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133(+) glioma-initiating cells and explored the potential of combining PI-103 with stem cell-delivered secretable tumor necrosis factor apoptosis-inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G(0)-G(1) arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell-delivered S-TRAIL. Using bimodal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas.

  19. Effects of Long-term Physical Training on the Bearers of a Float during the Nagasaki Kunchi Festival

    PubMed Central

    Shibata, Shigemori; Kawano, Hiroaki; Maemura, Koji

    2017-01-01

    Objective The Nagasaki Kunchi Festival is one of the most famous festivals in Nagasaki. The bearers the floats that are used in this festival undergo long-term training for the performance. However, there have not been any studies on the effects of this training on the health of the float bearers. Methods Thirty-four men ranging in age from 20 to 49 years (mean age: 35.7±7.6 years) were included in the study. We examined the following parameters before and after the training: body weight (BW), body mass index (BMI), body fat percentage, muscle volume, systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse rate (PR), pulse pressure (PP), bearing power, arterial pressure volume index (API), and arterial velocity pulse index (AVI). Results For all participants, the BW, BMI, body fat percentage, and PR were significantly decreased, and the muscle volume and bearing power were significantly increased after the training; however, there were no significant changes in the SBP, DBP, PP, API, or AVI. In the participants with hypertension, in addition to decreases in BW, BMI, body fat percentage, PR, and PP, the SBP, DBP, and API were significantly decreased after the training. Conclusion Training for bearing a float during Nagasaki Kunchi effectively improved the body structure of all participants and reduced the BP and API in participants with hypertension. PMID:28049988

  20. 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

  1. Myxoma Virus Infection Promotes NK Lysis of Malignant Gliomas In Vitro and In Vivo

    PubMed Central

    Ogbomo, Henry; Zemp, Franz J.; Lun, Xueqing; Zhang, Jiqing; Stack, Danuta; Rahman, Masmudur M.; Mcfadden, Grant; Mody, Christopher H.; Forsyth, Peter A.

    2013-01-01

    Myxoma virus (MYXV) is a well-established oncolytic agent against different types of tumors. MYXV is also known for its immunomodulatory properties in down-regulating major histocompatibility complex (MHC) I surface expression (via the M153R gene product, a viral E3-ubiquitin ligase) and suppressing T cell killing of infected target cells. MHC I down-regulation, however, favors NK cell activation. Brain tumors including gliomas are characterized by high MHC I expression with impaired NK activity. We thus hypothesized that MYXV infection of glioma cells will promote NK cell-mediated recognition and killing of gliomas. We infected human gliomas with MYXV and evaluated their susceptibility to NK cell-mediated cytotoxicity. MYXV enhanced NK cell-mediated killing of glioma cells (U87 cells, MYXV vs. Mock: 51.73% vs. 28.63%, P = .0001, t test; U251 cells, MYXV vs. Mock: 40.4% vs. 20.03%, P .0007, t test). Using MYXV M153R targeted knockout (designated vMyx-M153KO) to infect gliomas, we demonstrate that M153R was responsible for reduced expression of MHC I on gliomas and enhanced NK cell-mediated antiglioma activity (U87 cells, MYXV vs. vMyx-M153KO: 51.73% vs. 25.17%, P = .0002, t test; U251 cells, MYXV vs. vMyx-M153KO: 40.4% vs. 19.27, P = .0013, t test). Consequently, NK cell-mediated lysis of established human glioma tumors in CB-17 SCID mice was accelerated with improved mouse survival (log-rank P = .0072). These results demonstrate the potential for combining MYXV with NK cells to effectively kill malignant gliomas. PMID:23762498

  2. Myxoma virus infection promotes NK lysis of malignant gliomas in vitro and in vivo.

    PubMed

    Ogbomo, Henry; Zemp, Franz J; Lun, Xueqing; Zhang, Jiqing; Stack, Danuta; Rahman, Masmudur M; McFadden, Grant; Mody, Christopher H; Forsyth, Peter A

    2013-01-01

    Myxoma virus (MYXV) is a well-established oncolytic agent against different types of tumors. MYXV is also known for its immunomodulatory properties in down-regulating major histocompatibility complex (MHC) I surface expression (via the M153R gene product, a viral E3-ubiquitin ligase) and suppressing T cell killing of infected target cells. MHC I down-regulation, however, favors NK cell activation. Brain tumors including gliomas are characterized by high MHC I expression with impaired NK activity. We thus hypothesized that MYXV infection of glioma cells will promote NK cell-mediated recognition and killing of gliomas. We infected human gliomas with MYXV and evaluated their susceptibility to NK cell-mediated cytotoxicity. MYXV enhanced NK cell-mediated killing of glioma cells (U87 cells, MYXV vs. Mock: 51.73% vs. 28.63%, P = .0001, t test; U251 cells, MYXV vs. Mock: 40.4% vs. 20.03%, P .0007, t test). Using MYXV M153R targeted knockout (designated vMyx-M153KO) to infect gliomas, we demonstrate that M153R was responsible for reduced expression of MHC I on gliomas and enhanced NK cell-mediated antiglioma activity (U87 cells, MYXV vs. vMyx-M153KO: 51.73% vs. 25.17%, P = .0002, t test; U251 cells, MYXV vs. vMyx-M153KO: 40.4% vs. 19.27, P = .0013, t test). Consequently, NK cell-mediated lysis of established human glioma tumors in CB-17 SCID mice was accelerated with improved mouse survival (log-rank P = .0072). These results demonstrate the potential for combining MYXV with NK cells to effectively kill malignant gliomas.

  3. Glutamine Metabolism in Gliomas.

    PubMed

    Szeliga, Monika; Albrecht, Jan

    2016-01-01

    By histological, morphological criteria, and malignancy, brain tumors are classified by WHO into grades I (most benign) to IV (highly malignant), and gliomas are the most frequently occurring class throughout the grades. Similar to peripheral tumors, the growth of glia-derived tumor cells largely depends on glutamine (Gln), which is vividly taken up by the cells, using mostly ASCT2 and SN1 as Gln carriers. Tumor growth-promoting effects of Gln are associated with its phosphate-activated glutaminase (GA) (specifically KGA)-mediated degradation to glutamate (Glu) and/or with its entry to the energy- and intermediate metabolite-generating pathways related to the tricarboxylic acid cycle. However, a subclass of liver-type GA are absent in glioma cells, a circumstance which allows phenotype manipulations upon their transfection to the cells. Gln-derived Glu plays a major role in promoting tumor proliferation and invasion. Glu is relatively inefficiently recycled to Gln and readily leaves the cells by exchange with the extracellular pool of the glutathione (GSH) precursor Cys mediated by xc- transporter. This results in (a) cell invasion-fostering interaction of Glu with ionotropic Glu receptors in the surrounding tissue, (b) intracellular accumulation of GSH which increases tumor resistance to radio- and chemotherapy.

  4. Occupation and adult gliomas.

    PubMed

    Carozza, S E; Wrensch, M; Miike, R; Newman, B; Olshan, A F; Savitz, D A; Yost, M; Lee, M

    2000-11-01

    Lifetime job histories from a population-based, case-control study of gliomas diagnosed among adults in the San Francisco Bay area between August 1991 and April 1994 were evaluated to assess occupational risk factors. Occupational data for 476 cases and 462 controls were analyzed, with adjustment for age, gender, education, and race. Imprecise increased risks were observed for physicians and surgeons (odds ratio (OR) = 3.5, 95% confidence interval (CI): 0.7, 17.6), artists (OR = 1.9, 95% CI: 0.5, 6.5), foundry and smelter workers (OR = 2.6, 95% CI: 0.5, 13.1), petroleum and gas workers (OR = 4.9, 95% CI: 0.6, 42.2), and painters (OR = 1.6, 95% CI: 0.5, 4.9). Legal and social service workers, shippers, janitors, motor vehicle operators, and aircraft operators had increased odds ratios only with longer duration of employment. Physicians and surgeons, foundry and smelter workers, petroleum and gas workers, and painters showed increased risk for both astrocytic and nonastrocytic tumors. Artists and firemen had increased risk for astrocytic tumors only, while messengers, textile workers, aircraft operators, and vehicle manufacturing workers showed increased risk only for nonastrocytic tumors. Despite study limitations, including small numbers for many of the occupational groups, a high percentage of proxy respondents among cases, and lack of specific exposure information, associations were observed for several occupations previously reported to be at higher risk for brain tumors generally and gliomas specifically.

  5. 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 ...

  6. [Controversy on treatments for gliomas].

    PubMed

    Nomura, K

    1998-09-01

    Gliomas are representative primary malignant brain tumors, and with such tumors it is difficult to define the advanced stage. If the advanced stage indicates no curability by surgery alone, most gliomas would belong to this criterion because of their poor prognosis without any completely effective treatment. In this sense, no one could show a standard therapy to treat these unfortunate patients, for example, patients with glioblastoma, they could permit only 1 year survived even they had any applicable treatments to the lesions, these days. Treatment for low-grade gliomas has been most controversial for a long time, and no standard treatments have been determined so far. In this paper, as the treatment of low-grade gliomas it was intended to report what must be done for this patient and the present results of opinion survey for the treatment of gliomas which was done to professors of 80 institutes, from schools of medicine at all universities and medical colleges in Japan. For high-grade gliomas, some effectiveness of radiation therapy was disclosed as well as chemotherapy from recent papers. Gene therapy was also discussed briefly, its present status and future.

  7. Targeting of human glioma xenografts in vivo utilizing radiolabeled antibodies

    SciTech Connect

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

    1990-06-01

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

  8. CK2 inhibition induced PDK4-AMPK axis regulates metabolic adaptation and survival responses in glioma.

    PubMed

    Dixit, Deobrat; Ahmad, Fahim; Ghildiyal, Ruchi; Joshi, Shanker Datt; Sen, Ellora

    2016-05-15

    Understanding mechanisms that link aberrant metabolic adaptation and pro-survival responses in glioma cells is crucial towards the development of new anti-glioma therapies. As we have previously reported that CK2 is associated with glioma cell survival, we evaluated its involvement in the regulation of glucose metabolism. Inhibition of CK2 increased the expression of metabolic regulators, PDK4 and AMPK along with the key cellular energy sensor CREB. This increase was concomitant with altered metabolic profile as characterized by decreased glucose uptake in a PDK4 and AMPK dependent manner. Increased PDK4 expression was CREB dependent, as exogenous inhibition of CREB functions abrogated CK2 inhibitor mediated increase in PDK4 expression. Interestingly, PDK4 regulated AMPK phosphorylation which in turn affected cell viability in CK2 inhibitor treated glioma cells. CK2 inhibitor 4,5,6,7-Tetrabromobenzotriazole (TBB) significantly retarded the growth of glioma xenografts in athymic nude mouse model. Coherent with the in vitro findings, elevated senescence, pAMPK and PDK4 levels were also observed in TBB-treated xenograft tissue. Taken together, CK2 inhibition in glioma cells drives the PDK4-AMPK axis to affect metabolic profile that has a strong bearing on their survival.

  9. The impact of coexisting genetic mutations on murine optic glioma biology

    PubMed Central

    Kaul, Aparna; Toonen, Joseph A.; Gianino, Scott M.; Gutmann, David H.

    2015-01-01

    Background Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology. Methods Nf1+/− mice were intercrossed with Nf1flox/flox mice, which were then crossed with Nf1flox/flox; GFAP-Cre mice, to generate Nf1flox/mut; GFAP-Cre (FMC) mice. These mice were additionally mated with conditional KIAA1549:BRAF knock-in or Ptenflox/wt mice to generate Nf1flox/mut; f-BRAF; GFAP-Cre (FMBC) mice or Nf1flox/mut; Ptenflox/wt; GFAP-Cre (FMPC) mice, respectively. The resulting optic gliomas were analyzed for changes in tumor volume, proliferation, and retinal ganglion cell loss. Results While KIAA1549:BRAF conferred no additional biological properties on Nf1 optic glioma, FMPC mice had larger optic gliomas with greater proliferative indices and microglial infiltration. In addition, all 3 Nf1 murine optic glioma strains exhibited reduced retinal ganglion cell survival and numbers; however, FMPC mice had greater retinal nerve fiber layer thinning near the optic head relative to FMC and FMBC mice. Conclusions Collectively, these experiments demonstrate genetic cooperativity between Nf1 loss and Pten heterozygosity relevant to optic glioma biology and further underscore the value of employing genetically engineered mouse strains to define the contribution of discovered molecular alterations to brain tumor pathogenesis. PMID:25246427

  10. 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

  11. 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

  12. 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.

  13. Isocitrate dehydrogenase mutations in gliomas

    PubMed Central

    Waitkus, Matthew S.; Diplas, Bill H.; Yan, Hai

    2016-01-01

    Over the last decade, extraordinary progress has been made in elucidating the underlying genetic causes of gliomas. In 2008, our understanding of glioma genetics was revolutionized when mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) were identified in the vast majority of progressive gliomas and secondary glioblastomas (GBMs). IDH enzymes normally catalyze the decarboxylation of isocitrate to generate α-ketoglutarate (αKG), but recurrent mutations at Arg132 of IDH1 and Arg172 of IDH2 confer a neomorphic enzyme activity that catalyzes reduction of αKG into the putative oncometabolite D-2-hydroxyglutate (D2HG). D2HG inhibits αKG-dependent dioxygenases and is thought to create a cellular state permissive to malignant transformation by altering cellular epigenetics and blocking normal differentiation processes. Herein, we discuss the relevant literature on mechanistic studies of IDH1/2 mutations in gliomas, and we review the potential impact of IDH1/2 mutations on molecular classification and glioma therapy. PMID:26188014

  14. Culture and characteristics of hormone-responsive neuroblastoma x glioma hybrid cells

    SciTech Connect

    Hamprecht, B.; Glaser, T.; Reiser, G.; Bayer, E.; Propst, F.

    1985-01-01

    Neuroblastoma x glioma hybrid cells were generated by cell fusion of the 6-thioguanine-resistant clonal mouse neuroblastoma cells and the bromodeoxyuridine-resistant rat glioma cells, selection, and cloning. Every characteristics generally ascribed to neurons has been observed with the hybrid cells. The paper explores the morphological differentiation of hybrid cells, procedures for testing the hormonal regulation of intracellular levels of cyclic, (/sup 3/H)AMP in hybrid cells, hormonal regulation of adenylate cyclase in homogenates of hyrbid cells, intracellular levels of cyclic GMP, and uptake of guanidinium ions in hybrid cells.

  15. [Genetics and brain gliomas].

    PubMed

    Alentorn, Agusti; Labussière, Marianne; Sanson, Marc; Delattre, Jean-Yves; Hoang-Xuan, Khê; Idbaih, Ahmed

    2013-05-01

    Chromosome arms 1p and 19q codeletion, corresponding to an unbalanced reciprocal translocation t(1;19)(q10;p10), is seen in oligodendroglial tumours and is associated with better prognosis and better chemosensitivity. BRAF abnormalities are observed in pilocytic astrocytomas (tandem duplication-rearrangement) and in pleomorphic xanthoastrocytomas (BRAF V600E mutation). The vast majority of primary or de novo glioblastomas exhibit genetic abnormalities disrupting the intracellular signaling pathways of: transmembrane tyrosine kinase receptors to growth factors and their downstream signaling pathways (i.e. NF1-RAS-RAF-MAPK and PTEN-PI3K-AKT-TSC-mTOR); RB and; TP53. IDH1 and IDH2 mutations are frequent in diffuse grade II and grade III gliomas and in secondary glioblastomas. They are diagnostic and favorable independent prognostic biomarkers. In contrast, they are rare in primary or de novo glioblastomas and not reported in pilocytic astrocytomas. Germlin mutations in MSH2/MLH1/PMS2/MSH6, CDKN2A, TSC1/TSC2, PTEN, TP53 and NF1/NF2 predispose to glial tumors in the setting of hereditary cancer predisposition syndromes. Single nucleotide polymorphisms in TERT,CCDC26, CDKN2A/CDKN2B, RTEL, EGFR and PHLDB1 confer an inherited susceptibility to glial tumors.

  16. Glutamine Addiction In Gliomas.

    PubMed

    Márquez, Javier; Alonso, Francisco J; Matés, José M; Segura, Juan A; Martín-Rufián, Mercedes; Campos-Sandoval, José A

    2017-03-09

    Cancer cells develop and succeed by shifting to different metabolic programs compared with their normal cell counterparts. One of the classical hallmarks of cancer cells is their higher glycolysis rate and lactate production even in the presence of abundant O2 (Warburg effect). Another common metabolic feature of cancer cells is a high rate of glutamine (Gln) consumption normally exceeding their biosynthetic and energetic needs. The term Gln addiction is now widely used to reflect the strong dependence shown by most cancer cells for this essential nitrogen substrate after metabolic reprogramming. A Gln/glutamate (Glu) cycle occurs between host tissues and the tumor in order to maximize its growth and proliferation rates. The mechanistic basis for this deregulated tumor metabolism and how these changes are connected to oncogenic and tumor suppressor pathways are becoming increasingly understood. Based on these advances, new avenues of research have been initiated to find novel therapeutic targets and to explore strategies that interfere with glutamine metabolism as anticancer therapies. In this review, we provided an updated overview of glutamine addiction in glioma, the most prevalent type of brain tumor.

  17. Molecular signalling pathways in canine gliomas.

    PubMed

    Boudreau, C E; York, D; Higgins, R J; LeCouteur, R A; Dickinson, P J

    2017-03-01

    In this study, we determined the expression of key signalling pathway proteins TP53, MDM2, P21, AKT, PTEN, RB1, P16, MTOR and MAPK in canine gliomas using western blotting. Protein expression was defined in three canine astrocytic glioma cell lines treated with CCNU, temozolamide or CPT-11 and was further evaluated in 22 spontaneous gliomas including high and low grade astrocytomas, high grade oligodendrogliomas and mixed oligoastrocytomas. Response to chemotherapeutic agents and cell survival were similar to that reported in human glioma cell lines. Alterations in expression of key human gliomagenesis pathway proteins were common in canine glioma tumour samples and segregated between oligodendroglial and astrocytic tumour types for some pathways. Both similarities and differences in protein expression were defined for canine gliomas compared to those reported in human tumour counterparts. The findings may inform more defined assessment of specific signalling pathways for targeted therapy of canine gliomas.

  18. 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.

  19. 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.

  20. Mutant IDH1 and thrombosis in gliomas.

    PubMed

    Unruh, Dusten; Schwarze, Steven R; Khoury, Laith; Thomas, Cheddhi; Wu, Meijing; Chen, Li; Chen, Rui; Liu, Yinxing; Schwartz, Margaret A; Amidei, Christina; Kumthekar, Priya; Benjamin, Carolina G; Song, Kristine; Dawson, Caleb; Rispoli, Joanne M; Fatterpekar, Girish; Golfinos, John G; Kondziolka, Douglas; Karajannis, Matthias; Pacione, Donato; Zagzag, David; McIntyre, Thomas; Snuderl, Matija; Horbinski, Craig

    2016-12-01

    Mutant isocitrate dehydrogenase 1 (IDH1) is common in gliomas, and produces D-2-hydroxyglutarate (D-2-HG). The full effects of IDH1 mutations on glioma biology and tumor microenvironment are unknown. We analyzed a discovery cohort of 169 World Health Organization (WHO) grade II-IV gliomas, followed by a validation cohort of 148 cases, for IDH1 mutations, intratumoral microthrombi, and venous thromboemboli (VTE). 430 gliomas from The Cancer Genome Atlas were analyzed for mRNAs associated with coagulation, and 95 gliomas in a tissue microarray were assessed for tissue factor (TF) protein. In vitro and in vivo assays evaluated platelet aggregation and clotting time in the presence of mutant IDH1 or D-2-HG. VTE occurred in 26-30 % of patients with wild-type IDH1 gliomas, but not in patients with mutant IDH1 gliomas (0 %). IDH1 mutation status was the most powerful predictive marker for VTE, independent of variables such as GBM diagnosis and prolonged hospital stay. Microthrombi were far less common within mutant IDH1 gliomas regardless of WHO grade (85-90 % in wild-type versus 2-6 % in mutant), and were an independent predictor of IDH1 wild-type status. Among all 35 coagulation-associated genes, F3 mRNA, encoding TF, showed the strongest inverse relationship with IDH1 mutations. Mutant IDH1 gliomas had F3 gene promoter hypermethylation, with lower TF protein expression. D-2-HG rapidly inhibited platelet aggregation and blood clotting via a novel calcium-dependent, methylation-independent mechanism. Mutant IDH1 glioma engraftment in mice significantly prolonged bleeding time. Our data suggest that mutant IDH1 has potent antithrombotic activity within gliomas and throughout the peripheral circulation. These findings have implications for the pathologic evaluation of gliomas, the effect of altered isocitrate metabolism on tumor microenvironment, and risk assessment of glioma patients for VTE.

  1. Quercetin derivatives as potent inducers of selective cytotoxicity in glioma cells.

    PubMed

    Dell'Albani, Paola; Di Marco, Barbara; Grasso, Sonia; Rocco, Concetta; Foti, Mario C

    2017-04-01

    Quercetin (Q) is a flavonoid widely distributed in the plant kingdom and well-known for its ability to exert antioxidant, prooxidant and anticarcinogenic activities in several tumor cells. Furthermore, quercetin plays an important role both in the regulation of key elements in cellular signal transduction pathways related to apoptotic cell death, and in cell cycle progression. Several studies have reported of toxic effects of Q against glioma cell lines. In this study, the effects of Q and of some Q-derivatives (acyl esters and bromo-derivatives) on U373-MG and 9L glioma cell lines survival are analyzed. The 24-hour treatment of glioma cells with several concentrations of Q (25, 50 and 100μM) did not cause any cytotoxic effects, while the administration of Q-derivatives, such as acylated and brominated quercetin, caused a sharp increase in cell death. Among all tested derivatives, 3-O-decanoylquercetin 10 manifested the strongest cytotoxic effect at a concentration as low as 25μM both in U373-MG (ca. 40% viability after 24h) and in 9L cells (ca. 20% viability after 24h). The cytotoxic effects of the Q-derivatives 3 and 10-13 were proven to be satisfactorily selective for glioma cells. When Q-derivatives were in fact administered to mouse primary astroglial or human fibroblast cell cultures, a higher cell survival rate (~90-70% and 55-45%, respectively) was observed relative to that detected in glioma cells. These results prove that selective esterification and bromination of Q increase to a great extent the toxicity of this polyphenol against glioma cells, thereby providing a possible new tool for cyto-specific glioma therapy.

  2. Cellular factors promoting resistance to effective treatment of glioma with oncolytic Myxoma virus

    PubMed Central

    Zemp, Franz J.; McKenzie, Brienne A.; Lun, Xueqing; Reilly, Karlyne M.; McFadden, Grant; Yong, V. Wee; Forsyth, Peter A.

    2014-01-01

    Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the patient's immune response to the virus infection limits the therapy's utility, investigations into the specific cell type(s) involved in this response have been performed using non-specific pharmacological inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumours, and robust monocyte, T and NK cell infiltration 3 days following MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumour-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumour-resident macrophage population. Virotherapy of CPA-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multi-faceted cellular immune response that can be overcome with CPA-mediated lymphoablation. PMID:25336188

  3. Free-space optics technology employed in an UMTS release 4 bearer independent core network access part

    NASA Astrophysics Data System (ADS)

    Bibac, Ionut

    2005-08-01

    The UMTS Bearer Independent Core Network program introduced the 3rd Generation Partnership Program Release 4 BICN architecture into the legacy UMTS TDM-switched network. BICN is the application of calI server archltecture for voice and circuit switched data, enabling the provisioning of traditional circuit-switched services using a packet-switched transport network. Today"s business climate has made it essential for service providers to develop a comprehensive networking strategy that means introduction of RCBICN networks. The R4-BICN solution to the evolution of the Core Network in UMTS will enable operators to significantly reduce the capital and operational costs of delivering both traditional voice sewices and new multimedia services. To build the optical backbone, which can support the third generation (3G) packetized infrastructure, the operators could choose a fibre connection, or they could retain the benefits of a wireless connectivity by using a FSO - Free Space Optical lmk, the only wireless technology available that is capable of achieving data rates up to 2.4 Gbit/s. FSO offers viable alternatives for both core transmission networks and for replacing microwaves links in NodeB - RNC access networks. The paper and presentation aim to demonstrate the manner in which FSO products and networks are employed into R4-BICN design solutions.

  4. Platelet-derived growth factor receptor alpha in glioma: a bad seed.

    PubMed

    Liu, Kun-Wei; Hu, Bo; Cheng, Shi-Yuan

    2011-09-01

    Recent collaborative, large-scale genomic profiling of the most common and aggressive brain tumor glioblastoma multiforme(GBM) has significantly advanced our understanding of this disease. The gene encoding platelet-derived growth factor receptor alpha(PDGFRα) was identified as the third of the top 11 amplified genes in clinical GBM specimens. The important roles of PDGFRα signaling during normal brain development also implicate the possible pathologic consequences of PDGFRα over-activation in glioma. Although the initial clinical trials using PDGFR kinase inhibitors have been predominantly disappointing, diagnostic and treatment modalities involving genomic profiling and personalized medicine are expected to improve the therapy targeting PDGFRα signaling. In this review, we discuss the roles of PDGFRαsignaling during development of the normal central nervous system(CNS) and in pathologic conditions such as malignant glioma. We further compare various animal models of PDGF-induced gliomagenesis and their potential as a novel platform of pre-clinical drug testing. We then summarize our recent publication and how these findings will likely impact treatments for gliomas driven by PDGFRα overexpression. A better understanding of PDGFRα signaling in glioma and their microenvironment, through the use of human or mouse models, is necessary to design a more effective therapeutic strategy against gliomas harboring the aberrant PDGFRα signaling.

  5. CXCR4 increases in-vivo glioma perivascular invasion, and reduces radiation induced apoptosis: A genetic knockdown study

    PubMed Central

    Yadav, Viveka Nand; Zamler, Daniel; Baker, Gregory J.; Kadiyala, Padma; Erdreich-Epstein, Anat; DeCarvalho, Ana C.; Mikkelsen, Tom; Castro, Maria G.; Lowenstein, Pedro R.

    2016-01-01

    Glioblastoma (GBM) is a highly invasive brain tumor. Perivascular invasion, autovascularization and vascular co-option occur throughout the disease and lead to tumor invasion and progression. The molecular basis for perivascular invasion, i.e., the interaction of glioma tumor cells with endothelial cells is not well characterized. Recent studies indicate that glioma cells have increased expression of CXCR4. We investigated the in-vivo role of CXCR4 in perivascular invasion of glioma cells using shRNA-mediated knock down of CXCR4. We show that primary cultures of human glioma stem cells HF2303 and mouse glioma GL26-Cit cells exhibit significant migration towards human (HBMVE) and mouse (MBVE) brain microvascular endothelial cells. Blocking CXCR4 on tumor cells with AMD3100 in-vitro, inhibits migration of GL26-Cit and HF2303 toward MBVE and HBMVE cells. Additionally, genetic down regulation of CXCR4 in mouse glioma GL26-Cit cells inhibits their in-vitro migration towards MBVE cells; in an in-vivo intracranial mouse model, these cells display reduced tumor growth and perivascular invasion, leading to increased survival. Quantitative analysis of brain sections showed that CXCR4 knockdown tumors are less invasive. Lastly, we tested the effects of radiation on CXCR4 knock down GL26-Cit cells in an orthotopic brain tumor model. Radiation treatment increased apoptosis of CXCR4 downregulated tumor cells and prolonged median survival. In summary, our data suggest that CXCR4 signaling is critical for perivascular invasion of GBM cells and targeting this receptor makes tumors less invasive and more sensitive to radiation therapy. Combination of CXCR4 knock down and radiation treatment might improve the efficacy of GBM therapy. PMID:27863376

  6. [Therapeutic strategies and prospects of gliomas].

    PubMed

    Taillibert, Sophie; Pedretti, Marta; Sanson, Marc

    2004-10-23

    The prognosis and the treatment of gliomas depend on age, performance status and histological grade. Symptomatic treatment relies on steroids against cerebral edema, anti-epileptic drugs for seizures and perioperatively, prevention of thrombo-embolism and digestive complications, physiotherapy. Specific therapies include surgery, radiotherapy and chemotherapy. Surgery is necessary for histological diagnosis. In low grade gliomas, it has a significant impact in terms of survival. In malignant gliomas, surgery provides symptomic relief without clearly improving survival. Radiation therapy has been shown to improve survival in malignant glioma, but not in asymptomatic low grade tumors. Chemotherapy has a modest efficacy in glioblastomas, whereas oligodendrogliomas with 1p 19q deletion are chemosensitive tumors.

  7. Practical molecular pathologic diagnosis of infiltrating gliomas.

    PubMed

    Pekmezci, Melike; Perry, Arie

    2015-03-01

    Recent advances in molecular diagnostics have led to better understanding of glioma tumorigenesis and biology. Numerous glioma biomarkers with diagnostic, prognostic, and predictive value have been identified. Although some of these markers are already part of the routine clinical management of glioma patients, data regarding others are limited and difficult to apply routinely. In addition, multiple methods for molecular subclassification have been proposed either together with or as an alternative to the current morphologic classification and grading scheme. This article reviews the literature regarding glioma biomarkers and offers a few practical suggestions.

  8. Myeloid-derived suppressor cells in gliomas

    PubMed Central

    Kaminska, Bozena

    2016-01-01

    Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of early myeloid progenitors and precursors at different stages of differentiation into granulocytes, macrophages, and dendritic cells. Blockade of their differentiation into mature myeloid cells in cancer results in an expansion of this population. High-grade gliomas are the most common malignant tumours of the central nervous system (CNS), with a poor prognosis despite intensive radiation and chemotherapy. Histopathological and flow cytometry analyses of human and rodent experimental gliomas revealed the extensive heterogeneity of immune cells infiltrating gliomas and their microenvironment. Immune cell infiltrates consist of: resident (microglia) and peripheral macrophages, granulocytes, myeloid-derived suppressor cells, and T lymphocytes. Intratumoural density of glioma-associated MDSCs correlates positively with the histological grade of gliomas and patient’s survival. MDSCs have the ability to attract T regulatory lymphocytes to the tumour, but block the activation of tumour-reactive CD4+ T helper cells and cytotoxic CD8+ T cells. Immunomodulatory mechanisms employed by malignant gliomas pose an appalling challenge to brain tumour immunotherapy. In this mini-review we describe phenotypic and functional characteristics of MDSCs in humans and rodents, and their occurrence and potential roles in glioma progression. While understanding the complexity of immune cell interactions in the glioma microenvironment is far from being accomplished, there is significant progress that may lead to the development of immunotherapy for gliomas. PMID:28373814

  9. Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade.

    PubMed

    Tao, Bang-Bao; He, Hua; Shi, Xiu-hua; Wang, Chun-lin; Li, Wei-qing; Li, Bing; Dong, Yan; Hu, Guo-Han; Hou, Li-Jun; Luo, Chun; Chen, Ju-xiang; Chen, Huai-rui; Yu, Yu-hong; Sun, Qing-fang; Lu, Yi-Cheng

    2013-05-01

    Gliomas are the most common neoplasms in the central nervous system. The lack of efficacy of glioma therapies necessitates in-depth studies of glioma pathology, especially of the underlying molecular mechanisms that transform normal glial cells into tumor cells. Here we report that a deubiquitinating enzyme, ubiquitin-specific protease 2a (USP2a), and its substrate, fatty acid synthase (FASN), are over-expressed in glioma tissue. Using real-time quantitative polymerase chain reaction (PCR), Western blot and immunohistochemistry, we examined the expression and cellular distribution of USP2a and FASN in human glioma tissues. The expression patterns of USP2a and FASN correlated with the pathologic and clinical characteristics of the patients. Real-time PCR analysis showed that the expression levels of USP2a and its substrate FASN were higher in high-grade (World Health Organization [WHO] grades III and IV) glioma tissues than in low-grade (WHO grades I and II) glioma tissues. Western blot analysis indicated that the average optical densitometry ratio of USP2a and its substrate FASN in high-grade gliomas was higher than in low-grade gliomas. Moreover, statistical analysis of grade-classified glioma samples showed that the level of USP2a and FASN expression increased with the elevation of the WHO grade of glioma. USP2a protein expression was detected in the nucleus of glioma tissues and an increase in expression was significantly associated with the elevation of the WHO grade of glioma by immunohistochemistry. These findings expand our understanding of the molecular profiling of glioma and could shed light on new diagnostic criteria for gliomas.

  10. Potential regulation of glioma through the induction of apoptosis signaling via Egl-9 family hypoxia-inducible factor 3

    PubMed Central

    Mao, Ke; You, Chao; Lei, Ding; Zhang, Heng

    2017-01-01

    Glioma is an aggressive form of brain cancer that occurs following the abnormal proliferation of glial cells. Although glioma cannot spread to other organs, the morbidity and mortality rates of the disease are high, even following surgery, radiotherapy and chemotherapy. The function of Egl-9 family hypoxia-inducible factor 3 (Egln3) in cancer is controversial, and it is debated as to whether Egln3 positively or negatively regulates tumors. In the present study, a mouse model of low-grade glioma was successfully established. Through the use of immunohistochemical and western blot analyses, it was demonstrated that Egln3 expression in glioma tissue performed an important role in regulation by amplifying the signals for apoptosis, as determined by an increase in DNA fragments. Furthermore, Egln3 expression was inhibited by the administration of dimethyloxalylglycine, and the downregulated expression of Egln3 had marked effects on the regulation of glioma through apoptosis. The present study therefore provides evidence of an association between Egln3 expression and apoptosis in low-grade glioma. PMID:28356975

  11. Progression of motor deficits in glioma-bearing mice: impact of CNF1 therapy at symptomatic stages.

    PubMed

    Vannini, Eleonora; Maltese, Federica; Olimpico, Francesco; Fabbri, Alessia; Costa, Mario; Caleo, Matteo; Baroncelli, Laura

    2017-02-15

    Glioblastoma (GBM) is the most aggressive type of brain tumor. In this context, animal models represent excellent tools for the early detection and longitudinal mapping of neuronal dysfunction, that are critical in the preclinical validation of new therapeutic strategies. In a mouse glioma model, we developed sensitive behavioral readouts that allow early recognizing and following neurological symptoms. We injected GL261 cells into the primary motor cortex of syngenic mice and we used a battery of behavioral tests to longitudinally monitor the dysfunction induced by tumor growth. Grip strength test revealed an early onset of functional deficit associated to the glioma growth, with a significant forelimb weakness appearing 9 days after tumor inoculation. A later deficit was observed in the rotarod and in the grid walk tasks. Using this model, we found reduced tumor growth and maintenance of behavioral functions following treatment with Cytotoxic Necrotizing Factor 1 (CNF1) at a symptomatic stage. Our data provide a detailed and precise examination of how tumor growth reverberates on the behavioral functions of glioma-bearing mice, providing normative data for the study of therapeutic strategies for glioma treatment. The reduced tumor volume and robust functional sparing observed in CNF1-treated, glioma-bearing mice strengthen the notion that CNF1 delivery is a promising strategy for glioma therapy.

  12. The pathobiology of glioma tumors.

    PubMed

    Gladson, Candece L; Prayson, Richard A; Liu, Wei Michael

    2010-01-01

    The ongoing characterization of the genetic and epigenetic alterations in the gliomas has already improved the classification of these heterogeneous tumors and enabled the development of rodent models for analysis of the molecular pathways underlying their proliferative and invasive behavior. Effective application of the targeted therapies that are now in development will depend on pathologists' ability to provide accurate information regarding the genetic alterations and the expression of key receptors and ligands in the tumors. Here we review the mechanisms that have been implicated in the pathogenesis of the gliomas and provide examples of the cooperative nature of the pathways involved, which may influence the initial therapeutic response and the potential for development of resistance.

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

    ClinicalTrials.gov

    2017-01-12

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

  14. T Cells Enhance Stem-Like Properties and Conditional Malignancy in Gliomas

    PubMed Central

    Irvin, Dwain K.; Jouanneau, Emmanuel; Duvall, Gretchen; Zhang, Xiao-xue; Zhai, Yuying; Sarayba, Danielle; Seksenyan, Akop; Panwar, Akanksha; Black, Keith L.; Wheeler, Christopher J.

    2010-01-01

    Background Small populations of highly tumorigenic stem-like cells (cancer stem cells; CSCs) can exist within, and uniquely regenerate cancers including malignant brain tumors (gliomas). Many aspects of glioma CSCs (GSCs), however, have been characterized in non-physiological settings. Methods We found gene expression similarity superiorly defined glioma “stemness”, and revealed that GSC similarity increased with lower tumor grade. Using this method, we examined stemness in human grade IV gliomas (GBM) before and after dendritic cell (DC) vaccine therapy. This was followed by gene expression, phenotypic and functional analysis of murine GL26 tumors recovered from nude, wild-type, or DC-vaccinated host brains. Results GSC similarity was specifically increased in post-vaccine GBMs, and correlated best to vaccine-altered gene expression and endogenous anti-tumor T cell activity. GL26 analysis confirmed immune alterations, specific acquisition of stem cell markers, specifically enhanced sensitivity to anti-stem drug (cyclopamine), and enhanced tumorigenicity in wild-type hosts, in tumors in proportion to anti-tumor T cell activity. Nevertheless, vaccine-exposed GL26 cells were no more tumorigenic than parental GL26 in T cell-deficient hosts, though they otherwise appeared similar to GSCs enriched by chemotherapy. Finally, vaccine-exposed GBM and GL26 exhibited relatively homogeneous expression of genes expressed in progenitor cells and/or differentiation. Conclusions T cell activity represents an inducible physiological process capable of proportionally enriching GSCs in human and mouse gliomas. Stem-like gliomas enriched by strong T cell activity, however, may differ from other GSCs in that their stem-like properties may be disassociated from increased tumor malignancy and heterogeneity under specific host immune conditions. PMID:20539758

  15. 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

  16. Expressions of glia maturation factor-β by tumor cells and endothelia correlate with neovascularization and poor prognosis in human glioma

    PubMed Central

    Chen, Cong; Su, Xiao-rui; Shi, Yu; Wu, Jin-rong; Zhang, Peng; Zhang, Xin-li; Cui, You-hong; Ping, Yi-fang; Bian, Xiu-wu

    2016-01-01

    Glia maturation factor-β (GMF-β) has been reported to promote glial differentiation, and act as a negative prognostic indicator in certain cancers. However, its roles in glioma progression remain unclear. Since neurogenesis and vasculogenesis were proved to share some common regulators during gliomagenesis, we aim to explore the potential impact of GMF-β on tumor neovascularization and patient survival in glioma. In this study, we first detected GMF-β expression not only in tumor cells but also in microvascular endothelia by double immunohistochemical staining. Both tumoral and endothelial GMF-β expression levels were positively correlated with tumor grade and microvessel density (MVD), while negatively associated with poor prognoses of the patients. Interestingly, multivariate analysis demonstrated that endothelial GMF-β expression level was the only independent predictor of progression-free and overall survival of glioma patients. The results of in vitro angiogenesis assay showed that GMF-β knockdown significantly inhibited tubulogenesis of human U87 glioblastoma cells. Furthermore, GMF-β knockdown suppressed tumor growth and the formation of human-CD31 positive (glioma cell-derived) microvessels in a mouse orthotopic U87 glioma model. Our results demonstrated that GMF-β is an important player in glioma progression via promoting neovascularization. GMF-β may therefore be a novel prognostic marker as well as a potential therapeutic target for glioma. PMID:26515590

  17. Tubulin nitration in human gliomas.

    PubMed

    Fiore, Gabriella; Di Cristo, Carlo; Monti, Gianluca; Amoresano, Angela; Columbano, Laura; Pucci, Pietro; Cioffi, Fernando A; Di Cosmo, Anna; Palumbo, Anna; d'Ischia, Marco

    2006-02-06

    Immunohistochemical and biochemical investigations showed that significant protein nitration occurs in human gliomas, especially in grade IV glioblastomas at the level of astrocytes and oligodendrocytes and neurones. Enhanced alpha-tubulin immunoreactivity was co-present in the same elements in the glioblastomas. Proteomic methodologies were employed to identify a nitrated protein band at 55 kDa as alpha-tubulin. Peptide mass fingerprinting procedures demonstrated that tubulin is nitrated at Tyr224 in grade IV tumour samples but is unmodified in grade I samples and in non-cancerous brain tissue. These results provide the first characterisation of endogenously nitrated tubulin from human tumour samples.

  18. Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma.

    PubMed

    Raghunathan, Aditya; Olar, Adriana; Vogel, Hannes; Parker, John R; Coventry, Susan C; Debski, Robert; Albarracin, Constance T; Aldape, Kenneth D; Cahill, Daniel P; Powell, Suzanne Z; Fuller, Gregory N

    2012-08-01

    Mutations of isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (R132H), have been described in World Health Organization grade II and III diffuse gliomas and secondary glioblastoma. Immunohistochemistry using a mouse monoclonal antibody has a high specificity and sensitivity for detecting IDH1 R132H mutant protein in sections from formalin-fixed, paraffin-embedded tissue. Angiocentric glioma (AG), a unique neoplasm with mixed phenotypic features of diffuse glioma and ependymoma, has recently been codified as a grade I neoplasm in the 2007 World Health Organization classification of central nervous system tumors. The present study was designed to evaluate IDH1 R132H protein in AG. Three cases of AG were collected, and the diagnoses were confirmed. Expression of mutant IDH1 R132H protein was determined by immunohistochemistry on representative formalin-fixed, paraffin-embedded sections using the antihuman mouse monoclonal antibody IDH1 R132H (Dianova, Hamburg, Germany). Known IDH1 mutation-positive and IDH1 wild-type cases of grade II to IV glioma served as positive and negative controls. All 3 patients were male, aged 3, 5, and 15 years, with intra-axial tumors in the right posterior parietal-occipital lobe, right frontal lobe, and left frontal lobe, respectively. All 3 cases showed characteristic morphologic features of AG, including a monomorphous population of slender bipolar cells that diffusely infiltrated cortical parenchyma and ensheathed cortical blood vessels radially and longitudinally. All 3 cases were negative for the presence of IDH1 R132H mutant protein (0/3). All control cases showed appropriate reactivity. IDH1 R132H mutation has been described as a common molecular signature of grade II and III diffuse gliomas and secondary glioblastoma; however, AG, which exhibits some features of diffuse glioma, has not been evaluated. The absence of mutant IDH1 R132H protein expression in AG

  19. Incidence of gliomas by anatomic location

    PubMed Central

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

    2007-01-01

    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 × 1 × 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. PMID:17522333

  20. Bystander effect in glioma suicide gene therapy using bone marrow stromal cells.

    PubMed

    Li, Shaoyi; Gu, Chunyu; Gao, Yun; Amano, Shinji; Koizumi, Shinichiro; Tokuyama, Tsutomu; Namba, Hiroki

    2012-11-01

    An established rat intracranial glioma was successfully treated through the tumoricidal bystander effect generated by intratumoral injection of rat bone marrow stromal cells (BMSCs) transduced with the herpes simplex virus-thymidine kinase gene (BMSCtk cells) followed by systemic ganciclovir administration. In the present study, we tested the bystander effect of this treatment strategy when using human BMSCs as the vector cells. Human BMSCtk cells were mixed with various kinds of brain tumor cell lines (human and rat glioma cells) and examined in vitro and in vivo tumoricidal bystander effects, by co-culture study and co-implantation study in the nude mouse, respectively. A significant in vitro bystander effect was observed between human BMSCtk cells and any of the tumor cells examined in the ganciclovir-containing medium. A potent in vivo bystander effect against human and rat glioma cells was also demonstrated when ganciclovir was administered. Migratory activity of the human BMSCs toward the tumor cells was enhanced by the conditioned media obtained from both human and rat glioma cells compared to the fresh media. The results of this study have demonstrated that the bystander effect generated by BMSCtk cells and ganciclovir is not cell type-specific, suggesting that the strategy would be quite feasible for clinical use.

  1. A neurocentric perspective on glioma invasion

    PubMed Central

    Cuddapah, Vishnu Anand; Robel, Stefanie; Watkins, Stacey; Sontheimer, Harald

    2017-01-01

    Malignant gliomas are devastating tumours that frequently kill patients within 1 year of diagnosis. The major obstacle to a cure is diffuse invasion, which enables tumours to escape complete surgical resection and chemo- and radiation therapy. Gliomas use the same tortuous extracellular routes of migration that are travelled by immature neurons and stem cells, frequently using blood vessels as guides. They repurpose ion channels to dynamically adjust their cell volume to accommodate to narrow spaces and breach the blood-brain barrier through disruption of astrocytic endfeet, which envelop blood vessels. The unique biology of glioma invasion provides hitherto unexplored brain-specific therapeutic targets for this devastating disease. PMID:24946761

  2. Surgical management of low-grade gliomas.

    PubMed

    Gerard, Carter S; Straus, David; Byrne, Richard W

    2014-08-01

    Low-grade gliomas represent a wide spectrum of intra-axial brain tumors with diverse presentations, radiographic and surgical appearances, and prognoses. While there remains a role for biopsy, a growing body of evidence shows that aggressive surgical resection of low-grade gliomas may improve symptoms, extend progression-free survival (PFS), and even cure a select few patients. With the application of preoperative functional imaging, intraoperative navigation, and cortical stimulation, neurosurgeons are able to perform more complete resections while limiting the risk to patients. In this article, we describe the surgical management and current operative techniques used in the treatment of low-grade gliomas.

  3. A report on radiation-induced gliomas

    SciTech Connect

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

    1991-01-15

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

  4. Involvement of FOS-mediated miR-181b/miR-21 signalling in the progression of malignant gliomas.

    PubMed

    Tao, Tao; Wang, Yingyi; Luo, Hui; Yao, Lei; Wang, Lin; Wang, Jiajia; Yan, Wei; Zhang, Junxia; Wang, Huibo; Shi, Yan; Yin, Yu; Jiang, Tao; Kang, Chunsheng; Liu, Ning; You, Yongping

    2013-09-01

    Recently, a group of microRNAs (miRNAs) were shown to be dysregulated in gliomas, and involved in glioma development. However, the effect of miRNA-miRNA functional networks on gliomas is poorly understood. In this study, we identified that FBJ murine osteosarcoma viral oncogene homolog (FOS)-mediated miR-181b/miR-21 signalling was critical for glioma progression. Using microarrays and quantitative RT-PCR (qRT-PCR), we found increased FOS in high grade gliomas. FOS depletion (via FOS-shRNA), inhibited invasion and promoted apoptosis in glioma cells. Using microarrays, combined with Pearson correlation analysis, we found FOS positively correlated with miR-21 expression. Reduction of FOS inhibited miR-21 expression by binding to the miR-21 promoter using luciferase reporter assays. Introduction of miR-21 abrogated FOS knockdown-induced cell invasion and apoptosis. Moreover, bioinformatics and luciferase reporter assays showed that miR-181b modulated FOS expression by directly targeting the binding site within the 3'UTR. Expression of FOS with a FOS cDNA lacking 3'UTR overrided miR-181b-induced miR-21 expression and cell function. Finally, immunohistochemistry (IHC) and in situ hybridisation (ISH) analysis revealed a significant correlation in miR-181b, FOS and miR-21 expression in nude mouse tumour xenograft and human glioma tissues. To our knowledge, it is the first time to demonstrate that miR-181b/FOS/miR-21 signalling plays a critical role in the progression of gliomas, providing important clues for understanding the key roles of transcription factor mediated miRNA-miRNA functional network in the regulation of gliomas.

  5. Synergistic antitumor effect with indoleamine 2,3-dioxygenase inhibition and temozolomide in a murine glioma model.

    PubMed

    Hanihara, Mitsuto; Kawataki, Tomoyuki; Oh-Oka, Kyoko; Mitsuka, Kentaro; Nakao, Atsuhito; Kinouchi, Hiroyuki

    2016-06-01

    OBJECT Indoleamine 2,3-dioxygenase (IDO), a key enzyme of tryptophan (Trp) metabolism, is involved in tumor-derived immune suppression through depletion of Trp and accumulation of the metabolite kynurenine, resulting in inactivation of natural killer cells and generation of regulatory T cells (Tregs). It has been reported that high expression of IDO in cancer cells is associated with suppression of the antitumor immune response and is consistent with a poor prognosis. Thus, IDO may be a therapeutic target for malignant cancer. The authors have recently shown that IDO expression is markedly increased in human glioblastoma and secondary glioblastoma with malignant change, suggesting that IDO targeting may also have therapeutic potential for patients with glioma. The aim of this study was to investigate the antitumor effect of IDO inhibition and to examine the synergistic function of IDO inhibitor and temozolomide (TMZ) in a murine glioma model. METHODS Murine glioma GL261 cells and human glioma U87 cells were included in this study. The authors used 3 mouse models to study glioma cell growth: 1) a subcutaneous ectopic model, 2) a syngeneic intracranial orthotopic model, and 3) an allogenic intracranial orthotopic model. IDO inhibition was achieved via knockdown of IDO in GL261 cells using short hairpin RNA (shRNA) and through oral administration of the IDO inhibitor, 1-methyl-l-tryptophan (1-MT). Tumor volume in the subcutaneous model and survival time in the intracranial model were evaluated. RESULTS In the subcutaneous model, oral administration of 1-MT significantly suppressed tumor growth, and synergistic antitumor effects of 1-MT and TMZ were observed (p < 0.01). Mice containing intracranially inoculated IDO knockdown cells had a significantly longer survival period as compared with control mice (p < 0.01). CONCLUSIONS These results suggest that IDO expression is implicated in immunosuppression and tumor progression in glioma cells. Therefore, combining IDO

  6. Natural killer cells require monocytic Gr-1(+)/CD11b(+) myeloid cells to eradicate orthotopically engrafted glioma cells.

    PubMed

    Baker, Gregory J; Chockley, Peter; Zamler, Daniel; Castro, Maria G; Lowenstein, Pedro R

    2016-06-01

    Malignant gliomas are resistant to natural killer (NK) cell immune surveillance. However, the mechanisms used by these cancers to suppress antitumor NK cell activity remain poorly understood. We have recently reported on a novel mechanism of innate immune evasion characterized by the overexpression of the carbohydrate-binding protein galectin-1 by both mouse and rat malignant glioma. Here, we investigate the cytokine profile of galectin-1-deficient GL26 cells and describe the process by which these tumors are targeted by the early innate immune system in RAG1(-/-) and C57BL/6J mice. Our data reveal that galectin-1 knockdown in GL26 cells heightens their inflammatory status leading to the rapid recruitment of Gr-1(+)/CD11b(+) myeloid cells and NK1.1(+) NK cells into the brain tumor microenvironment, culminating in tumor clearance. We show that immunodepletion of Gr-1(+) myeloid cells in RAG1(-/-) mice permits the growth of galectin-1-deficient glioma despite the presence of NK cells, thus demonstrating an essential role for myeloid cells in the clearance of galectin-1-deficient glioma. Further characterization of tumor-infiltrating Gr-1(+)/CD11b(+) cells reveals that these cells also express CCR2 and Ly-6C, markers consistent with inflammatory monocytes. Our results demonstrate that Gr-1(+)/CD11b(+) myeloid cells, often referred to as myeloid-derived suppressor cells (MDSCs), are required for antitumor NK cell activity against galectin-1-deficient GL26 glioma. We conclude that glioma-derived galectin-1 represents an important factor in dictating the phenotypic behavior of monocytic Gr-1(+)/CD11b(+) myeloid cells. Galectin-1 suppression may be a valuable treatment approach for clinical glioma by promoting their innate immune-mediated recognition and clearance through the concerted effort of innate myeloid and lymphoid cell lineages.

  7. Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion

    PubMed Central

    Vinnakota, Katyayni; Hu, Feng; Ku, Min-Chi; Georgieva, Petya B.; Szulzewsky, Frank; Pohlmann, Andreas; Waiczies, Sonia; Waiczies, Helmar; Niendorf, Thoralf; Lehnardt, Seija; Hanisch, Uwe-Karsten; Synowitz, Michael; Markovic, Darko; Wolf, Susanne A.; Glass, Rainer; Kettenmann, Helmut

    2013-01-01

    Background Glioblastomas are the most aggressive primary brain tumors in humans. Microglia/brain macrophage accumulation in and around the tumor correlates with malignancy and poor clinical prognosis of these tumors. We have previously shown that microglia promote glioma expansion through upregulation of membrane type 1 matrix metalloprotease (MT1-MMP). This upregulation depends on signaling via the Toll-like receptor (TLR) adaptor molecule myeloid differentiation primary response gene 88 (MyD88). Methods Using in vitro, ex vivo, and in vivo techniques, we identified TLR2 as the main TLR controlling microglial MT1-MMP expression and promoting microglia-assisted glioma expansion. Results The implantation of mouse GL261 glioma cells into TLR2 knockout mice resulted in significantly smaller tumors, reduced MT1-MMP expression, and enhanced survival rates compared with wild-type control mice. Tumor expansion studied in organotypic brain slices depended on both parenchymal TLR2 expression and the presence of microglia. Glioma-derived soluble factors and synthetic TLR2 specific ligands induced MT1-MMP expression in microglia from wild-type mice, but no such change in MT1-MMP gene expression was observed in microglia from TLR2 knockout mice. We also found evidence that TLR1 and TLR6 cofunction with TLR2 as heterodimers in regulating MT1-MMP expression in vitro. Conclusions Our results thus show that activation of TLR2 along with TLRs 1 and/or 6 converts microglia into a glioma supportive phenotype. PMID:24014382

  8. CacyBP/SIP inhibits Doxourbicin-induced apoptosis of glioma cells due to activation of ERK1/2.

    PubMed

    Tang, Yuan; Zhan, Wenjian; Cao, Tong; Tang, Tianjin; Gao, Yong; Qiu, Zhichao; Fu, Chunling; Qian, Fengyuan; Yu, Rutong; Shi, Hengliang

    2016-03-01

    Calcyclin-binding protein or Siah-1-interacting protein (CacyBP/SIP) was previously reported to promote the proliferation of glioma cells. However, the effect of CacyBP/SIP on apoptosis of glioma is poorly understood. Here, our study shows that CacyBP/SIP plays a role in inhibiting doxorubicin (DOX) induced apoptosis of glioma cells U251 and U87. Overexpression of CacyBP/SIP obviously suppressed the DOX-induced cell apoptosis. On the contrary, silencing of CacyBP/SIP significantly promoted it. Further investigation indicated that inhibition of apoptosis by CacyBP/SIP was relevant to its nuclear translocation in response to the DOX treatment. Importantly, we found that the level of p-ERK1/2 in nuclei was related to the nuclear accumulation of CacyBP/SIP. Finally, the role of CacyBP/SIP was confirmed in vivo in a mouse model with the cell line stably silencing CacyBP/SIP. Taken together, our results suggest that CacyBP/SIP plays an important role in inhibiting apoptosis of glioma cells which might be mediated by ERK1/2 signaling pathway, which will provide some guidance for the treatment of glioma.

  9. Targeting immune checkpoints in malignant glioma

    PubMed Central

    Li, Tete; Liu, Yong-Jun; Chen, Wei; Chen, Jingtao

    2017-01-01

    Malignant glioma is the most common and a highly aggressive cancer in the central nervous system (CNS). Cancer immunotherapy, strategies to boost the bodys anti-cancer immune responses instead of directly targeting tumor cells, recently achieved great success in treating several human solid tumors. Although once considered immune privileged and devoid of normal immunological functions, CNS is now considered a promising target for cancer immunotherapy, featuring the recent progresses in neurobiology and neuroimmunology and a highly immunosuppressive state in malignant glioma. In this review, we focus on immune checkpoint inhibitors, specifically, antagonizing monoclonal antibodies for programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO). We discuss advances in the working mechanisms of these immune checkpoint molecules, their status in malignant glioma, and current preclinical and clinical trials targeting these molecules in malignant glioma. PMID:27756892

  10. 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

  11. Photochemical internalization of bleomycin for glioma treatment

    PubMed Central

    Mathews, Marlon S.; Blickenstaff, Joseph W.; Shih, En-Chung; Zamora, Genesis; Vo, Van; Sun, Chung-Ho; Hirschberg, Henry; Madsen, Steen J.

    2012-01-01

    Abstract. We study the use of photochemical internalization (PCI) for enhancing chemotherapeutic response to malignant glioma cells in vitro. Two models are studied: monolayers consisting of F98 rat glioma cells and human glioma spheroids established from biopsy-derived glioma cells. In both cases, the cytotoxicity of aluminum phthalocyanine disulfonate (AlPcS2a)-based PCI of bleomycin was compared to AlPcS2a-photodynamic therapy (PDT) and chemotherapy alone. Monolayers and spheroids were incubated with AlPcS2a (PDT effect), bleomycin (chemotherapy effect), or AlPcS2a+bleomycin (PCI effect) and were illuminated (670 nm). Toxicity was evaluated using colony formation assays or spheroid growth kinetics. F98 cells in monolayer/spheroids were not particularly sensitive to the effects of low radiant exposure (1.5  J/cm2 @ 5  mW/cm2) AlPcS2a-PDT. Bleomycin was moderately toxic to F98 cells in monolayer at relatively low concentrations—incubation of F98 cells in 0.1  μg/ml for 4 h resulted in 80% survival, but less toxic in human glioma spheroids respectively. In both in vitro systems investigated, a significant PCI effect is seen. PCI using 1.5  J/cm2 together with 0.25  μg/ml bleomycin resulted in approximately 20% and 18% survival of F98 rat glioma cells and human glioma spheroids, respectively. These results show that AlPcS2a-mediated PCI can be used to enhance the efficacy of chemotherapeutic agents such as bleomycin in malignant gliomas. PMID:22612148

  12. 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

  13. The interface between glial progenitors and gliomas

    PubMed Central

    Canoll, Peter

    2009-01-01

    The mammalian brain and spinal cord contain heterogeneous populations of cycling, immature cells. These include cells with stem cell-like properties as well as progenitors in various stages of early glial differentiation. This latter population is distributed widely throughout gray and white matter and numerically represents an extremely large cell pool. In this review, we discuss the possibility that the glial progenitors that populate the adult CNS are one source of gliomas. Indeed, the marker phenotypes, morphologies, and migratory properties of cells in gliomas strongly resemble glial progenitors in many ways. We review briefly some salient features of normal glial development and then examine the similarities and differences between normal progenitors and cells in gliomas, focusing on the phenotypic plasticity of glial progenitors and the responses to growth factors in promoting proliferation and migration of normal and glioma cells, and discussing known mutational changes in gliomas in the context of how these might affect the proliferative and migratory behaviors of progenitors. Finally, we will discuss the “cancer stem cell” hypothesis in light of the possibility that glial progenitors can generate gliomas. PMID:18784926

  14. 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

  15. Microglia-glioma cross-talk: a two way approach to new strategies against glioma.

    PubMed

    Arcuri, Cataldo; Fioretti, Bernard; Bianchi, Roberta; Mecca, Carmen; Tubaro, Claudia; Beccari, Tommaso; Franciolini, Fabio; Giambanco, Ileana; Donato, Rosario

    2017-01-01

    Glioblastoma (GBM) is the most malignant and aggressive among primary brain tumors, characterized by very low life expectancy. In vivo, glioma and glioblastoma in particular contain large numbers of immune cells (myeloid cells) such as microglia and tumour-infiltrating macrophages (or glioma associated macrophages). These glioma-infiltrating myeloid cells comprise up to 30% of total tumor mass and have been suggested to play several roles in glioma progression including proliferation, survival, motility and immunosuppression. Although tumor microglia and macrophages can acquire proinflammatory (M1) phenotype being capable of releasing proinflammatory cytokines, phagocytosing and presenting antigens, their effector immune function in gliomas appears to be suppressed by the acquisition of an anti-inflammatory (M2) phenotype. In the present work we review the microglia-glioma interactions to highlight the close relationship between the two cell types and the factors that can influence their properties (chemokines, cytokines, S100B protein). A future therapeutic possibility might be to simultaneously targeting, for example with nanomedicine, glioma cells and microglia to push the microglia towards an antitumor phenotype (M1) and/or prevent glioma cells from "conditioning" by microglia.

  16. Targeting and therapy of human glioma xenografts in vivo utilizing radiolabeled antibodies

    SciTech Connect

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

    1990-02-01

    Radiolabeled antibodies provide a potential basis for selective radiotherapy of human gliomas. We have measured tumor targeting by radiolabeled monoclonal antibodies directed against neuroectodermal and tumor-associated antigens in nude mice bearing human glioma xenografts. Monoclonal P96.5, a mouse IgG2a immunoglobulin, defines an epitope of a human melanoma cell surface protein and specifically binds the U-251 human glioma as measured by immunoperoxidase histochemistry. IIIIn-radiolabeled P96.5 specifically targets the U-251 human glioma xenograft and yields 87.0 microCi of tumor activity/g/100 microCi injected activity compared to 4.5 microCi following administration of 100 microCi radiolabeled irrelevant monoclonal antibody. Calculations of targeting ratios demonstrate the deposited dose to be 11.6 times greater with radiolabeled P96.5 administration compared to irrelevant monoclonal antibody. The dose found in normal organs is less than 20% of that in the tumor, further supporting specific targeting of the human glioma xenograft by this antibody. Monoclonal antibody ZME018, which defines a second melanoma-associated antigen, demonstrates positive immunoperoxidase staining of the tumor, but comparatively decreased targeting. To test the therapeutic potential of 90Y-radiolabeled P96.5 and ZME018, tumors and normal sites were implanted with miniature thermoluminescent dosimeters. Average absorbed doses of 3770 +/- 445 (SEM) and 645 +/- 48 cGy in tumor, 353 +/- 41 and 222 +/- 13 cGy in a contralateral control i.m. site, 980 +/- 127 and 651 +/- 63 cGy in liver, and 275 +/- 14 and 256 +/- 18 cGy in total body were observed 7 days following administration of 100 microCi 90Y-radiolabeled P96.5 and ZME018, respectively. Calculations of absorbed dose by the medical internal radiation dose method confirmed thermoluminescent dosimeter absorbed dose measurements.

  17. Biphasic Dependence of Glioma Survival and Cell Migration on CD44 Expression Level.

    PubMed

    Klank, Rebecca L; Decker Grunke, Stacy A; Bangasser, Benjamin L; Forster, Colleen L; Price, Matthew A; Odde, Thomas J; SantaCruz, Karen S; Rosenfeld, Steven S; Canoll, Peter; Turley, Eva A; McCarthy, James B; Ohlfest, John R; Odde, David J

    2017-01-03

    While several studies link the cell-surface marker CD44 to cancer progression, conflicting results show both positive and negative correlations with increased CD44 levels. Here, we demonstrate that the survival outcomes of genetically induced glioma-bearing mice and of high-grade human glioma patients are biphasically correlated with CD44 level, with the poorest outcomes occurring at intermediate levels. Furthermore, the high-CD44-expressing mesenchymal subtype exhibited a positive trend of survival with increased CD44 level. Mouse cell migration rates in ex vivo brain slice cultures were also biphasically associated with CD44 level, with maximal migration corresponding to minimal survival. Cell simulations suggest that cell-substrate adhesiveness is sufficient to explain this biphasic migration. More generally, these results highlight the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.

  18. Molecular Diagnostics of Gliomas Using Next Generation Sequencing of a Glioma-Tailored Gene Panel.

    PubMed

    Zacher, Angela; Kaulich, Kerstin; Stepanow, Stefanie; Wolter, Marietta; Köhrer, Karl; Felsberg, Jörg; Malzkorn, Bastian; Reifenberger, Guido

    2017-03-01

    Current classification of gliomas is based on histological criteria according to the World Health Organization (WHO) classification of tumors of the central nervous system. Over the past years, characteristic genetic profiles have been identified in various glioma types. These can refine tumor diagnostics and provide important prognostic and predictive information. We report on the establishment and validation of gene panel next generation sequencing (NGS) for the molecular diagnostics of gliomas. We designed a glioma-tailored gene panel covering 660 amplicons derived from 20 genes frequently aberrant in different glioma types. Sensitivity and specificity of glioma gene panel NGS for detection of DNA sequence variants and copy number changes were validated by single gene analyses. NGS-based mutation detection was optimized for application on formalin-fixed paraffin-embedded tissue specimens including small stereotactic biopsy samples. NGS data obtained in a retrospective analysis of 121 gliomas allowed for their molecular classification into distinct biological groups, including (i) isocitrate dehydrogenase gene (IDH) 1 or 2 mutant astrocytic gliomas with frequent α-thalassemia/mental retardation syndrome X-linked (ATRX) and tumor protein p53 (TP53) gene mutations, (ii) IDH mutant oligodendroglial tumors with 1p/19q codeletion, telomerase reverse transcriptase (TERT) promoter mutation and frequent Drosophila homolog of capicua (CIC) gene mutation, as well as (iii) IDH wildtype glioblastomas with frequent TERT promoter mutation, phosphatase and tensin homolog (PTEN) mutation and/or epidermal growth factor receptor (EGFR) amplification. Oligoastrocytic gliomas were genetically assigned to either of these groups. Our findings implicate gene panel NGS as a promising diagnostic technique that may facilitate integrated histological and molecular glioma classification.

  19. 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

  20. 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.

  1. 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.

  2. 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

  3. Phenotypic Transition as a Survival Strategy of Glioma.

    PubMed

    Ichikawa, Tomotsugu; Otani, Yoshihiro; Kurozumi, Kazuhiko; Date, Isao

    2016-07-15

    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.

  4. EFEMP2 is upregulated in gliomas and promotes glioma cell proliferation and invasion

    PubMed Central

    Wang, Long; Chen, Qianxue; Chen, Zhibiao; Tian, Daofeng; Xu, Haitao; Cai, Qiang; Liu, Baohui; Deng, Gang

    2015-01-01

    Gliomas are the most common and aggressive form of primary brain tumor. Although EGF-containing fibulin-like extracellular matrix protein 2 (EFEMP2), an extracellular matrix (ECM) glycoprotein, is regarded as a candidate oncogene, little is known about the association of EFEMP2 and gliomas. Here, the expression of EFEMP2 was significantly increased in glioma tissues (n=60) compared to non-tumorous brain tissues (n=25). Silencing of EFEMP2 expression through RNA interference in two glioma cell lines (U87 and U373) remarkably inhibited cell proliferation and G1/S transition. More importantly, EFEMP2 silencing significantly induced cell apoptosis via increasing the ratio of Bax and Bcl-2. Additionally, knockdown of EFEMP2 significantly inhibited the invasive ability of both glioma cells, which was associated with the downregulated expression of metalloproteinase-2 (MMP-2) and MMP-9. In conclusion, expression of EFEMP2 was associated with the oncogenic potential of gliomas and silencing of its expression can suppress cancer cell growth and metastasis. Inhibition of EFEMP2 may be a therapeutic strategy for gliomas. PMID:26617746

  5. Differential Glioma-Associated Tumor Antigen Expression Profiles of Human Glioma Cells Grown in Hypoxia

    PubMed Central

    Ge, Lisheng; Cornforth, Andrew N.; Hoa, Neil T.; Delgado, Christina; Chiou, Shiun Kwei; Zhou, Yi Hong; Jadus, Martin R.

    2012-01-01

    Human U251 and D54 glioma cells were tested for expression of 25 glioma-associated tumor antigen precursor proteins (TAPP) under hypoxic (1% O2) or normoxic (21% O2) conditions. Hypoxic glioma cell lines increased their mRNA expression for nine TAPP (Aim2, Art-4, EphA2, EZH2, Fosl1, PTH-rP, Sox 11, Whsc2 and YKL-40), as assessed by quantitative reverse transcriptase real-time/polymerase chain reaction (qRT-PCR). Increased differences with three hypoxic-induced TAPP: EZH2, Whsc2 and YKL-40 were shown at the protein levels by fluorescent antibody staining and quantitative electrophoretic analysis. Two TAPP (MRP3 and Trp1) were down-regulated by hypoxia in glioma cell lines. Growing the glioma cells under hypoxia for 13 days, followed by returning them back to normoxic conditions for 7 days, and restored the original normoxic TAPP profile. Thus, hypoxia was an environmental factor that stimulated the transient expression of these antigens. Intracranial xenografts grown in nude mice derived from U251 cells that had been cultured under neurosphere stem cell conditions showed increased expression of Whsc2 or YKL-40, demonstrating that these in vitro properties of glioma also occur in vivo. Whsc2-specific cytotoxic T lymphocytes killed the hypoxic U251 glioma cells better than normoxic glioma cells. The antigens expressed by hypoxic tumor cells may be a better source of starting tumor material for loading dendritic cells for novel immunotherapy of glioma using tumor-associated antigens. PMID:22957023

  6. Differential glioma-associated tumor antigen expression profiles of human glioma cells grown in hypoxia.

    PubMed

    Ge, Lisheng; Cornforth, Andrew N; Hoa, Neil T; Delgado, Christina; Chiou, Shiun Kwei; Zhou, Yi Hong; Jadus, Martin R

    2012-01-01

    Human U251 and D54 glioma cells were tested for expression of 25 glioma-associated tumor antigen precursor proteins (TAPP) under hypoxic (1% O(2)) or normoxic (21% O(2)) conditions. Hypoxic glioma cell lines increased their mRNA expression for nine TAPP (Aim2, Art-4, EphA2, EZH2, Fosl1, PTH-rP, Sox 11, Whsc2 and YKL-40), as assessed by quantitative reverse transcriptase real-time/polymerase chain reaction (qRT-PCR). Increased differences with three hypoxic-induced TAPP: EZH2, Whsc2 and YKL-40 were shown at the protein levels by fluorescent antibody staining and quantitative electrophoretic analysis. Two TAPP (MRP3 and Trp1) were down-regulated by hypoxia in glioma cell lines. Growing the glioma cells under hypoxia for 13 days, followed by returning them back to normoxic conditions for 7 days, and restored the original normoxic TAPP profile. Thus, hypoxia was an environmental factor that stimulated the transient expression of these antigens. Intracranial xenografts grown in nude mice derived from U251 cells that had been cultured under neurosphere stem cell conditions showed increased expression of Whsc2 or YKL-40, demonstrating that these in vitro properties of glioma also occur in vivo. Whsc2-specific cytotoxic T lymphocytes killed the hypoxic U251 glioma cells better than normoxic glioma cells. The antigens expressed by hypoxic tumor cells may be a better source of starting tumor material for loading dendritic cells for novel immunotherapy of glioma using tumor-associated antigens.

  7. A stabilized peptide ligand for multifunctional glioma targeted drug delivery.

    PubMed

    Ying, Man; Shen, Qing; Zhan, Changyou; Wei, Xiaoli; Gao, Jie; Xie, Cao; Yao, Bingxin; Lu, Weiyue

    2016-12-10

    Peptide ligands consisting of l-amino acids are subject to proteolysis in vivo. When modified on the surface of nanocarriers, those peptide ligands would readily degrade and the targeting efficacy is significantly attenuated. It has received increasing scrutiny to design stable peptide ligands for targeted drug delivery. Here, we present the design of a stable peptide ligand by the formation of a head-to-tail amide bond as an example. Even though the linear l-peptide A7R (termed (L)A7R) can bind specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) that are overexpressed on glioma cells, neovasculature and glioma vasculogenic mimicry (VM), the tumor-homing capacity of (L)A7R is greatly impaired in vivo due to proteolysis (e.g. in the serum). A cyclic A7R (cA7R) peptide was identified by computer-aided peptide design and synthesized with high yield by combining solid phase peptide synthesis and native chemical ligation. The binding of cA7R to both receptors was theoretically and experimentally assessed. In our simulated model hydrophobic and ionic interactions dominated the binding of (L)A7R to receptors. It is very interesting that cA7R adopting a different structure from (L)A7R retained high binding affinities to receptors without affecting the hydrophobic and ionic interactions. After head-to-tail cyclization by the formation of an amide bond, cA7R exhibited exceptional stability in mouse serum. Either cA7R or (L)A7R was conjugated on the surface of doxorubicin (DOX) loaded liposomes (cA7R-LS/DOX or (L)A7R-LS/DOX). The results of in vitro cellular assays indicated that cA7R-LS/DOX not only displayed stronger anti-proliferative effect against glioma cells, but also demonstrated to be more efficient in destruction of VM and HUVEC tubes in comparison to (L)A7R-LS/DOX and plain liposomes (LS/DOX, without peptide conjugation). cA7R conjugation could achieve significantly higher accumulation of liposomes in glioma than did (L

  8. 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

  9. 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

  10. Multigene sets for clinical application in glioma.

    PubMed

    de Groot, John F; Sulman, Erik P; Aldape, Kenneth D

    2011-04-01

    Diffuse gliomas are a heterogeneous group of malignancies with highly variable outcomes, and diagnosis is largely based on histologic appearance. Tumor classification according to cell type and grade provides some prognostic information. However, significant clinical and biologic heterogeneity exists in glioma, even after accounting for known clinicopathologic variables. Significant advances in knowledge of the molecular genetics of brain tumors have occurred in the past decade, largely because of the availability of high-throughput profiling techniques, including new sequencing methodologies and multidimensional profiling by The Cancer Genome Atlas project. The large amount of data generated from these efforts has enabled the identification of prognostic and predictive factors and helped to identify pathways driving tumor growth. Implementing these signatures into the clinic to personalize therapy presents a new challenge. Identification of relevant biomarkers, especially when coupled with clinical trials of newer targeted therapies, will enable better patient stratification and individualization of treatment for patients with glioma.

  11. 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

  12. Molecular alterations of KIT oncogene in gliomas.

    PubMed

    Gomes, Ana L; Reis-Filho, Jorge S; Lopes, José M; Martinho, Olga; Lambros, Maryou B K; Martins, Albino; Schmitt, Fernando; Pardal, Fernando; Reis, Rui M

    2007-01-01

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

  13. Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas

    PubMed Central

    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.

    2013-01-01

    The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10–30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (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% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 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 non-brainstem 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

  14. Brain stem glioma: two case studies.

    PubMed

    Rosenblum, Ruth K

    2005-01-01

    The paths taken by each family in coming to terms with the dismal prognosis associated with brain stem glioma can be quite different. The case studies of 2 school-age girls diagnosed with a brain stem glioma within weeks of each other are presented. The multi-disciplinary team response to each family was individualized at each stage of diagnosis, treatment, and end-of-life care, as expected. The ultimate chronologic union of these 2 families as each child neared death was somewhat uncanny. The experience of each family, and their relationship with the team through this process, was an intense challenge and learning experience.

  15. [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.

  16. Mutual antagonism between Sox10 and NFIA regulates diversification of glial lineages and glioma subtypes.

    PubMed

    Glasgow, Stacey M; Zhu, Wenyi; Stolt, C Claus; Huang, Teng-Wei; Chen, Fuyi; LoTurco, Joseph J; Neul, Jeffrey L; Wegner, Michael; Mohila, Carrie; Deneen, Benjamin

    2014-10-01

    Lineage progression and diversification is regulated by the coordinated action of unique sets of transcription factors. Oligodendrocytes (OL) and astrocytes (AS) comprise the glial sub-lineages in the CNS, and the manner in which their associated regulatory factors orchestrate lineage diversification during development and disease remains an open question. Sox10 and NFIA are key transcriptional regulators of gliogenesis associated with OL and AS. We found that NFIA inhibited Sox10 induction of OL differentiation through direct association and antagonism of its function. Conversely, we found that Sox10 antagonized NFIA function and suppressed AS differentiation in mouse and chick systems. Using this developmental paradigm as a model for glioma, we found that this relationship similarly regulated the generation of glioma subtypes. Our results describe the antagonistic relationship between Sox10 and NFIA that regulates the balance of OL and AS fate during development and demonstrate for the first time, to the best of our knowledge, that the transcriptional processes governing glial sub-lineage diversification oversee the generation of glioma subtypes.

  17. 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.

  18. 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.

  19. Gene therapy for malignant glioma.

    PubMed

    Okura, Hidehiro; Smith, Christian A; Rutka, James T

    2014-01-01

    Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.

  20. 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.

  1. Gliomas and exposure to wood preservatives.

    PubMed

    Cordier, S; Poisson, M; Gerin, M; Varin, J; Conso, F; Hemon, D

    1988-10-01

    A case-referent study was undertaken to look for occupational risk factors among patients with glioma treated in a neurological hospital in Paris between 1975 and 1984. In the study group were 125 men with gliomas (aged less than or equal to 65) and 238 patients (also less than or equal to 65) admitted for non-neoplastic, non-malformative vascular diseases in the same department during the same period constituting the reference group. All diagnoses were confirmed by tomodensitometry. Information on occupational history was obtained from a postal questionnaire and from medical records. Comparison of cases and referents showed a significant excess risk among teachers (OR = 4.1) and a raised risk among wood workers (OR = 1.6). Four of nine cases of glioma who had been employed as wood workers reported that a colleague had suffered from glioma (those reports were confirmed by hospital records). None were reported among 11 referent wood workers. Using a complementary questionnaire on wood work, exposure assessment to wood preservatives and solvents showed that frequent exposure to organochlorine wood preservatives and to organic solvents occurred more often among cases than referent wood workers (p less than 0.10).

  2. White Matter Change Revealed by Diffusion Tensor Imaging in Gliomas

    PubMed Central

    Won, Young Il; Kim, Chi Heon; Park, Chul-Kee; Koo, Bang-Bon; Lee, Jong-Min; Jung, Hee-Won

    2016-01-01

    Background Tumor-related white matter change is detected at late stages with magnetic resonance imaging (MRI), when mass effect or prominent edema is present. We analyzed if diffusion tensor imaging (DTI) white matter change earlier than conventional MRI. Methods Twenty-six patients with gliomas (World Health Organization grade II, 5; grade III, 12; and grade IV, 9) within 2 cm from the posterior limb of the internal capsule (IC) were studied. Fifteen normal adults were enrolled as controls. Fluid attenuation inversion recovery MRI showed a high signal change at the posterior limb of the IC (HSIC) in 9 patients with grade III or IV gliomas. We classified the gliomas as WHO grade II (gliomas II), grade III or IV without HSIC [gliomas III/IV(-)] and grade III or IV with HSIC [gliomas III/IV(+)], as an indicator of the increase in the severity of the white matter changes. Fractional anisotropy (FA) and apparent diffusion coefficients (ADC) were calculated for the pyramidal tract. Tumor progression along pyramidal tract was evaluated by follow-up MRI in 16 patients at 40±18 months. Results FA showed no significant difference between gliomas II and control (p=0.694), but was lower in gliomas III/IV(-) and gliomas III/IV(+) (p<0.001). ADCs were higher in gliomas II, gliomas III/IV(-) and gliomas III/IV(+) than control (p<0.001). Tumor progression was detected in 2/16 patients. Conclusion DTI detected white matter changes that appeared to be normal in MRI. ADC changed even in low grade glioma, indicating ADC may be a better parameter for the early detection of white matter change. PMID:27867919

  3. [Histological and molecular classification of gliomas].

    PubMed

    Figarella-Branger, D; Colin, C; Coulibaly, B; Quilichini, B; Maues De Paula, A; Fernandez, C; Bouvier, C

    2008-01-01

    Gliomas are the most frequent tumors of the central nervous system. The WHO classification, based on the presumed cell origin, distinguishes astrocytic, oligodendrocytic and mixed gliomas. A grading system is based on the presence of the following criteria: increased cellular density, nuclear atypias, mitosis, vascular proliferation and necrosis. The main histological subtype of grade I gliomas are pilocytic astrocytomas, which are benign. Diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas are low-grade (II) or high-grade (III and IV) tumors. Glioblastomas correspond to grade IV astrocytomas. C. Daumas-Duport et al. have proposed another classification based on histology and imaging data, which distinguishes oligodendrogliomas and mixed gliomas of grade A (without endothelial proliferation and/or contrast enhancement), oligodendrogliomas and mixed gliomas of grade B (with endothelial proliferation or contrast enhancement), glioblastomas and glioneuronal malignant tumors. Both classifications lack reproducibility. Many studies have searched for a molecular classification. Recurrent abnormalities in gliomas have been found. They encompassed recurrent chromosomal alterations, such as lost of chromosome 10, gain of chromosome 7, deletion of chromosome 1p and 19q, but also activation of the Akt pathway (amplification of EGFR), dysregulation of the cell cycle (deletion of p16, p53). These studies have enabled the description of two molecular subtypes for glioblastomas. De novo glioblastomas, which occur in young patients without of a prior history of brain tumor and harbor frequent amplification of EGFR, deletion of p16 and mutation of PTEN while mutation of p53 is infrequent. Secondary glioblastomas occur in the context of a preexisting low-grade glioma and are characterized by more frequent mutation of p53. On the other side, combined complete deletion of 1p and 19q as the result of the translocation t(1;19)(q10;p10) is highly specific of oligodendrogliomas

  4. 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

  5. [Classification of gliomas. Current progress and perspectives].

    PubMed

    Capper, D; Reifenberger, G

    2015-06-01

    The diagnostic subdivision of gliomas is traditionally based on histological features as defined by the World Health Organization (WHO) classification of tumors of the central nervous system. In recent years molecular studies have identified a number of genetic and epigenetic markers that could contribute to an improved tumor classification and better prediction of response to therapy and prognosis in the individual patient. The most important molecular tests with differential diagnostic relevance in patients with astrocytic and oligodendroglial tumors include the detection of genetic mutations in the isocitrate dehydrogenase 1 (IDH1), IDH2, alpha thalassemia/mental retardation syndrome X-linked (ATRX), histone H3.3 (H3F3A) and v-raf murine sarcoma viral oncogene homolog B (BRAF) genes as well as the demonstration of codeletions of chromosomal arms 1p and 19q. Important predictive markers that have been linked to the response to alkylating chemotherapy are O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients and 1p/19q codel status in anaplastic glioma patients. Oncogenic c11orf95/RELA fusion gene formation is characteristic for a subgroup of patients with supratentorial ependymoma. In addition to diagnostic testing of individual genes, novel microarray and next generation sequencing (NGS) techniques show promising perspectives in glioma diagnostics. The assessment of DNA methylation profiles using DNA methylation arrays representing 450,000 CpG dinucleotides distributed throughout the human genome (450 k array test) now allows the robust molecular classification of gliomas into clinically relevant entities and variants. Moreover, glioma-associated gene panel NGS promises the timely parallel sequencing of relevant diagnostic and predictive marker genes in a single test. It will now be a major task to integrate these novel results and techniques into the conventional histological procedures in the up-coming revision of the

  6. Computer Simulation of Glioma Growth and Morphology

    PubMed Central

    Frieboes, Hermann B.; Lowengrub, John S.; Wise, S.; Zheng, X.; Macklin, Paul; Bearer, Elaine; Cristini, Vittorio

    2007-01-01

    Despite major advances in the study of glioma, the quantitative links between intra-tumor molecular/cellular properties, clinically observable properties such as morphology, and critical tumor behaviors such as growth and invasiveness remain unclear, hampering more effective coupling of tumor physical characteristics with implications for prognosis and therapy. Although molecular biology, histopathology, and radiological imaging are employed in this endeavor, studies are severely challenged by the multitude of different physical scales involved in tumor growth, i.e., from molecular nanoscale to cell microscale and finally to tissue centimeter scale. Consequently, it is often difficult to determine the underlying dynamics across dimensions. New techniques are needed to tackle these issues. Here, we address this multi-scalar problem by employing a novel predictive three-dimensional mathematical and computational model based on first-principle equations (conservation laws of physics) that describe mathematically the diffusion of cell substrates and other processes determining tumor mass growth and invasion. The model uses conserved variables to represent known determinants of glioma behavior, e.g., cell density and oxygen concentration, as well as biological functional relationships and parameters linking phenomena at different scales whose specific forms and values are hypothesized and calculated based on in-vitro and in-vivo experiments and from histopathology of tissue specimens from human gliomas. This model enables correlation of glioma morphology to tumor growth by quantifying interdependence of tumor mass on the microenvironment (e.g., hypoxia, tissue disruption) and on the cellular phenotypes (e.g., mitosis and apoptosis rates, cell adhesion strength). Once functional relationships between variables and associated parameter values have been informed, e.g. from histopathology or intra-operative analysis, this model can be used for disease diagnosis

  7. 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.

  8. Terahertz reflectometry imaging for low and high grade gliomas

    NASA Astrophysics Data System (ADS)

    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

    2016-10-01

    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.

  9. Receptor-Mediated Drug Delivery Systems Targeting to Glioma

    PubMed Central

    Wang, Shanshan; Meng, Ying; Li, Chengyi; Qian, Min; Huang, Rongqin

    2015-01-01

    Glioma has been considered to be the most frequent primary tumor within the central nervous system (CNS). The complexity of glioma, especially the existence of the blood-brain barrier (BBB), makes the survival and prognosis of glioma remain poor even after a standard treatment based on surgery, radiotherapy, and chemotherapy. This provides a rationale for the development of some novel therapeutic strategies. Among them, receptor-mediated drug delivery is a specific pattern taking advantage of differential expression of receptors between tumors and normal tissues. The strategy can actively transport drugs, such as small molecular drugs, gene medicines, and therapeutic proteins to glioma while minimizing adverse reactions. This review will summarize recent progress on receptor-mediated drug delivery systems targeting to glioma, and conclude the challenges and prospects of receptor-mediated glioma-targeted therapy for future applications.

  10. 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

  11. Oncolytic adenoviruses: A thorny path to glioma cure

    PubMed Central

    Ulasov, I.V.; Borovjagin, A.V.; Schroeder, B.A.; Baryshnikov, A.Y.

    2014-01-01

    Glioblastoma Multiforme (GBM) is a rapidly progressing brain tumor. Despite the relatively low percentage of cancer patients with glioma diagnoses, recent statistics indicate that the number of glioma patients may have increased over the past decade. Current therapeutic options for glioma patients include tumor resection, chemotherapy, and concomitant radiation therapy with an average survival of approximately 16 months. The rapid progression of gliomas has spurred the development of novel treatment options, such as cancer gene therapy and oncolytic virotherapy. Preclinical testing of oncolytic adenoviruses using glioma models revealed both positive and negative sides of the virotherapy approach. Here we present a detailed overview of the glioma virotherapy field and discuss auxiliary therapeutic strategies with the potential for augmenting clinical efficacy of GBM virotherapy treatment. PMID:25685829

  12. Progress on molecular biomarkers and classification of malignant gliomas.

    PubMed

    Zhang, Chuanbao; Bao, Zhaoshi; Zhang, Wei; Jiang, Tao

    2013-06-01

    Gliomas are the most common primary intracranial tumors in adults. Anaplastic gliomas (WHO grade III) and glioblastomas (WHO grade IV) represent the major groups of malignant gliomas in the brain. Several diagnostic, predictive, and prognostic biomarkers for malignant gliomas have been reported over the last few decades, and these markers have made great contributions to the accuracy of diagnosis, therapeutic decision making, and prognosis of patients. However, heterogeneity in patient outcomes may still be observed, which highlights the insufficiency of a classification system based purely on histopathology. Great efforts have been made to incorporate new information about the molecular landscape of gliomas into novel classifications that may potentially guide treatment. In this review, we summarize three distinctive biomarkers, three most commonly altered pathways, and three classifications based on microarray data in malignant gliomas.

  13. 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

  14. [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.

  15. 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.

  16. Establishment of a green fluorescent protein tracing murine model focused on the functions of host components in necrosis repair and the niche of subcutaneously implanted glioma.

    PubMed

    Lu, Zhao-Hui; Lv, Ke; Zhang, Jin-Shi; Dai, Chun-Gang; Liu, Bin; Ma, Xiao-Yu; He, Lin-Ming; Jia, Jing-Yun; Chen, Yan-Ming; Dai, Xing-Liang; Wang, Ai-Dong; Dong, Jun; Zhang, Quan-Bin; Lan, Qing; Huang, Qiang

    2014-02-01

    Due to progress in the research of glioma stem cells and the glioma niche, development of an animal model that facilitates the elucidation of the roles of the host tissue and cells is necessary. The aim of the present study was to develop a subcutaneous xenograft green fluorescent protein nude mouse model and use this model to analyze the roles of host cells in tumor necrosis repair. Tumors derived from the human glioma stem/progenitor cell line SU3 were subcutaneously implanted in green fluorescent protein nude mice. The implanted tumors were then passed from animal to animal for 10 generations. Finally, subcutaneous xenografts were assayed with traditional pathology, immunopathological techniques and fluorescence photography. For each generation, the tumorigenicity rate was 100%. Subcutaneous xenografts were rich in blood vessels, and necrotic and hemorrhagic foci, which highly expressed hypoxia-inducible factor-1α, tumor necrosis factor, Ki-67, CD68 and CD11b. In the interstitial tissue, particularly in old hemorrhagic foci, there were numerous cells expressing green fluorescent protein, CD68 and CD11b. Green fluorescent protein nude mouse subcutaneous xenografts not only consistently maintained the high invasiveness and tumorigenicity of glioma stem/progenitor cells, but also consisted of a high concentration of tumor blood vessels and necrotic and hemorrhagic foci. Subcutaneous xenografts also expressed high levels of tumor microenvironment-related proteins and host-derived tumor interstitial molecules. The model has significant potential for further research on tumor tissue remodeling and the tumor microenvironment.

  17. 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

  18. Characteristics of gliomas in patients with somatic IDH mosaicism.

    PubMed

    Bonnet, Charlotte; Thomas, Laure; Psimaras, Dimitri; Bielle, Franck; Vauléon, Elodie; Loiseau, Hugues; Cartalat-Carel, Stéphanie; Meyronet, David; Dehais, Caroline; Honnorat, Jérôme; Sanson, Marc; Ducray, François

    2016-03-31

    IDH mutations are found in the majority of adult, diffuse, low-grade and anaplastic gliomas and are also frequently found in cartilaginous tumors. Ollier disease and Maffucci syndrome are two enchondromatosis syndromes characterized by the development of multiple benign cartilaginous tumors due to post-zygotic acquisition of IDH mutations. In addition to skeletal tumors, enchondromatosis patients sometimes develop gliomas. The aim of the present study was to determine whether gliomas in enchondromatosis patients might also result from somatic IDH mosaicism and whether their characteristics are similar to those of sporadic IDH-mutated gliomas. For this purpose, we analyzed the characteristics of 6 newly diagnosed and 32 previously reported cases of enchondromatosis patients who developed gliomas and compared them to those of a consecutive series of 159 patients with sporadic IDH-mutated gliomas. As was the case with sporadic IDH mutated gliomas, enchondromatosis gliomas were frequently located in the frontal lobe (54 %) and consisted of diffuse low-grade (73 %) or anaplastic gliomas (21 %). However, they were diagnosed at an earlier age (25.6 years versus 44 years, p < 0.001) and were more frequently multicentric (32 % versus 1 %, p < 0.001) and more frequently located within the brainstem than sporadic IDH mutated gliomas (21 % versus 1 %, p < 0.001). Their molecular profile was characterized by IDH mutations and loss of ATRX expression. In two patients, the same IDH mutation was demonstrated in the glioma and in a cartilaginous tumor. In contrast to sporadic IDH mutated gliomas, no enchondromatosis glioma harbored a 1p/19q co-deletion (0/6 versus 59/123, p = 0.03). The characteristics of gliomas in patients with enchondromatosis suggest that these tumors, as cartilaginous tumors, result from somatic IDH mosaicism and that the timing of IDH mutation acquisition might affect the location and molecular characteristics of gliomas. Early

  19. IGFBP2 expression predicts IDH-mutant glioma patient survival.

    PubMed

    Huang, Lin Eric; Cohen, Adam L; Colman, Howard; Jensen, Randy L; Fults, Daniel W; Couldwell, William T

    2017-01-03

    Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2.

  20. 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

  1. Targeting tumor-associated macrophages in an experimental glioma model with a recombinant immunotoxin to folate receptor beta.

    PubMed

    Nagai, Taku; Tanaka, Masashi; Tsuneyoshi, Yasuhiro; Xu, Baohui; Michie, Sara A; Hasui, Kazuhisa; Hirano, Hirofumi; Arita, Kazunori; Matsuyama, Takami

    2009-10-01

    Tumor-associated macrophages (TAMs) are frequently found in glioblastomas and a high degree of macrophage infiltration is associated with a poor prognosis for glioblastoma patients. However, it is unclear whether TAMs in glioblastomas promote tumor growth. In this study, we found that folate receptor beta (FR beta) was expressed on macrophages in human glioblastomas and a rat C6 glioma implanted subcutaneously in nude mice. To target FR beta-expressing TAMs, we produced a recombinant immunotoxin consisting of immunoglobulin heavy and light chain Fv portions of an anti-mouse FR beta monoclonal antibody and Pseudomonas exotoxin A. Injection of the immunotoxin into C6 glioma xenografts in nude mice significantly depleted TAMs and reduced tumor growth. The immunotoxin targeting FR beta-expressing macrophages will provide a therapeutic tool for human glioblastomas.

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

    ClinicalTrials.gov

    2016-12-07

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

  3. Combined Efficacy of Cediranib and Quinacrine in Glioma Is Enhanced by Hypoxia and Causally Linked to Autophagic Vacuole Accumulation

    PubMed Central

    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

  4. Nanotechnology Applications for Diffuse Intrinsic Pontine Glioma.

    PubMed

    Bredlau, Amy Lee; Dixit, Suraj; Chen, Chao; Broome, Ann-Marie

    2017-01-01

    Diffuse intrinsic pontine gliomas (DIPGs) are invariably fatal tumors found in the pons of elementary school aged children. These tumors are grade II-IV gliomas, with a median survival of less than 1 year from diagnosis when treated with standard of care (SOC) therapy. Nanotechnology may offer therapeutic options for the treatment of DIPGs. Multiple nanoparticle formulations are currently being investigated for the treatment of DIPGs. Nanoparticles based upon stable elements, polymer nanoparticles, and organic nanoparticles are under development for the treatment of brain tumors, including DIPGs. Targeting of nanoparticles is now possible as delivery techniques that address the difficulty in crossing the blood brain barrier (BBB) are developed. Theranostic nanoparticles, a combination of therapeutics and diagnostic nanoparticles, improve imaging of the cancerous tissue while delivering therapy to the local region. However, additional time and attention should be directed to developing a nanoparticle delivery system for treatment of the uniformly fatal pediatric disease of DIPG.

  5. Anaplastic glioma: current treatment and management.

    PubMed

    Le Rhun, Emilie; Taillibert, Sophie; Chamberlain, Marc C

    2015-06-01

    Anaplastic glioma (AG) is divided into three morphology-based groups (anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma) as well as three molecular groups (glioma-CpG island methylation phenotype [G-CIMP] negative, G-CIMP positive non-1p19q codeleted tumors and G-CIMP positive codeleted tumors). The RTOG 9402 and EORTC 26951 trials established radiotherapy plus (procarbazine, lomustine, vincristine) chemotherapy as the standard of care in 1p/19q codeleted AG. Uni- or non-codeleted AG are currently best treated with radiotherapy only or alkylator-based chemotherapy only as determined by the NOA-04 trial. Maturation of NOA-04 and results of the currently accruing studies, CODEL (for codeleted AG) and CATNON (for uni or non-codeleted AG), will likely refine current up-front treatment recommendations for AG.

  6. Trends in Malignant Glioma Monoclonal Antibody Therapy

    PubMed Central

    Chekhonin, Ivan; Gurina, Olga

    2015-01-01

    Although new passive and active immunotherapy methods are emerging, unconjugated monoclonal antibodies remain the only kind of biological preparations approved for high-grade glioma therapy in clinical practice. In this review, we combine clinical and experimental data discussion. As antiangiogenic therapy is the standard of care for recurrent glioblastoma multiforme (GBM), we analyze major clinical trials and possible therapeutic combinations of bevacizumab, the most common monoclonal antibody to vascular endothelial growth factor (VEGF). Another humanized antibody to gain recognition in GBM is epidermal growth factor (EGFR) antagonist nimotuzumab. Other antigens (VEGF receptor, platelet-derived growth factor receptor, hepatocyte growth factor and c-Met system) showed significance in gliomas and were used to create monoclonal antibodies applied in different malignant tumors. We assess the role of genetic markers (isocitrate dehydrogenase, O6-methylguanine-DNA methyltransnsferase) in GBM treatment outcome prediction. Besides antibodies studied in clinical trials, we focus on perspective targets and briefly list other means of passive immunotherapy.

  7. 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

  8. Serum proteomics of glioma: methods and applications.

    PubMed

    Somasundaram, Kumaravel; Nijaguna, Mamatha B; Kumar, Durairaj Mohan

    2009-10-01

    The prognosis of patients with glioblastoma, the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation and chemotherapy. Genetic heterogeneity of glioblastoma warrants extensive studies in order to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. Serum biomarkers have the potential to revolutionize the process of cancer diagnosis, grading, prognostication and treatment response monitoring. Besides having the advantage that serum can be obtained through a less invasive procedure, it contains molecules at an extraordinary dynamic range of ten orders of magnitude in terms of their concentrations. While the conventional methods, such as 2DE, have been in use for many years, the ability to identify the proteins through mass spectrometry techniques such as MALDI-TOF led to an explosion of interest in proteomics. Relatively new high-throughput proteomics methods such as SELDI-TOF and protein microarrays are expected to hasten the process of serum biomarker discovery. This review will highlight the recent advances in the proteomics platform in discovering serum biomarkers and the current status of glioma serum markers. We aim to provide the principles and potential of the latest proteomic approaches and their applications in the biomarker discovery process. Besides providing a comprehensive list of available serum biomarkers of glioma, we will also propose how these markers will revolutionize the clinical management of glioma patients.

  9. 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.

  10. Steroid requirements during radiotherapy for malignant gliomas.

    PubMed

    Marantidou, Athina; Levy, Christine; Duquesne, Alyette; Ursu, Renata; Bailon, Olivier; Coman, Irene; Belin, Catherine; Carpentier, Antoine F

    2010-10-01

    Radiotherapy (RT) is the standard treatment for high-grade gliomas. However, toxicity may develop during RT, such as brain edema or worsening of neurological symptoms. Surprisingly, no dedicated study had focused on steroid requirements during RT in adult patients with malignant gliomas. We evaluated prospectively all patients with malignant gliomas treated by RT in a single center from July 2006 to May 2009. Age, sex, initial Karnofsky performance status (KPS), tumor localization and histology, type of surgical resection, clinical target volume, total dose and duration of RT, concomitant treatment with temozolomide, and steroid dosage during RT and at 1 and 3 months after RT were recorded in all patients. Most of the 80 patients (70%) were already taking steroids before RT. Half of them (55%) required initiation or further steroids increase during RT. The median time to steroid increase was 8 days. Only 13% of patients remained free of steroids during RT, and the mean maximal dosage of prednisone was 55 ± 48 mg. At 3 months after RT, 29% of patients were free of steroids, and the mean prednisone dosage was 32 ± 50 mg. Unresected tumors and initial KPS ≤80% were the only variables associated with higher steroid requirements on multivariate analysis. In our series, almost all patients required steroids during RT. Poor initial KPS and biopsy were associated with higher steroid requirements.

  11. Autophagy and Akt promote survival in glioma.

    PubMed

    Fan, Qi-Wen; Weiss, William A

    2011-05-01

    Signaling through phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR is frequently activated in cancers including glioblastoma multiforme (GBM), where this kinase network regulates survival. It is thus surprising that inhibitors of these pathways induce minimal cell death in glioma. We showed that the dual PtdIns3K-mTOR inhibitor PI-103 induces autophagy in therapy-resistant, PTEN-mutant glioma, with blockade of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) contributing independently to autophagy. Inhibition of autophagosome maturation synergizes with PI-103 to induce apoptosis through the Bax-dependent intrinsic mitochondrial pathway, indicating that PI-103 induces autophagy as a survival pathway in this setting. Not all inhibitors of PtdIns3K-Akt-mTOR signaling synergize with inhibitors of autophagy. The allosteric mTORC1 inhibitor rapamycin fails to induce apoptosis in conjunction with blockade of autophagy, due to feedback-activation of Akt. Apoptosis in the setting of rapamycin therapy requires concurrent inhibition of both autophagy and of PtdIns3K-Akt. Moreover, the clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 cooperates with the clinical lysosomotropic autophagy inhibitor chloroquine to induce apoptosis in PTEN-mutant glioma xenografts in vivo, offering a therapeutic approach translatable to patients.

  12. Perspectives in Intraoperative Diagnostics of Human Gliomas

    PubMed Central

    Tyurikova, O.; Dembitskaya, Y.; Yashin, K.; Mishchenko, M.; Vedunova, M.; Medyanik, I.; Kazantsev, V.

    2015-01-01

    Amongst large a variety of oncological diseases, malignant gliomas represent one of the most severe types of tumors. They are also the most common type of the brain tumors and account for over half of the astrocytic tumors. According to different sources, the average life expectancy of patients with various glioblastomas varies between 10 and 12 months and that of patients with anaplastic astrocytic tumors between 20 and 24 months. Therefore, studies of the physiology of transformed glial cells are critical for the development of treatment methods. Modern medical approaches offer complex procedures, including the microsurgical tumor removal, radiotherapy, and chemotherapy, supplemented with photodynamic therapy and immunotherapy. The most radical of them is surgical resection, which allows removing the largest part of the tumor, reduces the intracranial hypertension, and minimizes the degree of neurological deficit. However, complete removal of the tumor remains impossible. The main limitations are insufficient visualization of glioma boundaries, due to its infiltrative growth, and the necessity to preserve healthy tissue. This review is devoted to the description of advantages and disadvantages of modern intraoperative diagnostics of human gliomas and highlights potential perspectives for development of their treatment. PMID:26543495

  13. Low-grade gliomas: introduction and overview.

    PubMed

    Piepmeier, J M; Christopher, S

    1997-08-01

    This issue of the Journal of Neuro-Oncology is devoted to recent investigations of low-grade gliomas. The purpose of this issue is not to debate the relative merits and liabilities of different management strategies for low-grade gliomas, but to present new data concerning novel and innovative approaches to evaluating these lesions. The common theme of many of these reports represents a departure from grading systems that primarily depend on a morphology-based analysis from light microscopy to classify these tumors. The purpose of this review is to present the reasoning behind the selection of authors for this issue of the Journal of Neuro-Oncology and to provide a format for presentation of new ideas concerning these interesting tumors. It is clear that standard classification systems that address only the morphological characteristics of tumor cells can not adequately represent the wide variation in biological activity that is found with these lesions. It is hoped that these articles will stimulate further interest and research into low-grade gliomas that will one day lead to more effective therapy.

  14. A role for ion channels in perivascular glioma invasion

    PubMed Central

    Thompson, Emily G.

    2017-01-01

    Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuro-peptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials. PMID:27424110

  15. Association Between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma.

    PubMed

    Zigmont, Victoria; Garrett, Amy; Peng, Jin; Seweryn, Michal; Rempala, Grzegorz A; Harris, Randall; Holloman, Christopher; Gundersen, Thomas E; Ahlbom, Anders; Feychting, Maria; Johannesen, Tom Borge; Grimsrud, Tom Kristian; Schwartzbaum, Judith

    2015-01-01

    There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case-control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D [25(OH)D], an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P = .04). Men diagnosed ≤ 56 showed a borderline positive trend (P = .08). High levels (>66 nmol/L) of 25(OH)D in men >56 were inversely related to high grade glioma from ≥2 yr before diagnosis (OR = 0.59; 95% CI = 0.38, 0.91) to ≥15 yr before diagnosis (OR = 0.61; 95% CI = 0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease.

  16. 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

  17. Association between Prediagnostic Serum 25-Hydroxyvitamin D Concentration and Glioma

    PubMed Central

    Zigmont, Victoria; Garrett, Amy; Peng, Jin; Seweryn, Michal; Rempala, Grzegorz A.; Harris, Randall; Holloman, Christopher; Gundersen, Thomas E.; Ahlbom, Anders; Feychting, Maria; Johannesen, Tom Borge; Grimsrud, Tom Kristian; Schwartzbaum, Judith

    2016-01-01

    There are no previous studies of the association between prediagnostic serum vitamin D concentration and glioma. Vitamin D has immunosuppressive properties; as does glioma. It was, therefore, our hypothesis that elevated vitamin D concentration would increase glioma risk. We conducted a nested case–control study using specimens from the Janus Serum Bank cohort in Norway. Blood donors who were subsequently diagnosed with glioma (n = 592), between 1974 and 2007, were matched to donors without glioma (n = 1112) on date and age at blood collection and sex. We measured 25-hydroxyvitamin D (25(OH)D), an indicator of vitamin D availability, using liquid chromatography coupled with mass spectrometry. Seasonally adjusted odds ratios (ORs) and 95% confidence intervals (95%CIs) were estimated for each control quintile of 25(OH)D using conditional logistic regression. Among men diagnosed with high grade glioma >56, we found a negative trend (P=.04). Men diagnosed ≤ 56 showed a borderline positive trend (P=.08). High levels (>66 nmol/L) of 25(OH)D in men > 56 were inversely related to high grade glioma from ≥ 2 years before diagnosis (OR=0.59; 95%CI=0.38,0.91) to ≥ 15 years before diagnosis (OR=0.61; 95%CI=0.38,0.96). Our findings are consistent long before glioma diagnosis and are therefore unlikely to reflect preclinical disease. PMID:26317248

  18. Unsupervised analysis of transcriptomic profiles reveals six glioma subtypes.

    PubMed

    Li, Aiguo; Walling, Jennifer; Ahn, Susie; Kotliarov, Yuri; Su, Qin; Quezado, Martha; Oberholtzer, J Carl; Park, John; Zenklusen, Jean C; Fine, Howard A

    2009-03-01

    Gliomas are the most common type of primary brain tumors in adults and a significant cause of cancer-related mortality. Defining glioma subtypes based on objective genetic and molecular signatures may allow for a more rational, patient-specific approach to therapy in the future. Classifications based on gene expression data have been attempted in the past with varying success and with only some concordance between studies, possibly due to inherent bias that can be introduced through the use of analytic methodologies that make a priori selection of genes before classification. To overcome this potential source of bias, we have applied two unsupervised machine learning methods to genome-wide gene expression profiles of 159 gliomas, thereby establishing a robust glioma classification model relying only on the molecular data. The model predicts for two major groups of gliomas (oligodendroglioma-rich and glioblastoma-rich groups) separable into six hierarchically nested subtypes. We then identified six sets of classifiers that can be used to assign any given glioma to the corresponding subtype and validated these classifiers using both internal (189 additional independent samples) and two external data sets (341 patients). Application of the classification system to the external glioma data sets allowed us to identify previously unrecognized prognostic groups within previously published data and within The Cancer Genome Atlas glioblastoma samples and the different biological pathways associated with the different glioma subtypes offering a potential clue to the pathogenesis and possibly therapeutic targets for tumors within each subtype.

  19. Cystoid angiocentric glioma: A case report and literature review

    PubMed Central

    Cheng, Sainan; Lü, Yubo; Xu, Shangchen; Liu, Qiang; Lee, Pearlene

    2015-01-01

    Angiocentric glioma is a rare subtype of neuroepithelial tumor that is associated with a history of epilepsy. We report a case of cystoid angiocentric glioma associated with an area of calcification. This 25 year old male patient presented with tonic clonic spasm. He underwent craniotomy with complete resection of the lesion. Pathologic specimen showed monomorphous bipolar cells with angiocentric growth pattern. PMID:26629293

  20. A role for ion channels in perivascular glioma invasion.

    PubMed

    Thompson, Emily G; Sontheimer, Harald

    2016-10-01

    Malignant gliomas are devastating tumors, frequently killing those diagnosed in little over a year. The profuse infiltration of glioma cells into healthy tissue surrounding the main tumor mass is one of the major obstacles limiting the improvement of patient survival. Migration along the abluminal side of blood vessels is one of the salient features of glioma cell invasion. Invading glioma cells are attracted to the vascular network, in part by the neuropeptide bradykinin, where glioma cells actively modify the gliovascular interface and undergo volumetric alterations to navigate the confined space. Critical to these volume modifications is a proposed hydrodynamic model that involves the flux of ions in and out of the cell, followed by osmotically obligated water. Ion and water channels expressed by the glioma cell are essential in this model of invasion and make opportune therapeutic targets. Lastly, there is growing evidence that vascular-associated glioma cells are able to control the vascular tone, presumably to free up space for invasion and growth. The unique mechanisms that enable perivascular glioma invasion may offer critical targets for therapeutic intervention in this devastating disease. Indeed, a chloride channel-blocking peptide has already been successfully tested in human clinical trials.

  1. 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.

  2. 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

  3. 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

  4. Androglobin knockdown inhibits growth of glioma cell lines

    PubMed Central

    Huang, Bo; Lu, Yi-Sheng; Li, Xia; Zhu, Zhi-Chuan; Li, Kui; Liu, Ji-Wei; Zheng, Jing; Hu, Ze-Lan

    2014-01-01

    Globin family was famous for oxygen supply function of its members such as hemoglobin and myoglobin. With the progress of research, several members of this protein family have been proven to play roles in tumors including glioma. Androglobin (ADGB) is a recently identified member of globin family with very few studies about its function. In the present study, we show that ADGB plays an oncogene role in glioma. Lentiviral vector mediated ADGB knockdown inhibited the proliferation of glioma cell lines determined by MTT assay and colony formation assay. ADGB knockdown also increased the apoptosis of glioma cell line U251 assessed by flow cytometry. In addition, western blot showed that ADGB knockdown altered levels of several proteins related to proliferation, survival or apoptosis in U251 cells. These findings suggest ADGB is involved in the progression of glioma in vitro. PMID:24966926

  5. Expression of the galectin-9-Tim-3 pathway in glioma tissues is associated with the clinical manifestations of glioma.

    PubMed

    Liu, Zengjin; Han, Huamin; He, Xin; Li, Shouwei; Wu, Chenxing; Yu, Chunjiang; Wang, Shengdian

    2016-03-01

    Glioma is known to induce local and systemic immunosuppression, which inhibits antitumor T cell responses. The galectin-9-Tim-3-pathway negatively regulates T cell pathways in the tumor immunosuppressive environment. The present study assessed the expression of Tim-3 and galectin-9 in glioma patients, and evaluated the association between the expression of Tim-3 and galectin-9 with clinical characteristics. The present study identified that Tim-3 expression was significantly increased in peripheral blood T cells of glioma patients compared with those of healthy controls, and was additionally increased on tumor-infiltrating T cells. The expression of Tim-3 on tumor-infiltrating T cells was associated with the World Health Organization (WHO) grade of glioma, but negatively correlated with the Karnofsky Performance Status score of the glioma patients. Immunohistochemical analysis revealed that the expression of galectin-9 in tumor tissues was associated with Tim-3 expression on tumor-infiltrating T cells and the WHO grade of glioma. These findings suggest that the galectin-9-Tim-3 pathway may be critical in the immunoevasion of glioma and may be a potent target for immunotherapy in glioma patients.

  6. The Glioma International Case-Control Study: A Report From the Genetic Epidemiology of Glioma International Consortium

    PubMed Central

    Amirian, E. Susan; Armstrong, Georgina N.; Zhou, Renke; Lau, Ching C.; Claus, Elizabeth B.; Barnholtz-Sloan, Jill S.; Il'yasova, Dora; Schildkraut, Joellen; Ali-Osman, Francis; Sadetzki, Siegal; Johansen, Christoffer; Houlston, Richard S.; Jenkins, Robert B.; Lachance, Daniel; Olson, Sara H.; Bernstein, Jonine L.; Merrell, Ryan T.; Wrensch, Margaret R.; Davis, Faith G.; Lai, Rose; Shete, Sanjay; Amos, Christopher I.; Scheurer, Michael E.; Aldape, Kenneth; Alafuzoff, Irina; Brännström, Thomas; Broholm, Helle; Collins, Peter; Giannini, Caterina; Rosenblum, Marc; Tihan, Tarik; Melin, Beatrice S.; Bondy, Melissa L.

    2016-01-01

    Decades of research have established only a few etiological factors for glioma, which is a rare and highly fatal brain cancer. Common methodological challenges among glioma studies include small sample sizes, heterogeneity of tumor subtypes, and retrospective exposure assessment. Here, we briefly describe the Glioma International Case-Control (GICC) Study (recruitment, 2010–2013), a study being conducted by the Genetic Epidemiology of Glioma International Consortium that integrates data from multiple data collection sites, uses a common protocol and questionnaire, and includes biospecimen collection. To our knowledge, the GICC Study is the largest glioma study to date that includes collection of blood samples, which will allow for genetic analysis and interrogation of gene-environment interactions. PMID:26656478

  7. 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

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

    PubMed

    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.

  9. 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.

  10. 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

  11. Number of glioma polyploid giant cancer cells (PGCCs) associated with vasculogenic mimicry formation and tumor grade in human glioma

    PubMed Central

    2013-01-01

    Background Polyploid giant cancer cells (PGCCs) contribute to solid tumor heterogeneity. This study investigated the relationships among PGCCs numbers, vasculogenic mimicry (VM) formation, and tumor grades in glioma. Methods A total of 76 paraffin-embedded glioma tissue samples, including 28 cases of low grade and 48 cases of high grade gliomas, were performed with H&E and immunohistochemical staining for Ki-67 and hemoglobin. The size of PGCCs nuclei was measured by a micrometer using H&E section and defined as at least three times larger than the nuclei of regular diploid cancer cells. The number of PGCCs and different blood supply patterns were compared in different grade gliomas. Microcirculation patterns in tumors were assessed using CD31 immunohistochemical and PAS histochemical double staining. Human glioma cancer cell line C6 was injected into the chicken embryonating eggs to form xenografts, which was used to observe the PGCCs and microcirculation patterns. Results In human glioma, the number of PGCCs increased with the grade of tumors (χ2 = 4.781, P = 0.015). There were three kinds of microcirculation pattern in human glioma including VM, mosaic vessel (MV) and endothelium dependent vessel. PGCCs were able to generate erythrocytes via budding to form VM. The walls of VM were positive (or negative) for PAS staining and negative for CD31 staining. There were more VM and MVs in high grade gliomas than those in low grade gliomas. The differences have statistical significances for VM (t = 3.745, P = 0.000) and MVs (t = 4.789, P = 0.000). PGCCs, VM and MVs can also be observed in C6 chicken embryonating eggs xenografts. Conclusions The data demonstrated presence of PGCCs, VM and MVs in glioma and PGCCs generating erythrocytes contribute the formation of VM and MVs. PMID:24422894

  12. Identification of Small Molecule Inhibitors of Human Cytochrome c Oxidase That Target Chemoresistant Glioma Cells.

    PubMed

    Oliva, Claudia R; Markert, Tahireh; Ross, Larry J; White, E Lucile; Rasmussen, Lynn; Zhang, Wei; Everts, Maaike; Moellering, Douglas R; Bailey, Shannon M; Suto, Mark J; Griguer, Corinne E

    2016-11-11

    The enzyme cytochrome c oxidase (CcO) or complex IV (EC 1.9.3.1) is a large transmembrane protein complex that serves as the last enzyme in the respiratory electron transport chain of eukaryotic mitochondria. CcO promotes the switch from glycolytic to oxidative phosphorylation (OXPHOS) metabolism and has been associated with increased self-renewal characteristics in gliomas. Increased CcO activity in tumors has been associated with tumor progression after chemotherapy failure, and patients with primary glioblastoma multiforme and high tumor CcO activity have worse clinical outcomes than those with low tumor CcO activity. Therefore, CcO is an attractive target for cancer therapy. We report here the characterization of a CcO inhibitor (ADDA 5) that was identified using a high throughput screening paradigm. ADDA 5 demonstrated specificity for CcO, with no inhibition of other mitochondrial complexes or other relevant enzymes, and biochemical characterization showed that this compound is a non-competitive inhibitor of cytochrome c When tested in cellular assays, ADDA 5 dose-dependently inhibited the proliferation of chemosensitive and chemoresistant glioma cells but did not display toxicity against non-cancer cells. Furthermore, treatment with ADDA 5 led to significant inhibition of tumor growth in flank xenograft mouse models. Importantly, ADDA 5 inhibited CcO activity and blocked cell proliferation and neurosphere formation in cultures of glioma stem cells, the cells implicated in tumor recurrence and resistance to therapy in patients with glioblastoma. In summary, we have identified ADDA 5 as a lead CcO inhibitor for further optimization as a novel approach for the treatment of glioblastoma and related cancers.

  13. SURVIVAL ADVANTAGE COMBINING A BRAF INHIBITOR AND RADIATION IN BRAF V600E-MUTANT GLIOMA

    PubMed Central

    Dasgupta, Tina; Olow, Aleksandra K.; Yang, Xiaodong; Hashizume, Rintaro; 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.

    2016-01-01

    Purpose 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 radiation (RT) in human HGGs in vitro and in vivo. Methods 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. Results 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. Conclusions 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. PMID:26384810

  14. 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.

  15. 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

  16. Adoptive cell transfer therapy for malignant gliomas.

    PubMed

    Ishikawa, Eiichi; Takano, Shingo; Ohno, Tadao; Tsuboi, Koji

    2012-01-01

    To date, various adoptive immunotherapies have been attempted for treatment of malignant gliomas using nonspecific and/or specific effector cells. Since the late 1980s, with the development of rIL-2, the efficacy of lymphokine-activated killer (LAK) cell therapy with or without rIL-2 for malignant gliomas had been tested with some modifications in therapeutic protocols. With advancements in technology, ex vivo expanded tumor specific cytotoxic T-lymphocytes (CTL) or those lineages were used in clinical trials with higher tumor response rates. In addition, combinations of those adoptive cell transfer using LAK cells, CTLs or natural killer (NK) cells with autologous tumor vaccine (ATV) therapy were attempted. Also, a strategy of high-dose (or lymphodepleting) chemotherapy followed by adoptive cell transfer has been drawing attentions recently. The most important role of these clinical studies using cell therapy was to prove that these ex vivo expanded effector cells could kill tumor cells in vivo. Although recent clinical results could demonstrate radiologic tumor shrinkage in a number of cases, cell transfer therapy alone has been utilized less frequently, because of the high cost of ex vivo cell expansion, the short duration of antitumor activity in vivo, and the recent shift of interest to vaccine immunotherapy. Nevertheless, NK cell therapy using specific feeder cells or allergenic NK cell lines have potentials to be a good choice of treatment because of easy ex vivo expansion and their efficacy especially when combined with vaccine therapy as they are complementary to each other. Also, further studies are expected to clarify the efficacy of the high-dose chemotherapy followed by a large scale cell transfer therapy as a new therapeutic strategy for malignant gliomas.

  17. The cyclic AMP pathway is a sex-specific modifier of glioma risk in type 1 neurofibromatosis patients

    PubMed Central

    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.

    2014-01-01

    Identifying modifiers of glioma risk in patients with type 1 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 ADCY8 which 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. PMID:25381154

  18. Enhancement of 5-aminolevulinic acid-based fluorescence detection of side population-defined glioma stem cells by iron chelation

    PubMed Central

    Wang, Wenqian; Tabu, Kouichi; Hagiya, Yuichiro; Sugiyama, Yuta; Kokubu, Yasuhiro; Murota, Yoshitaka; Ogura, Shun-ichiro; Taga, Tetsuya

    2017-01-01

    Cancer stem cells (CSCs) are dominantly responsible for tumor progression and chemo/radio-resistance, resulting in tumor recurrence. 5-aminolevulinic acid (ALA) is metabolized to fluorescent protoporphyrin IX (PpIX) specifically in tumor cells, and therefore clinically used as a reagent for photodynamic diagnosis (PDD) and therapy (PDT) of cancers including gliomas. However, it remains to be clarified whether this method could be effective for CSC detection. Here, using flow cytometry-based analysis, we show that side population (SP)-defined C6 glioma CSCs (GSCs) displayed much less 5-ALA-derived PpIX fluorescence than non-GSCs. Among the C6 GSCs, cells with ultralow PpIX fluorescence exhibited dramatically higher tumorigenicity when transplanted into the immune-deficient mouse brain. We further demonstrated that the low PpIX accumulation in the C6 GSCs was enhanced by deferoxamine (DFO)-mediated iron chelation, not by reserpine-mediated inhibition of PpIX-effluxing ABCG2. Finally, we found that the expression level of the gene for heme oxygenase-1 (HO-1), a heme degradation enzyme, was high in C6 GSCs, which was further up-regulated when treated with 5-ALA. Our results provide important new insights into 5-ALA-based PDD of gliomas, particularly photodetection of SP-defined GSCs by iron chelation based on their ALA-PpIX-Heme metabolism. PMID:28169355

  19. 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

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

    ClinicalTrials.gov

    2013-10-07

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

  1. Xeroderma pigmentosum complementation group f polymorphisms influence risk of glioma.

    PubMed

    Cheng, Hong-Bin; Xie, Chen; Zhang, Ru-You; Hu, Shao-Shan; Wang, Zhi; Yue, Wu

    2013-01-01

    We conducted an exploratory investigation of whether variation in six common SNPs of xeroderma pigmentosum complementation group F (XPF) is associated with risk of glioma in a Chinese population. Six single nucleotide polymorphisms (SNPs) were genotyped in 207 glioma cases and 236 cancer-free controls by a 384-well plate format on the Sequenom MassARRAY platform (Sequenom, San Diego, USA). The rs1800067 G and rs2276466 G allele frequencies were significantly higher in the glioma group than controls. Individuals with the rs1800067 GG genotype were at greater risk of glioma when compared with the A/A genotype in the codominant model, with an OR (95% CI) of 2.63 (1.04-7.25). The rs2276466 polymorphism was significantly associated with moderate increased risk of glioma in codominant and dominant models, with ORs (95% CI) of 1.90 (1.05-3.44) and 1.55 (1.07-2.47), respectively. The combination genotype of rs1800067 G and rs2276466 G alleles was associated with a reduced risk of glioma (OR=0.44, 95% CI=0.19-0.98). These findings indicate that genetic variants of the XPF gene have critical functions in the development of glioma.

  2. Hugl-1 inhibits glioma cell growth in intracranial model.

    PubMed

    Liu, Xuejiao; Lu, Dong; Ma, Peng; Liu, Huaqiang; Cao, Yuewen; Sang, Ben; Zhu, Xianlong; Shi, Qiong; Hu, Jinxia; Yu, Rutong; Zhou, Xiuping

    2015-10-01

    Drosophila lethal (2) giant larvae (lgl) has been reported as a tumor suppressor and could regulate the Drosophila hippo signaling. Human giant larvae-1(Hugl-1), one human homologue of Drosophila lgl, also has been reported to be involved in the development of some human cancers. However, whether Hugl-1 is associated with the pathogenesis of malignant gliomas remains poorly understood. In the present work, we examined the effect of Hugl-1 on glioma cell growth both in vitro and in vivo. Firstly, we found that Hugl-1 protein levels decreased in the human glioma tissues, suggesting that Hugl-1 is involved in glioma progression. Unfortunately, either stably or transiently over-expressing Hugl-1 did not affect glioma cell proliferation in vitro. In addition, Hugl-1 over-expression did not regulate hippo signaling pathway. Interestingly, over-expression of Hugl-1 not only inhibited gliomagenesis but also markedly inhibited cell proliferation and promoted the apoptosis of U251 cells in an orthotopic model of nude mice. Taken together, this study provides the evidence that Hugl-1 inhibits glioma cell growth in intracranial model of nude mice, suggesting that Hugl-1 might be a potential tumor target for glioma therapy.

  3. Understanding inherited genetic risk of adult glioma – a review

    PubMed Central

    Rice, Terri; Lachance, Daniel H.; Molinaro, Annette M.; Eckel-Passow, Jeanette E.; Walsh, Kyle M.; Barnholtz-Sloan, Jill; Ostrom, Quinn T.; Francis, Stephen S.; Wiemels, Joseph; Jenkins, Robert B.; Wiencke, John K.; Wrensch, Margaret R.

    2016-01-01

    During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families. PMID:26941959

  4. Understanding inherited genetic risk of adult glioma - a review.

    PubMed

    Rice, Terri; Lachance, Daniel H; Molinaro, Annette M; Eckel-Passow, Jeanette E; Walsh, Kyle M; Barnholtz-Sloan, Jill; Ostrom, Quinn T; Francis, Stephen S; Wiemels, Joseph; Jenkins, Robert B; Wiencke, John K; Wrensch, Margaret R

    2016-03-01

    During the past six years, researchers have made major progress identifying common inherited genetic variation that increases risk for primary adult glioma. This paper summarizes knowledge about rare familial cancer syndromes that include adult glioma and reviews the available literature on the more recently discovered common inherited variation. Ten independent inherited variants in eight chromosomal regions have been convincingly associated with increased risk for adult glioma. Most of these variants increase relative risk of primary adult glioma by 20% to 40%, but the TP53 variant rs78378222 confers a two-fold relative risk (ie, 200%), and rs557505857 on chromosome 8 confers a six-fold relative risk of IDH-mutated astrocytomas and oligodendroglial tumors (ie, 600%). Even with a six-fold relative risk, the overall risk of developing adult glioma is too low for screening for the high-risk variant on chromosome 8. Future studies will help clarify which inherited adult glioma risk variants are associated with subtypes defined by histology and/or acquired tumor mutations. This review also provides an information sheet for primary adult glioma patients and their families.

  5. 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.

  6. Evaluation of nano-magnetic fluid on malignant glioma cells

    PubMed Central

    Xu, Hongsheng; Zong, Hailiang; Ma, Chong; Ming, Xing; Shang, Ming; Li, Kai; He, Xiaoguang; Cao, Lei

    2017-01-01

    The temperature variation rule of nano-magnetic fluid in the specific magnetic field and the effect on the treatment of malignant glioma were examined. The temperature variation of nano-magnetic fluid in the specific magnetic field was investigated by heating in vitro, and cell morphology was observed through optical microscopy and electron microscopy. MTT detection also was used to detect the effect of Fe3O4 nanometer magnetic fluid hyperthermia (MFH) on the proliferation of human U251 glioma cell line. The Fe3O4 nano MFH experiment was used to detect the inhibition rate of the tumor volume in nude mice with tumors. The results of the experiment showed that the heating ability of magnetic fluid was positively correlated with its concentration at the same intensity of the magnetic field. The results also indicated the prominent inhibitory effect of nanometer MFH on the proliferation of glioma cells, which was a dose-dependent relationship with nanometer magnetic fluid concentration. The hyperthermia experiment of nude mice with tumors displayed a significant inhibiting effect of Fe3O4 nanometer magnetic fluid in glioma volume. These results explain that iron (II, III) oxide (Fe3O4) nanometer MFH can inhibit the proliferation of U251 glioma cells, and has an obvious inhibitory effect on glioma volume, which plays a certain role in the treatment of brain glioma. PMID:28356945

  7. 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

  8. Evaluation of nano-magnetic fluid on malignant glioma cells.

    PubMed

    Xu, Hongsheng; Zong, Hailiang; Ma, Chong; Ming, Xing; Shang, Ming; Li, Kai; He, Xiaoguang; Cao, Lei

    2017-02-01

    The temperature variation rule of nano-magnetic fluid in the specific magnetic field and the effect on the treatment of malignant glioma were examined. The temperature variation of nano-magnetic fluid in the specific magnetic field was investigated by heating in vitro, and cell morphology was observed through optical microscopy and electron microscopy. MTT detection also was used to detect the effect of Fe3O4 nanometer magnetic fluid hyperthermia (MFH) on the proliferation of human U251 glioma cell line. The Fe3O4 nano MFH experiment was used to detect the inhibition rate of the tumor volume in nude mice with tumors. The results of the experiment showed that the heating ability of magnetic fluid was positively correlated with its concentration at the same intensity of the magnetic field. The results also indicated the prominent inhibitory effect of nanometer MFH on the proliferation of glioma cells, which was a dose-dependent relationship with nanometer magnetic fluid concentration. The hyperthermia experiment of nude mice with tumors displayed a significant inhibiting effect of Fe3O4 nanometer magnetic fluid in glioma volume. These results explain that iron (II, III) oxide (Fe3O4) nanometer MFH can inhibit the proliferation of U251 glioma cells, and has an obvious inhibitory effect on glioma volume, which plays a certain role in the treatment of brain glioma.

  9. 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.

  10. DNA sequences within glioma-derived extracellular vesicles can cross the intact blood-brain barrier and be detected in peripheral blood of patients

    PubMed Central

    Lázaro-Ibáñez, Elisa; Peris-Celda, María; Alonso, Marta M.; Guzmán-De-Villoria, Juan; Fernández-Carballal, Carlos; de Mendivil, Ana Ortiz; García-Duque, Sara; Escobedo-Lucea, Carmen; Prat-Acín, Ricardo; Belda-Iniesta, Cristóbal; Ayuso-Sacido, Angel

    2017-01-01

    Tumor-cell-secreted extracellular vesicles (EVs) can cross the disrupted blood-brain barrier (BBB) into the bloodstream. However, in certain gliomas, the BBB remains intact, which might limit EVs release. To evaluate the ability of tumor-derived EVs to cross the BBB, we used an orthotopic xenotransplant mouse model of human glioma-cancer stem cells featuring an intact BBB. We demonstrated that all types of tumor cells-derived EVs−apoptotic bodies, shedding microvesicles and exosomes−cross the intact BBB and can be detected in the peripheral blood, which provides a minimally invasive method for their detection compared to liquid biopsies obtained from cerebrospinal fluid (CSF). Furthermore, these EVs can be readily distinguished from total murine EVs, since they carry human-specific DNA sequences relevant for GBM biology. In a small cohort of glioma patients, we finally demonstrated that peripheral blood EVs cargo can be successfully used to detect the presence of IDH1G395A, an essential biomarker in the current management of human glioma PMID:27902458

  11. Use of cardiac glycosides and risk of glioma.

    PubMed

    Seliger, Corinna; Meier, Christoph R; Jick, Susan S; Uhl, Martin; Bogdahn, Ulrich; Hau, Peter; Leitzmann, M F

    2016-04-01

    Cardiac glycosides induce apoptotic effects on glioma cells, but whether cardiac glycosides protect against risk for glioma is unknown. We therefore explored the relation between glycoside use and glioma risk using a large and validated database. We performed a case-control analysis using the Clinical Practice Research Datalink involving 2005 glioma cases diagnosed between 1995 and 2012 that were individually matched to 20,050 controls on age, gender, general practice, and number of years of active history in the database. Conditional logistic regression analysis was used to evaluate the association between cardiac glycosides and the risk of glioma adjusting for body mass index and smoking. We also examined use of common heart failure and arrhythmia medications to differentiate between a specific glycoside effect and a generic effect of treatment for congestive heart failure or arrhythmia. Cardiac glycoside use was inversely related to glioma incidence. After adjustment for congestive heart failure, arrhythmia, diabetes, and common medications used to treat those conditions, the OR of glioma was 0.47 (95% CI 0.27-0.81, Bonferroni-corrected p value = 0.024) for use versus non-use of cardiac glycosides, based on 17 exposed cases. In contrast, no associations were noted for other medications used to treat congestive heart failure or arrhythmias. The OR of glioma in people with congestive heart failure was 0.65 (95% CI 0.40-1.04), and for arrhythmia it was 1.01 (95% CI 0.78-1.31). These data indicate that cardiac glycoside use is independently associated with reduced glioma risk.

  12. IGFBP2 expression predicts IDH-mutant glioma patient survival

    PubMed Central

    Huang, Lin Eric; Cohen, Adam L.; Colman, Howard; Jensen, Randy L.; Fults, Daniel W.; Couldwell, William T.

    2017-01-01

    Mutations of the isocitrate dehydrogenase (IDH) 1 and 2 genes occur in ~80% of lower-grade (WHO grade II and grade III) gliomas. Mutant IDH produces (R)-2-hydroxyglutarate, which induces DNA hypermethylation and presumably drives tumorigenesis. Interestingly, IDH mutations are associated with improved survival in glioma patients, but the underlying mechanism for the difference in survival remains unclear. Through comparative analyses of 286 cases of IDH-wildtype and IDH-mutant lower-grade glioma from a TCGA data set, we report that IDH-mutant gliomas have increased expression of tumor-suppressor genes (NF1, PTEN, and PIK3R1) and decreased expression of oncogenes(AKT2, ARAF, ERBB2, FGFR3, and PDGFRB) and glioma progression genes (FOXM1, IGFBP2, and WWTR1) compared with IDH-wildtype gliomas. Furthermore, each of these genes is prognostic in overall gliomas; however, within the IDH-mutant group, none remains prognostic except IGFBP2 (encodinginsulin-like growth factor binding protein 2). Through validation in an independent cohort, we show that patients with low IGFBP2 expressiondisplay a clear advantage in overall and disease-free survival, whereas those with high IGFBP2 expressionhave worse median survival than IDH-wildtype patients. These observations hold true across different histological and molecular subtypes of lower-grade glioma. We propose therefore that an unexpected biological consequence of IDH mutations in glioma is to ameliorate patient survival by promoting tumor-suppressor signaling while inhibiting that of oncogenes, particularly IGFBP2. PMID:27852048

  13. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues

    PubMed Central

    Cherry, Allison E; Stella, Nephi

    2014-01-01

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including GBM. GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease. PMID:25158675

  14. G protein-coupled receptors as oncogenic signals in glioma: emerging therapeutic avenues.

    PubMed

    Cherry, A E; Stella, N

    2014-10-10

    Gliomas are the most common malignant intracranial tumors. Newly developed targeted therapies for these cancers aim to inhibit oncogenic signals, many of which emanate from receptor tyrosine kinases, including the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR). Unfortunately, the first-generation treatments targeting these oncogenic signals provide little survival benefit in both mouse xenograft models and human patients. The search for new treatment options has uncovered several G protein-coupled receptor (GPCR) candidates and generated a growing interest in this class of proteins as alternative therapeutic targets for the treatment of various cancers, including glioblastoma multiforme (GBM). GPCRs constitute a large family of membrane receptors that influence oncogenic pathways through canonical and non-canonical signaling. Accordingly, evidence indicates that GPCRs display a unique ability to crosstalk with receptor tyrosine kinases, making them important molecular components controlling tumorigenesis. This review summarizes the current research on GPCR functionality in gliomas and explores the potential of modulating these receptors to treat this devastating disease.

  15. Microglia isolated from patients with glioma gain antitumor activities on poly (I:C) stimulation.

    PubMed

    Kees, Tim; Lohr, Jennifer; Noack, Johannes; Mora, Rodrigo; Gdynia, Georg; Tödt, Grischa; Ernst, Aurélie; Radlwimmer, Bernhard; Falk, Christine S; Herold-Mende, Christel; Régnier-Vigouroux, Anne

    2012-01-01

    The role of microglia, the brain-resident macrophages, in glioma biology is still a matter of debate. Clinical observations and in vitro studies in the mouse model indicate that microglia and macrophages that infiltrate the brain tumor tissue in high numbers play a tumor-supportive role. Here, we provide evidence that human microglia isolated from brain tumors indeed support tumor cell growth, migration, and invasion. However, after stimulation with the Toll-like receptor 3 agonist poly (I:C), microglia secrete factors that exerted toxic and suppressive effects on different glioblastoma cell lines, as assessed in cytotoxicity, migration, and tumor cell spheroid invasion assays. Remarkably, these effects were tumor-specific because the microglial factors impaired neither growth nor viability of astrocytes and neurons. Culture supernatants of tumor cells inhibited the poly (I:C) induction of this microglial M1-like, oncotoxic profile. Microglia stimulation before coculture with tumor cells circumvented the tumor-mediated suppression, as demonstrated by the ability to kill and phagocytose glioma cells. Our results show, for the first time to our knowledge, that human microglia exert tumor-supporting functions that are overridden by tumor-suppressing activities gained after poly (I:C) stimulation.

  16. Localisation of malignant glioma by a radiolabelled human monoclonal antibody.

    PubMed Central

    Phillips, J; Alderson, T; Sikora, K; Watson, J

    1983-01-01

    Human monoclonal antibodies were produced by fusing intratumoral lymphocytes from patients with malignant gliomas with a human myeloma line. One antibody was selected for further study after screening for binding activity to glioma cell lines. The patient from whom it was derived developed recurrent glioma. 1 mg of antibody was purified, radiolabelled with 131I, and administered intravenously. The distribution of antibody was determined in the blood, CSF and tumour cyst fluid and compared with that of a control human monoclonal immunoglobulin. Antibody localisation in the tumour was observed and confirmed by external scintiscanning. Images PMID:6101173

  17. Noscapine inhibits tumor growth in TMZ-resistant gliomas.

    PubMed

    Jhaveri, Niyati; Cho, Heeyeon; Torres, Shering; Wang, Weijun; Schönthal, Axel H; Petasis, Nicos A; Louie, Stan G; Hofman, Florence M; Chen, Thomas C

    2011-12-22

    Noscapine, a common oral antitussive agent, has been shown to have potent antitumor activity in a variety of cancers. Treatment of glioblastoma multiforme (GBM) with temozolomide (TMZ), its current standard of care, is problematic because the tumor generally recurs and is then resistant to this drug. We therefore investigated the effects of noscapine on human TMZ-resistant GBM tumors. We found that noscapine significantly decreased TMZ-resistant glioma cell growth and invasion. Using the intracranial xenograft model, we showed that noscapine increased survival of animals with TMZ-resistant gliomas. Thus noscapine can provide an alternative therapeutic approach for the treatment of TMZ-resistant gliomas.

  18. 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

  19. 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

  20. Extracts from Glioma Tissues following Cryoablation Have Proapoptosis, Antiproliferation, and Anti-Invasion Effects on Glioma Cells

    PubMed Central

    Liu, Tianzhu; Wang, Xin; Yin, Zhilin; Pan, Jun; Guo, Hongbo; Zhang, Shizhong

    2014-01-01

    Objective. This study is to investigate the in vivo apoptotic processes in glioma tissues following cryoablation and the effects of glioma tissue extracts on GL261 glioma cells in vitro. Methods. TUNEL and flow cytometry analysis were performed to detect the apoptotic processes in the glioma tissues following cryoablation and in the GL261 cells treated with cryoablated tumor extracts. The scratch assay, the transwell assay, and Western blot analysis were carried out to evaluate the effects of cryoablated tumor extracts on the migration, invasion, and proliferation of tumor cells. Results. Our in vivo results indicated that the rapid-onset apoptosis was induced via the intrinsic pathway and the delayed apoptosis was triggered through the extrinsic pathway. The in vitro results showed that extracts from glioma tissues following cryoablation induced apoptosis via extrinsic pathways in GL261 glioma cells. Furthermore, cryoablated tumor extracts significantly inhibited the migration and proliferation of these cells, which would be related to the inhibition of ERK1/2 pathway and the activation of P38 pathway. Conclusion. Glioma cells surviving in cryoablation undergo intrinsic or extrinsic apoptosis. Augmenting the induction of apoptosis or enhancing the cryosensitization of tumor cells by coupling cryoablation with specific chemotherapy effectively increases the efficiency of this therapeutic treatment. PMID:24818132

  1. 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

  2. SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.

    PubMed

    Robert, Stephanie M; Buckingham, Susan C; Campbell, Susan L; Robel, Stefanie; Holt, Kenneth T; Ogunrinu-Babarinde, Toyin; Warren, Paula P; White, David M; Reid, Meredith A; Eschbacher, Jenny M; Berens, Michael E; Lahti, Adrienne C; Nabors, Louis B; Sontheimer, Harald

    2015-05-27

    Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.

  3. Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3

    PubMed Central

    Cuddapah, Vishnu Anand; Turner, Kathryn L.; Seifert, Stefanie; Sontheimer, Harald

    2013-01-01

    Previous reports demonstrate that cell migration in the nervous system is associated with stereotypic changes in intracellular calcium concentration ([Ca2+]i), yet the target of these changes are largely unknown. We examined chemotactic migration/invasion of human gliomas to study how [Ca2+]i regulates cellular movement and to identify downstream targets. Gliomas are primary brain cancers which spread exclusively within the brain, frequently migrating along blood vessels to which they are chemotactically attracted by bradykinin activating G protein-coupled receptors. Using simultaneous Fura-2 Ca2+ imaging and amphotericin B perforated patch-clamp electrophysiology, we find that bradykinin raises [Ca2+]i and induces a biphasic voltage response. This voltage response is mediated by the coordinated activation of Ca2+-dependent, TRAM-34-sensitive KCa3.1 channels, and Ca2+-depdenent, DIDS- and gluconate-sensitive Cl− channels. A significant portion of these Cl− currents can be attributed to Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation of ClC-3, a voltage-gated Cl−channel/transporter, since pharmacological inhibition of CaMKII or shRNA-mediated knockdown of ClC-3 inhibited Ca2+-activated Cl− currents. Western blots show that KCa3.1 and ClC-3 are expressed in tissue samples obtained from patients diagnosed with Grade IV gliomas. Both KCa3.1 and ClC-3 co-localize to the invading processes of glioma cells. Importantly, inhibition of either channel abrogates bradykinin-induced chemotaxis and reduces tumor expansion in mouse brain slices in situ. These channels should be further explored as future targets for anti-invasive drugs. Furthermore, this data elucidates a novel mechanism placing cation and anion channels downstream of ligand-mediated [Ca2+]i increases, which likely play similar roles in other migratory cells in the nervous system. PMID:23345219

  4. 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

  5. Gene therapy and targeted toxins for glioma.

    PubMed

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

    2011-06-01

    The most common primary brain tumor in adults is glioblastoma. These tumors are highly invasive and aggressive with a mean survival time of 15-18 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.

  6. 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

  7. Survival after stereotactic biopsy of malignant gliomas

    SciTech Connect

    Coffey, R.J.; Lunsford, L.D.; Taylor, F.H.

    1988-03-01

    For many patients with malignant gliomas in inaccessible or functionally important locations, stereotactic biopsy followed by radiation therapy (RT) may be a more appropriate initial treatment than craniotomy and tumor resection. We studied the long term survival in 91 consecutive patients with malignant gliomas diagnosed by stereotactic biopsy: 64 had glioblastoma multiforme (GBM) and 27 had anaplastic astrocytoma (AA). Sixty-four per cent of the GBMs and 33% of the AAs involved deep or midline cerebral structures. The treatment prescribed after biopsy, the tumor location, the histological findings, and the patient's age at presentation (for AAs) were statistically important factors determining patient survival. If adequate RT (tumor dose of 5000 to 6000 cGy) was not prescribed, the median survival was less than or equal to 11 weeks regardless of tumor histology or location. The median survival for patients with deep or midline tumors who completed RT was similar in AA (19.4 weeks) and GBM (27 weeks) cases. Histology was an important predictor of survival only for patients with adequately treated lobar tumors. The median survival in lobar GBM patients who completed RT was 46.9 weeks, and that in lobar AA patients who completed RT was 129 weeks. Cytoreductive surgery had no statistically significant effect on survival. Among the clinical factors examined, age of less than 40 years at presentation was associated with prolonged survival only in AA patients. Constellations of clinical features, tumor location, histological diagnosis, and treatment prescribed were related to survival time.

  8. 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.

  9. ATRX Loss Promotes Tumor Growth and Impairs Non-Homologous End Joining DNA Repair in Glioma

    PubMed Central

    Koschmann, Carl; Calinescu, Anda-Alexandra; Nunez, Felipe J.; Mackay, Alan; Fazal-Salom, Janet; Thomas, Daniel; Mendez, Flor; Kamran, Neha; Dzaman, Marta; Mulpuri, Lakshman; Krasinkiewicz, Johnathon; Doherty, Robert; Lemons, Rosemary; Brosnan-Cashman, Jackie A.; Li, Youping; Roh, Soyeon; Zhao, Lili; Appelman, Henry; Ferguson, David; Gorbunova, Vera; Meeker, Alan; Jones, Chris; Lowenstein, Pedro R.; Castro, Maria G.

    2017-01-01

    Recent work in human glioblastoma (GBM) has documented recurrent mutations in the histone chaperone protein ATRX. We developed an animal model of ATRX-deficient GBM and show that loss of ATRX reduces median survival and increases genetic instability. Further, analysis of genome-wide data for human gliomas showed that ATRX mutation is associated with increased mutation rate at the single nucleotide variant (SNV) level. In mouse tumors, ATRX deficiency impairs non-homologous end joining (NHEJ) and increases sensitivity to DNA-damaging agents that induce double-stranded DNA breaks. We propose that ATRX loss results in a genetically unstable tumor, which is more aggressive when left untreated, but is more responsive to double-stranded DNA-damaging agents, resulting in improved overall survival. PMID:26936505

  10. Most human non-GCIMP glioblastoma subtypes evolve from a common proneural-like precursor glioma

    PubMed Central

    Ozawa, Tatsuya; Riester, Markus; Cheng, Yu-Kang; Huse, Jason T; Squatrito, Massimo; Helmy, Karim; Charles, Nikki; Michor, Franziska; Holland, Eric C.

    2014-01-01

    SUMMARY To understand the relationships between the non-GCIMP glioblastoma (GBM) subgroups, we performed mathematical modeling to predict the temporal sequence of driver events during tumorigenesis. The most common order of evolutionary events is 1) chromosome (chr) 7 gain and chr10 loss, followed by 2) CDKN2A loss and/or TP53 mutation, and 3) alterations canonical for specific subtypes. We then developed a computational methodology to identify drivers of broad copy number changes, identifying PDGFA (chr7) and PTEN (chr10) as driving initial non-disjunction events. These predictions were validated using mouse modeling, showing that PDGFA is sufficient to induce proneural-like gliomas, and additional NF1 loss converts proneural to the mesenchymal subtype. Our findings suggest most non-GCIMP-mesenchymal GBMs arise as, and evolve from, a proneural-like precursor. PMID:25117714

  11. Challenges in Drug Discovery for Neurofibromatosis Type 1-Associated Low-Grade Glioma

    PubMed Central

    Ricker, Cora A.; Pan, Yuan; Gutmann, David H.; Keller, Charles

    2016-01-01

    Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that results from germline mutations of the NF1 gene, creating a predisposition to low-grade gliomas (LGGs; pilocytic astrocytoma) in young children. Insufficient data and resources represent major challenges to identifying the best possible drug therapies for children with this tumor. Herein, we summarize the currently available cell lines, genetically engineered mouse models, and therapeutic targets for these LGGs. Conspicuously absent are human tumor-derived cell lines or patient-derived xenograft models for NF1-LGG. New collaborative initiatives between patients and their families, research groups, and pharmaceutical companies are needed to create transformative resources and broaden the knowledge base relevant to identifying cooperating genetic drivers and possible drug therapeutics for this common pediatric brain tumor. PMID:28066715

  12. Experimental therapy of human glioma by means of a genetically engineered virus mutant

    SciTech Connect

    Martuza, R.L.; Malick, A.; Markert, J.M.; Ruffner, K.L.; Coen, D.M. )

    1991-05-10

    Malignant gliomas are the most common malignant brain tumors and are almost always fatal. A thymidine kinase-negative mutant of herpes simplex virus-1 (dlsptk) that is attenuated for neurovirulence was tested as a possible treatment for gliomas. In cell culture, dlsptk killed two long-term human glioma lines and three short-term human glioma cell populations. In nude mice with implanted subcutaneous and subrenal U87 human gliomas, intraneoplastic inoculation of dlsptk caused growth inhibition. In nude mice with intracranial U87 gliomas, intraneoplastic inoculation of dlsptk prolonged survival. Genetically engineered viruses such as dlsptk merit further evaluation as novel antineoplastic agents.

  13. Alpinetin targets glioma stem cells by suppressing Notch pathway.

    PubMed

    Wang, Jianpeng; Yan, Zhiyong; Liu, Xia; Che, Shusheng; Wang, Chao; Yao, Weicheng

    2016-07-01

    Glioma is among the most common human malignancies with poor prognosis. Glioma stem cells (GSCs) are the culprit of glioma, suggesting that GSCs are potential therapeutic targets. Notch signaling pathway plays a pivotal role for the function of GSCs, implying that suppression of Notch pathway may be an effective strategy for GSC-targeting therapy. In this study, we found that alpinetin, a natural compound, can suppress the proliferation and invasiveness of GSCs and induce apoptosis in GSCs. Immunoblot analysis and luciferase assay revealed that Notch signaling was suppressed by alpinetin. Furthermore, restoration of Notch signaling activity rescued the effect of alpinetin on GSC's function. The anti-tumor activity of alpinetin was further confirmed in an animal model. Collectively, targeting of GSC by alpinetin is an effective strategy for glioma therapy.

  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. Cognition and resective surgery for diffuse infiltrative glioma: an overview.

    PubMed

    Klein, Martin; Duffau, Hugues; De Witt Hamer, Philip C

    2012-06-01

    Compared to classical oncological outcome measures such as time to progression and survival, the importance of cognitive functioning in patients with diffuse infiltrative brain tumors has only recently been recognized. Apart from the relatively low incidence and the invariably fatal outcome of gliomas, the general assumption that cognitive assessment is time-consuming and burdensome contributes to this notion. Our understanding of the effects of brain surgery on cognition, for instance, is largely based on studies in surgical patients with refractory epilepsy, with only a limited number of studies in surgical patients with gliomas. The impact of other factors affecting cognition in glioma patients such as direct tumor effects, radiotherapy and chemotherapy, and medical treatment, including anti-epileptic drugs and steroids, have been studied more extensively. The purpose of this paper is to provide an overview of cognition in patients with diffuse infiltrative gliomas and the impact of resective surgery as well as other tumor and treatment-related factors.

  16. Salinomycin inhibits the tumor growth of glioma stem cells by selectively suppressing glioma-initiating cells.

    PubMed

    Chen, Tunan; Yi, Liang; Li, Fei; Hu, Rong; Hu, Shengli; Yin, Yi; Lan, Chuan; Li, Zhao; Fu, Chuhua; Cao, Liu; Chen, Zhi; Xian, Jishu; Feng, Hua

    2015-04-01

    Glioma‑initiating cells are a small population of cells that have the ability to undergo self‑renewal and initiate tumorigenesis. In the present study, the potential role of salinomycin, a polyether antibiotic, on the suppression of glioma cell growth was investigated. GL261 glioma cells were maintained in a stem‑cell‑like status [GL261 neurospheres (GL261‑NS)] or induced for differentiation [GL261 adherent cells (GL261‑AC)]. It was demonstrated that salinomycin significantly reduced the cell viability of GL261‑NS and GL261‑AC cells in a dose‑dependent manner, with a more substantial inhibition of GL261‑NS proliferation (P<0.05). The inhibitory effect of salinomycin on cell growth was more effective than that of 1‑(4‑amino‑2‑methyl‑5‑pyrimid l)‑methyl‑3‑(2‑chloroethyl)‑3‑nitrosourea hydrochloride and vincristine (P<0.05). Salinomycin depleted GL261‑NS from tumorspheres and induced cell apoptosis. In addition, salinomycin prolonged the median survival time of glioma‑bearing mice (P<0.05). Therefore, the present study indicated that salinomycin may preferentially inhibit glioma‑initiated cell growth by inducing apoptosis, suggesting that salinomycin may provide a valuable therapeutic strategy for the treatment of malignant glioma.

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

    PubMed Central

    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

  18. Malignant glioma following radiotherapy for unrelated primary tumors

    SciTech Connect

    Marus, G.; Levin, C.V.; Rutherfoord, G.S.

    1986-08-15

    Four cases are documented where a glioma was histologically verified in the irradiation field of a previously treated malignancy of a different cell line. Radiation-induced neoplasia in the central nervous system now has been established in the induction of meningioma and sarcoma. The association between therapeutic irradiation and glioma in the reported cases lends to the evidence that a causal relation does exist. This incidence is small and does not detract from the overall benefit of irradiation as a therapeutic modality.

  19. Targeting Pediatric Glioma with Apoptosis and Autophagy Manipulation

    DTIC Science & Technology

    2014-10-01

    13. SUPPLEMENTARY NOTES 14. ABSTRACT Gliomas are the most common and most deadly solid tumors that affect children . Treatment options are limited and...Gliomas are the most common and most deadly solid tumors that affect children . Treatment options are limited and cure rates are dismal. My laboratory has...tyrosine kinase inhibition. Society for Neuro- Oncology International Meetings Poster Presentation. November 2013. -Pierce AM, Keating AK. TAM Receptor

  20. Mitochondrial Dysfunction in Gliomas: Pharmacotherapeutic Potential of Natural Compounds

    PubMed Central

    Guntuku, Lalita; Naidu, G.M.; Yerra, Veera Ganesh

    2016-01-01

    Gliomas are the most common primary brain tumors either benign or malignant originating from the glial tissue. Glioblastoma multiforme (GBM) is the most prevalent and aggressive form among all gliomas, associated with decimal prognosis due to it's high invasive nature. GBM is also characterized by high recurrence rate and apoptosis resistance features which make the therapeutic targeting very challenging. Mitochondria are key cellular organelles that are acting as focal points in diverse array of cellular functions such as cellular energy metabolism, regulation of ion homeostasis, redox signaling and cell death. Eventual findings of mitochondrial dysfunction include preference of glycolysis over oxidative phosphorylation, enhanced reactive oxygen species generation and abnormal mitochondria mediated apoptotic machinery are frequently observed in various malignancies including gliomas. In particular, gliomas harbor mitochondrial structure abnormalities, genomic mutations in mtDNA, altered energy metabolism (Warburg effect) along with mutations in isocitrate dehydrogenase (IDH) enzyme. Numerous natural compounds have shown efficacy in the treatment of gliomas by targeting mitochondrial aberrant signaling cascades. Some of the natural compounds directly target the components of mitochondria whereas others act indirectly through modulating metabolic abnormalities that are consequence of the mitochondrial dysfunction. The present review offers a molecular insight into mitochondrial pathology in gliomas and therapeutic mechanisms of some of the promising natural compounds that target mitochondrial dysfunction. This review also sheds light on the challenges and possible ways to overcome the hurdles associated with these natural compounds to enter into the clinical market. PMID:26791479

  1. Risk of seizures in children with tectal gliomas.

    PubMed

    Dabscheck, Gabriel; Prabhu, Sanjay P; Manley, Peter E; Goumnerova, Liliana; Ullrich, Nicole J

    2015-09-01

    The objective of this study was to determine the prevalence of seizures in children with tectal gliomas and to determine if there are common clinical, electroencephalography (EEG), or radiologic findings that predict risk of seizures in these patients. We conducted a retrospective review of all patients with tectal gliomas over a 22-year period at a single institution. Data extraction included sex, age at presentation of tectal glioma and age of presentation with seizures, magnetic resonance imaging (MRI) findings, seizure frequency and semiology, and EEG findings. We identified 79 patients, 66 of whom had adequate imaging and clinical data for further analysis. Eight patients (12.1%) had a history of seizures. Three patients had a clear symptomatic cause of seizures. Three patients were diagnosed with a tectal glioma as an incidental finding after a first seizure. One patient had a history of febrile convulsions. One patient had a generalized seizure 5 years after presenting with macrocephaly. Although the risk of seizure in children with known tectal glioma was relatively high, we did not identify specific clinical, radiologic, EEG, or MRI features that are predictive of increased risk. Thus, in children with tectal gliomas who have seizures, alternative causes for the seizures must be sought.

  2. 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.

  3. 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.

  4. Human immunoglobulin G levels of viruses and associated glioma risk.

    PubMed

    Sjöström, Sara; Hjalmars, Ulf; Juto, Per; Wadell, Göran; Hallmans, Göran; Tjönneland, Anne; Halkjaer, Jytte; Manjer, Jonas; Almquist, Martin; Melin, Beatrice S

    2011-09-01

    Few consistent etiological factors have been identified for primary brain tumors. Inverse associations to asthma and low levels of varicella-zoster virus, immunoglobulin (Ig) levels in prevalent cases have indicted a role for the immune system in the development of glioma. Because samples from prevalent cases of glioma could be influenced by treatments such as steroids and chemotherapy, we investigated pre-diagnostic samples from three large Scandinavian cohorts. To test the hypothesis that immune response levels to these viruses are associated etiologically with glioma risk, we investigated pre-diagnostic immunoglobulin levels for cytomegalovirus (CMV), varicella-zoster virus (VZV), adenovirus (Ad), and Epstein-Barr virus (EBV) including the nuclear antigen (EBNA1) using plasma samples from 197 cases of adult glioma and 394 controls collected from population-based cohorts in Sweden and Denmark. Low VZV IgG levels were marginally significantly more common in glioma cases than the controls (odds ratio (OR) = 0.68, 95% CI 0.41-1.13) for the fourth compared with the first quartile (p = 0.06 for trend). These results were more prominent when analyzing cases with blood sampling at least 2 years before diagnosis (OR = 0.63, 95% CI 0.37-1.08) (p = 0.03). No association with glioma risk was observed for CMV, EBV, and adenovirus.

  5. Nicotinic acid inhibits glioma invasion by facilitating Snail1 degradation

    PubMed Central

    Li, Jiejing; Qu, Jiagui; Shi, Yu; Perfetto, Mark; Ping, Zhuxian; Christian, Laura; Niu, Hua; Mei, Shuting; Zhang, Qin; Yang, Xiangcai; Wei, Shuo

    2017-01-01

    Malignant glioma is a formidable disease that commonly leads to death, mainly due to the invasion of tumor cells into neighboring tissues. Therefore, inhibition of tumor cell invasion may provide an effective therapy for malignant glioma. Here we report that nicotinic acid (NA), an essential vitamin, inhibits glioma cell invasion in vitro and in vivo. Treatment of the U251 glioma cells with NA in vitro results in reduced invasion, which is accompanied by a loss of mesenchymal phenotype and an increase in cell-cell adhesion. At the molecular level, transcription of the adherens junction protein E-cadherin is upregulated, leading to accumulation of E-cadherin protein at the cell-cell boundary. This can be attributed to NA’s ability to facilitate the ubiquitination and degradation of Snail1, a transcription factor that represses E-cadherin expression. Similarly, NA transiently inhibits neural crest migration in Xenopus embryos in a Snail1-dependent manner, indicating that the mechanism of action for NA in cell migration is evolutionarily conserved. We further show that NA injection blocks the infiltration of tumor cells into the adjacent brain tissues and improves animal survival in a rat model of glioma. These results suggest that NA treatment may be developed into a potential therapy for malignant glioma. PMID:28256591

  6. Moving toward molecular classification of diffuse gliomas in adults.

    PubMed

    Theeler, Brett J; Yung, W K Alfred; Fuller, Gregory N; De Groot, John F

    2012-10-30

    Diffuse gliomas are a heterogenous group of neoplasms traditionally classified as grades II to IV based on histologic features, and with prognosis determined mainly by histologic grade and pretreatment clinical factors. Our understanding of the molecular basis of glioma initiation, tumor progression, and treatment failure is rapidly evolving. A molecular profile of diffuse gliomas is emerging. Studies evaluating gene expression and DNA methylation profile have found multiple glioma subtypes and an association between subtype and survival. The recent discovery of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations in glioma has provided reproducible prognostic biomarkers and novel therapeutic targets. Glioblastomas that exhibit CpG island hypermethylator phenotype, proneural gene expression, or IDH1 mutation identify a subset of patients with markedly improved prognosis. Accumulated evidence supports the stratification of both low-grade and anaplastic diffuse gliomas into prognostic groups using 1p/19q codeletion and IDH mutation status. A classification scheme incorporating clinical, pathologic, and molecular information may facilitate improved prognostication for patients treated in the clinic, the development of more effective clinical trials, and rational testing of targeted therapeutics.

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. DNA content and chromosomal composition of malignant human gliomas.

    PubMed

    Bigner, S H; Bjerkvig, R; Laerum, O D

    1985-11-01

    A short review is given on DNA aberrations and chromosomal composition of malignant human gliomas. By flow cytometric DNA analysis, a wide range of different ploidies has been reported in biopsied gliomas, from diploid to strongly aneuploid nuclear DNA. However, with the preparation and analysis methods used so far, no clear relationship between the type of ploidy and histology or prognosis has been established. A high proportion of glioblastomas is near-diploid, indicating a high degree of biologic malignancy is not necessarily connected to aberration of the nuclear DNA content. It is possible that improved methods giving a higher degree of resolution will allow separation of the near-diploid populations of malignant human gliomas from normal diploid cells and permit the detection of subpopulations with small differences from the dominant DNA mode. Chromosomal studies of malignant gliomas have confirmed that the majority of them have near-diploid stemlines. These populations are seldom normal diploid, however, as both numerical and structural abnormalities are usually present. In addition, chromosomal analyses have shown that when gliomas are bimodal, the polyploid populations are usually doubled versions of the near-diploid ones. In contrast to the near-diploid populations that characterize biopsied malignant gliomas, both FCM studies and karyotyping have demonstrated that permanent cultured cell lines derived from malignant gliomas are usually near-triploid or near-tetraploid. Sequential karyotypic studies of these tumors from biopsy through establishment in vitro have shown an evolutionary pattern consisting of doubling of the original stemline, followed by gains or losses of individual chromosomes with new marker formation in late culture. Evaluation of biopsied malignant gliomas by karyotyping has also demonstrated that subgroups of them are characterized by specific numerical and structural deviations. These groupings may prove useful in predicting prognosis

  12. 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

  13. 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.

  14. 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.

  15. Overexpression of IL-7 enhances cisplatin resistance in glioma.

    PubMed

    Cui, Lei; Fu, Jun; Pang, Jesse Chung-Sean; Qiu, Zhi-Kun; Liu, Xiao-Mei; Chen, Fu-Rong; Shi, Hong-Liu; Ng, Ho-Keung; Chen, Zhong-Ping

    2012-05-01

    Cisplatin is one of the most commonly used chemotherapeutic agents for glioma patients. In this study, array comparative genomic hybridization (aCGH) was used to identify genes associated with cisplatin resistance in a human glioma cell line. The cisplatin-resistant U251/CP2 cell line was derived by stepwise selection using cisplatin. The genetic aberrations of the U251 parental cell line and the U251/CP2 cells were analyzed using aCGH. RT-PCR was used to detect the expression of the altered genes revealed by aCGH. The sensitivity of glioma cells to cisplatin was determined by using the MTT assay. Apoptosis was detected using flow cytometry and western blot analysis. The IC 50 value of cisplatin in U251/CP2 cells was five times higher than its IC 50 in U251 cells. The U251 cells lost at least one copy each of the CFHR1 and CFHR3 genes, and both CFHR1 and CFHR3 were homozygously deleted in U251/CP2 cells. The U251/CP2 cells gained two to three copies of C8orf70 and IL-7 genes. IL-7 mRNA expression was studied in 12 glioma cell lines, and expression was positively correlated with the IC 50 of cisplatin. Furthermore, IL-7 mRNA expression was also positively correlated with the IC 50 of cisplatin in 91 clinical glioma specimens. Additionally, treatment with recombinant human IL-7 (rhIL-7) enhanced cisplatin resistance and increased the relative growth rate of the glioma cells. Moreover, the apoptosis induced by cisplatin could be inhibited by IL-7. In conclusion, our results suggest that IL-7 may play an important role in cisplatin resistance in glioma.

  16. Stem cell-mediated delivery of therapies in the treatment of glioma.

    PubMed

    Frosina, G

    2011-06-01

    High grade gliomas can be seldom controlled, due to the infiltrative nature of these tumors and the presence of cell populations resistant to radio- and chemotherapy. Current research aims to develop novel therapeutic approaches to track and eliminate the disseminated glioma-driving cells. Selected delivery of therapeutic agents taking advantage of the tropism of normal stem cells for glioma cells might be one.

  17. Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

    PubMed

    Pirozzi, Christopher J; Carpenter, Austin B; Waitkus, Matthew S; Wang, Catherine Y; Zhu, Huishan; Hansen, Landon J; Chen, Lee H; Greer, Paula K; Feng, Jie; Wang, Yu; Bock, Cheryl B; Fan, Ping; Spasojevic, Ivan; McLendon, Roger E; Bigner, Darell D; He, Yiping; Yan, Hai

    2017-02-01

    IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. Additionally, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell of origin for glioma; thus, altering the progression of tumorigenesis. Additionally, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.

  18. Mitochondrial Lon is over-expressed in high-grade gliomas, and mediates hypoxic adaptation: potential role of Lon as a therapeutic target in glioma

    PubMed Central

    Di, Kaijun; Lomeli, Naomi; Wood, Spencer D.; Vanderwal, Christopher D.; Bota, Daniela A.

    2016-01-01

    Mitochondrial dysfunction is a hallmark of cancer biology. Tumor mitochondrial metabolism is characterized by an abnormal ability to function in scarce oxygen conditions through glycolysis (the Warburg effect), and accumulation of mitochondrial DNA defects are present in both hereditary neoplasia and sporadic cancers. Mitochondrial Lon is a major regulator of mitochondrial metabolism and the mitochondrial response to free radical damage, and plays an essential role in the maintenance and repair of mitochondrial DNA. Despite these critical cellular functions of Lon, very little has been reported regarding its role in glioma. Lon expression in gliomas and its relevance with patient survival was examined using published databases and human tissue sections. The effect of Lon in glioma biology was investigated through siRNA targeting Lon. We also tested the in vitro antitumor activity of Lon inhibitor, CC4, in the glioma cell lines D-54 and U-251. High Lon expression was associated with high glioma tumor grade and poor patient survival. While Lon expression was elevated in response to a variety of stimuli, Lon knockdown in glioma cell lines decreased cell viability under normal conditions, and dramatically impaired glioma cell survival under hypoxic conditions. Furthermore, the Lon inhibitor, CC4, efficiently prohibited glioma cell proliferation and synergistically enhanced the therapeutic efficacy of the chemotherapeutic agents, temozolomide (TMZ) and cisplatin. We demonstrate that Lon plays a key role in glioma cell hypoxic survival and mitochondrial respiration, and propose Lon as a promising therapeutic target in the treatment of malignant gliomas. PMID:27764809

  19. Novel cancer-testis antigen expression on glioma cell lines derived from high-grade glioma patients.

    PubMed

    Akiyama, Yasuto; Komiyama, Masaru; Miyata, Haruo; Yagoto, Mika; Ashizawa, Tadashi; Iizuka, Akira; Oshita, Chie; Kume, Akiko; Nogami, Masahiro; Ito, Ichiro; Watanabe, Reiko; Sugino, Takashi; Mitsuya, Koichi; Hayashi, Nakamasa; Nakasu, Yoko; Yamaguchi, Ken

    2014-04-01

    Glioblastoma multiforme (GBM) is one of the most malignant and aggressive tumors, and has a very poor prognosis with a mean survival time of <2 years, despite intensive treatment using chemo-radiation. Therefore, novel therapeutic approaches including immunotherapy have been developed against GBM. For the purpose of identifying novel target antigens contributing to GBM treatment, we developed 17 primary glioma cell lines derived from high-grade glioma patients, and analyzed the expression of various tumor antigens and glioma-associated markers using a quantitative PCR and immunohistochemistry (IHC). A quantitative PCR using 54 cancer-testis (CT) antigen-specific primers showed that 36 CT antigens were positive in at least 1 of 17 serum-derived cell lines, and 17 antigens were positive in >50% cell lines. Impressively, 6 genes (BAGE, MAGE-A12, CASC5, CTAGE1, DDX43 and IL-13RA2) were detected in all cell lines. The expression of other 13 glioma-associated antigens than CT genes were also investigated, and 10 genes were detected in >70% cell lines. The expression of CT antigen and glioma-associated antigen genes with a high frequency were also verified in IHC analysis. Moreover, a relationship of antigen gene expressions with a high frequency to overall survival was investigated using the Repository of Molecular Brain Neoplasia Data (REMBRANDT) database of the National Cancer Institute, and expression of 6 genes including IL-13RA2 was inversely correlated to overall survival time. Furthermore, 4 genes including DDX43, TDRD1, HER2 and gp100 were identified as MGMT-relevant factors. In the present study, several CT antigen including novel genes were detected in high-grade glioma primary cell lines, which might contribute to developing novel immunotherapy and glioma-specific biomarkers in future.

  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. 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.

  2. 2-methoxyestradiol as a potential cytostatic drug in gliomas?

    PubMed

    Kirches, E; Warich-Kirches, M

    2009-01-01

    Gliomas of astrocytic origin show only a limited chemotherapy response. Chemoresistance is most pronounced in glioblastoma multiforme, the most common and most malignant glioma, with median survival times not much longer than one year. Failure of chemotherapy partly relies on protective mechanisms against the commonly used DNA alkylating agents, but also on the constitutive activation of the pro-survival PI3K-Akt pathway in glioma cells, which inhibits apoptosis. Therefore, new drugs with an alternative mechanism, independent of DNA alkylation, are required. The microtubule targeting drug 2-methoxyestradiol (2-ME) efficiently induces mitotic arrest, apoptosis, but also autophagic cell death in glioma cells in vitro. Moreover, it may be able to inhibit vascularization of the highly vascular gliobastomas, because the drug influences blood vessel sprouting via a HIF-1-dependent mechanism. Although high doses of i.p. injected 2-ME were recently shown to be effective in an orthothopic rat glioma model, clinical phase I/II trials revealed low oral bioavailability. One of the most exciting future perspectives will be the currently ongoing development of improved 2-ME analogs. Compounds, sulphamoylated at positions 3 and 17, combine sufficient toxicity against tumor cells with resistance against metabolic degradation and sufficient plasma levels in experimental animals. They were found to be superior in some animal models of tumor growth and vascularization, following oral application.

  3. Epo is involved in angiogenesis in human glioma.

    PubMed

    Nico, Beatrice; Annese, Tiziana; Guidolin, Diego; Finato, Nicoletta; Crivellato, Enrico; Ribatti, Domenico

    2011-03-01

    In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.

  4. Clinicopathologic implications of NF1 gene alterations in diffuse gliomas.

    PubMed

    Vizcaíno, M Adelita; Shah, Smit; Eberhart, Charles G; Rodriguez, Fausto J

    2015-09-01

    Recent studies have identified somatic alterations in the gene encoding for neurofibromin (NF1) in a subset of glioblastoma (GBM), usually associated with the mesenchymal molecular subtype. To understand the significance of NF1 genetic alterations in diffuse gliomas in general, we evaluated public databases and tested for NF1 copy number alterations in a cohort using fluorescence in situ hybridization. NF1 genetic loss (homozygous NF1 deletions or mutations with predicted functional consequences) was present in 30 (of 281) (11%) GBM and 21 (of 286) (7%) lower-grade gliomas in The Cancer Genome Atlas data. Furthermore, NF1 loss was associated with worse overall and disease-specific survival in the lower-grade glioma, but not GBM, Group in The Cancer Genome Atlas cohort. IDH1 or 2 mutations co-existed in lower-grade gliomas with NF1 loss (36%) but not in GBM. In our cohort studied by fluorescence in situ hybridization, NF1/17q (n = 2) or whole Ch17 (n = 3) losses were only identified in the GBM group (5/86 [6%]). Tumors with NF1/Ch17 loss were predominantly adult GBM (4/5); lacked EGFR amplification (0/4), strong p53 immunolabeling (1/5), or IDH1 (R132H) protein expression (0/5); but expressed the mesenchymal marker podoplanin in 4/5. NF1 genetic loss occurs in a subset of diffuse gliomas, and its significance deserves further exploration.

  5. 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.

  6. 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.

  7. 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.

  8. Clinical implications of molecular neuropathology and biomarkers for malignant glioma.

    PubMed

    Tabatabai, Ghazaleh; Hegi, Monika; Stupp, Roger; Weller, Michael

    2012-06-01

    Malignant gliomas are currently diagnosed based on morphological criteria and graded according to the World Health Organization classification of primary brain tumors. This algorithm of diagnosis and classification provides clinicians with an estimated prognosis of the natural course of the disease. It does not reflect the expected response to specific treatments beyond surgery (eg, radiotherapy or alkylating chemotherapy). Clinical experience has revealed that gliomas sharing similar histomorphological criteria might indeed have different clinical courses and exhibit highly heterogenous responses to treatments. This was very impressively demonstrated first for oligodendrogliomas. The presence or lack of combined deletions of the chromosomal segments 1p/19q was associated with different benefit from radiotherapy and chemotherapy. We review current molecular markers for malignant gliomas and discuss their current and future impact on clinical neuro-oncology.

  9. Silver nanoparticles: a novel radiation sensitizer for glioma?

    NASA Astrophysics Data System (ADS)

    Liu, Peidang; Huang, Zhihai; Chen, Zhongwen; Xu, Ruizhi; Wu, Hao; Zang, Fengchao; Wang, Cailian; Gu, Ning

    2013-11-01

    Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy.Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after Ag

  10. 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.

  11. [Gliomas – What I Have to Know in ten Questions].

    PubMed

    Gulden-Sala, Wiebke; Roth, Patrick; Brown, Michelle; Andratschke, Nicolaus; Weller, Michael; Stupp, Roger

    2016-03-16

    Gliomas are the most common primary tumors involving the central nervous system. They can manifest with diverse and non-specific general and neurological symptoms. The diagnostic gold standard is cerebral magnetic resonance imaging and subsequent histological confirmation of the diagnosis. Steroids, especially dexamethasone, are used in case of focal symptoms and of symptoms caused by increased intracranial pressure, and antiepileptic drugs are used to manage epileptic seizures. Non-enzyme-inducing antiepileptic drugs are preferable. Glioma patients have an inherently elevated thromboembolic risk, and therapeutic anticoagulation is indicated following a thromboembolic event. Surgery, radiotherapy and systemic therapy are used as tumor-specific therapy modalities in gliomas. Molecular markers play an increasing role in the prognosis and selection of therapy in daily oncological routine.

  12. Loss of heterozygosity of chromosome 10p in human gliomas

    SciTech Connect

    Kimmelman, A.C.; Liang, B.C.; Ross, D.A.

    1996-06-01

    Molecular loss of heterozygosity studies on human gliomas have shown several regions on chromosome 10 frequently deleted in higher grade tumors, suggesting that chromosome 10 may contain several tumor suppressor genes. We assessed loss of heterozygosity with microsatellite markers in 20 gliomas, consisting of various grades and containing two chromosome 10 copies. The locus that exhibited the most loss (69%) was the region bordered by D10S249 and D10S558 and inclusive of D10S594, with a linkage distance of 3 cM. This region was noted to be deleted in various grades of tumor, including low- and high-grade tumors. These results suggest that chromosome region 10p15 is involved in human gliomas of diverse grades and that this region may harbor genes important in the development of and progression to the malignant phenotype. 20 refs., 4 figs., 1 tab.

  13. Genomic Insights into Diffuse Intrinsic Pontine Glioma

    PubMed Central

    Lapin, Danielle H.; Tsoli, Maria; Ziegler, David S.

    2017-01-01

    Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor with a peak incidence in middle childhood and a median survival of less than 1 year. The dismal prognosis associated with DIPG has been exacerbated by the failure of over 250 clinical trials to meaningfully improve survival compared with radiotherapy, the current standard of care. The traditional practice to not biopsy DIPG led to a scarcity in available tissue samples for laboratory analysis that till recently hindered therapeutic advances. Over the past few years, the acquisition of patient derived tumor samples through biopsy and autopsy protocols has led to distinct breakthroughs in the identification of key oncogenic drivers implicated in DIPG development. Aberrations have been discovered in critical genetic drivers including histone H3, ACVR1, TP53, PDGFRA, and Myc. Mutations, previously not identified in other malignancies, highlight DIPG as a distinct biological entity. Identification of novel markers has already greatly influenced the direction of preclinical investigations and offers the exciting possibility of establishing biologically targeted therapies. This review will outline the current knowledge of the genomic landscape related to DIPG, overview preclinical investigations, and reflect how biological advances have influenced the focus of clinical trials toward targeted therapies.

  14. Antibody-based immunotherapy for malignant glioma

    PubMed Central

    Gedeon, Patrick C.; Riccione, Katherine A.; Fecci, Peter E.; Sampson, John H.

    2014-01-01

    Conventional therapy for malignant glioma (MG) fails to specifically eliminate tumor cells, resulting in toxicity that limits therapeutic efficacy. In contrast, antibody-based immunotherapy utilizes the immune system to eliminate tumor cells with exquisite specificity. Increased understanding of the pathobiology of MG and the profound immunosuppression present among patients with MG has revealed several biologic targets amenable to antibody-based immunotherapy. Novel antibody engineering techniques allow for the production of fully human antibodies or antibody fragments with vastly reduced antigen-binding dissociation constants, increasing safety when used clinically as therapeutics. In this report, we summarize the use of antibody-based immunotherapy for MG. Approaches currently under investigation include the use of antibodies or antibody fragments to: 1) redirect immune effector cells to target tumor mutations, 2) inhibit immunosuppressive signals and thereby stimulate an immunological response against tumor cells, and 3) provide co-stimulatory signals to evoke immunologic targeting of tumor cells. These approaches demonstrate highly compelling safety and efficacy for the treatment of MG, providing a viable adjunct to current standard-of-care therapy for MG. PMID:25173142

  15. MRI in treatment of adult gliomas.

    PubMed

    Henson, John W; Gaviani, Paola; Gonzalez, R Gilberto

    2005-03-01

    Diffuse astrocytomas of the adult cerebral hemispheres are unique among tumours in human beings in the extent to which their imaging features are related to histopathological characteristics and clinical behaviour. However, understanding is still restricted about the value of imaging features in the measurement of response and of progression in these tumours. The present approach used in clinical trials, which consists of an anatomical measurement of the enhancing tumour on MRI, has many problems, and might not be acceptable as a surrogate endpoint for survival in patients with glioblastoma who are enrolled in clinical trials. Dynamic imaging techniques, such as capillary permeability mapping, are being used in studies of new drugs that target specific molecular features of gliomas; however, the validity of these techniques has not been elucidated. Diffusion imaging can be valuable for fibre-tract mapping to assist surgical planning and might become useful in measuring early response to treatment in densely cellular tumours. Functional imaging techniques can be used to localise motor, sensory, and language-control areas before surgery. Intraoperative MRI has produced improvements in the extent of tumour resection, and molecular imaging is another technique on the horizon, which could come to have a role in clinical trials in the near future. Thus, as a rapidly expanding sphere of investigation, brain-tumour imaging is producing great excitement. The aim of these new techniques is to aid the identification of more effective treatments.

  16. Chemosensitivity of IDH1 mutant gliomas due to an impairment in PARP1-mediated DNA repair.

    PubMed

    Lu, Yanxin; Kwintkiewicz, Jakub; Liu, Yang; Tech, Katherine; Frady, Lauren N; Su, Yu-Ting; Bautista, Wendy; Moon, Seog In; MacDonald, Jeffrey; Edwend, Matthew G; Gilbert, Mark R; Yang, Chunzhang; Wu, Jing

    2017-02-15

    Mutations in isocitrate dehydrogenase (IDH) are the most prevalent genetic abnormalities in lower grade gliomas. The presence of these mutations in glioma is prognostic for better clinical outcomes with longer patient survival. In the present study, we found that defects in oxidative metabolism and 2-HG production confer chemosensitization in IDH1-mutated glioma cells. In addition, temozolomide (TMZ) treatment induced greater DNA damage and apoptotic changes in mutant glioma cells. The PARP1-associated DNA repair pathway was extensively compromised in mutant cells due to decreased NAD+ availability. Targeting the PARP DNA repair pathway extensively sensitized IDH1-mutated glioma cells to TMZ. Our findings demonstrate a novel molecular mechanism that defines chemosensitivity in IDH mutant gliomas. Targeting PARP-associated DNA repair may represent a novel therapeutic strategy for gliomas.

  17. 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.

  18. The transglutaminase 2 gene is aberrantly hypermethylated in glioma

    PubMed Central

    Dyer, Lisa M.; Schooler, Kevin P.; Ai, Lingbao; Klop, Corinne; Qiu, Jingxin; Robertson, Keith D.

    2010-01-01

    Transglutaminase 2 (TG2) is a ubiquitously expressed protein that catalyzes protein/protein crosslinking. Because extracellular TG2 crosslinks components of the extracellular matrix, TG2 is thought to function as a suppressor of cellular invasion. We have recently uncovered that the TG2 gene (TGM2) is a target for epigenetic silencing in breast cancer, highlighting a molecular mechanism that drives reduced TG2 expression, and this aberrant molecular event may contribute to invasiveness in this tumor type. Because tumor invasiveness is a primary determinant of brain tumor aggressiveness, we sought to determine if TGM2 is targeted for epigenetic silencing in glioma. Analysis of TGM2 gene methylation in a panel of cultured human glioma cells indicated that the 5′ flanking region of the TGM2 gene is hypermethylated and that this feature is associated with reduced TG2 expression as judged by immunoblotting. Further, culturing glioma cells in the presence of the global DNA demethylating agent 5-aza-2′-deoxycytidine and the histone deacetylase inhibitor Trichostatin A resulted in re-expression of TG2 in these lines. In primary brain tumors we observed that the TGM2 promoter is commonly hypermethylated and that this feature is a cancer-associated phenomenon. Using publically available databases, TG2 expression in gliomas was found to vary widely, with many tumors showing overexpression or underexpression of this gene. Since overexpression of TG2 leads to resistance to doxorubicin through the ectopic activation of NFκB, we sought to examine the effects of recombinant TG2 expression in glioma cells treated with commonly used brain tumor therapeutics. We observed that in addition to doxorubicin, TG2 expression drove resistance to CCNU; however, TG2 expression did not alter sensitivity to other drugs tested. Finally, a catalytically null mutant of TG2 was also able to support doxorubicin resistance in glioma cells indicating that transglutaminase activity is not necessary

  19. [Arteriovenous malformation-glioma association: study of four cases].

    PubMed

    Borges, Lia Raquel R; Malheiros, Suzana M F; Pelaez, Maria Paula; Stávale, João Norberto; Santos, Adrialdo J; Carrete, Henrique; Nogueira, Roberto Gomes; Ferraz, Fernando A P; Gabbai, Alberto A

    2003-06-01

    We reviewed the clinical presentation, imaging and histopathologic findings in 4 patients with the diagnosis of arteriovenous malformation associated with glioma that were operated on from 1991 to 2000 in our institution. Four patients (2 males; age between 15 and 52 years) presented with progressive headache with clinical evidence of intracranial hypertension (in 3) and partial seizures (in 1). CT scan showed a brain tumor without any detectable pathologic vessels. Histologic examination revealed astrocytic tumors associated with arteriovenous malformation. No patient presented the vascular component intermixed with the tumor. The arteriovenous-glioma association is rare and must be identified by a clear demarcation between the malformation and the tumor.

  20. Decreased Expression of MiRNA-204-5p Contributes to Glioma Progression and Promotes Glioma Cell Growth, Migration and Invasion

    PubMed Central

    Xia, Zhiqiang; Liu, Fang; Zhang, Jian; Liu, Li

    2015-01-01

    Gliomas are the most common malignant primary brain tumors in adults and exhibit a spectrum of aberrantly aggressive phenotype. Although increasing evidence indicated that the deregulation of microRNAs (miRNAs) contributes to tumorigenesis and invasion, little is known about the roles of miR-204-5p in human gliomas. In the present study, the expression of miR-204-5p in clinical glioma tissues was measured by qRT-PCR. The effects of miR-204-5p on glioma cell growth and metastasis were examined by overexpressing or inhibiting miR-204-5p. We found that the expression level of miR-204-5p was significantly reduced in clinical glioma tissues compared with normal brain tissues. Moreover, we revealed that the introduction of miR-204-5p dramatically suppressed glioma cell growth, migration and invasion. Furthermore, mechanistic investigations revealed that RAB22A, a member of the RAS oncogene family, is a direct functional target of miR-204-5p in gliomas. In vivo, restoring miR-204-5p expression in glioma cells suppressed tumorigenesis and increased overall host survival. Our findings suggest that miR-204-5p is a cancer suppressor miRNA and overexpression of miR-204-5p is a novel glioma treatment strategy. PMID:26134825

  1. Plasminogen kringle 5-engineered glioma cells block migration of tumor-associated macrophages and suppress tumor vascularization and progression.

    PubMed

    Perri, Sabrina R; Nalbantoglu, Josephine; Annabi, Borhane; Koty, Zafiro; Lejeune, Laurence; François, Moïra; Di Falco, Marcos R; Béliveau, Richard; Galipeau, Jacques

    2005-09-15

    Angiostatin, a well-characterized angiostatic agent, is a proteolytic cleavage product of human plasminogen encompassing the first four kringle structures. The fifth kringle domain (K5) of human plasminogen is distinct from angiostatin and has been shown, on its own, to act as a potent endothelial cell inhibitor. We propose that tumor-targeted K5 cDNA expression may act as an effective therapeutic intervention as part of a cancer gene therapy strategy. In this study, we provide evidence that eukaryotically expressed His-tagged human K5 cDNA (hK5His) is exported extracellularly and maintains predicted disulfide bridging conformation in solution. Functionally, hK5His protein produced by retrovirally engineered human U87MG glioma cells suppresses in vitro migration of both human umbilical vein endothelial cells and human macrophages. Subcutaneous implantation of Matrigel-embedded hK5His-producing glioma cells in nonobese diabetic/severe combined immunodeficient mice reveals that hK5His induces a marked reduction in blood vessel formation and significantly suppresses the recruitment of tumor-infiltrating CD45+ Mac3+ Gr1- macrophages. Therapeutically, we show in a nude mouse orthotopic brain cancer model that tumor-targeted K5 expression is capable of effectively suppressing glioma growth and promotes significant long-term survival (>120 days) of test animals. These data suggest that plasminogen K5 acts as a novel two-pronged anticancer agent, mediating its inhibitory effect via its action on host-derived endothelial cells and tumor-associated macrophages, resulting in a potent, clinically relevant antitumor effect.

  2. Immunohistochemical evaluation of tissue factor, fibrin/fibrinogen and D-dimers in canine gliomas.

    PubMed

    de la Fuente, Cristian; Pumarola, Martí; Blasco, Ester; Fernández, Francisco; Viu, Judit; Añor, Sònia

    2014-06-01

    In human gliomas, tissue factor (TF) is overexpressed, associated with the grade of malignancy and influences tumour biology. Intra-tumoural fibrin/fibrinogen deposition and activation of the fibrinolytic system also play a role in tumour cell proliferation and angiogenesis. The first aim of the present study was to investigate TF expression and the presence of fibrin/fibrinogen and D-dimers in canine glioma biopsies, graded according to the World Health Organization (WHO) classification of tumours of the central nervous system. The second aim was to investigate the occurrence of intravascular thrombosis (IVT) in canine gliomas, as a potential histological marker of glioma type or grade of malignancy. An immunohistochemical study using antibodies against TF, fibrin/fibrinogen and D-dimers was performed with 24 glioma samples, including 15 oligodendrogliomas, 6 astrocytomas and 3 mixed gliomas. Immunohistochemical data were statistically analysed to determine whether there was any relationship between glioma type and grade of malignancy. All gliomas were moderate to strongly positive for TF and the staining score was significantly higher (P = 0.04) in high-grade (III or IV) than in low-grade (II) gliomas. Intra-tumoural fibrin/fibrinogen deposition was detected in all tumour biopsies assessed, and D-dimers were detected in 17/24 gliomas. IVT was a frequent finding, but was not linked to a specific glioma type or malignancy grade. TF expression, fibrin/fibrinogen deposition, extravascular fibrinolytic system activation and IVT occur in canine gliomas. Canine glioma might be a suitable model for studying coagulation and fibrinolysis as potential therapeutic targets for human gliomas.

  3. Immunotherapeutic targeting of shared melanoma-associated antigens in a murine glioma model.

    PubMed

    Prins, Robert M; Odesa, Sylvia K; Liau, Linda M

    2003-12-01

    Immune-based treatments for central nervous system gliomas have traditionally lagged behind those of more immunogenic tumors such as melanoma. The relative paucity of defined glioma-associated antigens that can be targeted by the immune system may partially account for this situation. Antigens present on melanomas have been extensively characterized, both in humans and in murine preclinical models. Melanocytes and astrocytes are both derived embryologically from the neural ectoderm. Their neoplastic counterparts, malignant melanomas and gliomas, have been shown in humans to share common antigens at the RNA level. However, little is known concerning whether gliomas can be targeted by immune-based strategies that prime T cells to epitopes from melanoma-associated antigens (MAAs). In this study, we provide evidence that two common murine glioma cell lines (GL26 and GL261) express the melanoma antigens gp100 and tyrosinase-related protein 2 (TRP-2). To understand the immunogenicity of murine gliomas to CD8(+) T cells, we examined the ability of a MAA-specific CTL cell line to lyse the glioma cells, as well as the in vivo expansion of MAA-specific CD8(+) T cells in animals harboring gliomas. Both glioma cell lines were lysed by a human gp100-specific CTL cell line in vitro. Mice harboring s.c. GL26 gliomas possessed TRP-2-specific CD8(+) T cells, providing further evidence that these gliomas express the protein products in the context of MHC class I. Furthermore, MAA peptide-pulsed dendritic cells could prime T cells that specifically recognize GL26 glioma cells in vitro. Lastly, mice that were prevaccinated with human gp100 and TRP-2 peptide-pulsed dendritic cells had significantly extended survival when challenged with tumor cells in the brain, resulting in >50% long-term survival. These results suggest that shared MAAs on gliomas can be targeted immunotherapeutically, pointing the way to a new potential treatment option for patients with malignant gliomas.

  4. 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.

  5. Glioma Specific Extracellular Missense Mutations in the First Cysteine Rich Region of Epidermal Growth Factor Receptor (EGFR) Initiate Ligand Independent Activation.

    PubMed

    Ymer, Susie I; Greenall, Sameer A; Cvrljevic, Anna; Cao, Diana X; Donoghue, Jacqui F; Epa, V Chandana; Scott, Andrew M; Adams, Timothy E; Johns, Terrance G

    2011-04-18

    The epidermal growth factor receptor (EGFR) is overexpressed or mutated in glioma. Recently, a series of missense mutations in the extracellular domain (ECD) of EGFR were reported in glioma patients. Some of these mutations clustered within a cysteine-rich region of the EGFR targeted by the therapeutic antibody mAb806. This region is only exposed when EGFR activates and appears to locally misfold during activation. We expressed two of these mutations (R324L and E330K) in NR6 mouse fibroblasts, as they do not express any EGFR-related receptors. Both mutants were autophosphorylated in the absence of ligand and enhanced cell survival and anchorage-independent and xenograft growth. The ECD truncation that produces the de2-7EGFR (or EGFRvIII), the most common EGFR mutation in glioma, generates a free cysteine in this same region. Using a technique optimized for detecting disulfide-bonded dimers, we definitively demonstrated that the de2-7EGFR is robustly dimerized and that ablation of the free cysteine prevents dimerization and activation. Modeling of the R324L mutation suggests it may cause transient breaking of disulfide bonds, leading to similar disulfide-bonded dimers as seen for the de2-7EGFR. These ECD mutations confirm that the cysteine-rich region of EGFR around the mAb806 epitope has a significant role in receptor activation.

  6. Glioma Specific Extracellular Missense Mutations in the First Cysteine Rich Region of Epidermal Growth Factor Receptor (EGFR) Initiate Ligand Independent Activation

    PubMed Central

    Ymer, Susie I.; Greenall, Sameer A.; Cvrljevic, Anna; Cao, Diana X.; Donoghue, Jacqui F.; Epa, V. Chandana; Scott, Andrew M.; Adams, Timothy E.; Johns, Terrance G.

    2011-01-01

    The epidermal growth factor receptor (EGFR) is overexpressed or mutated in glioma. Recently, a series of missense mutations in the extracellular domain (ECD) of EGFR were reported in glioma patients. Some of these mutations clustered within a cysteine-rich region of the EGFR targeted by the therapeutic antibody mAb806. This region is only exposed when EGFR activates and appears to locally misfold during activation. We expressed two of these mutations (R324L and E330K) in NR6 mouse fibroblasts, as they do not express any EGFR-related receptors. Both mutants were autophosphorylated in the absence of ligand and enhanced cell survival and anchorage-independent and xenograft growth. The ECD truncation that produces the de2-7EGFR (or EGFRvIII), the most common EGFR mutation in glioma, generates a free cysteine in this same region. Using a technique optimized for detecting disulfide-bonded dimers, we definitively demonstrated that the de2-7EGFR is robustly dimerized and that ablation of the free cysteine prevents dimerization and activation. Modeling of the R324L mutation suggests it may cause transient breaking of disulfide bonds, leading to similar disulfide-bonded dimers as seen for the de2-7EGFR. These ECD mutations confirm that the cysteine-rich region of EGFR around the mAb806 epitope has a significant role in receptor activation. PMID:24212795

  7. 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.

  8. 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.

  9. Intratumoral oncolytic adenoviral treatment modulates the glioma microenvironment and facilitates systemic tumor-antigen-specific T cell therapy

    PubMed Central

    Qiao, Jian; Dey, Mahua; Chang, Alan L; Kim, Julius W; Miska, Jason; Ling, Alex; M Nettlebeck, Dirk; Han, Yu; Zhang, Lingjiao; Lesniak, Maciej S

    2015-01-01

    Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor and is associated with poor survival. Virotherapy is a promising candidate for the development of effective, novel treatments for GBM. Recent studies have underscored the potential of virotherapy in enhancing antitumor immunity despite the fact that its mechanisms remain largely unknown. Here, using a syngeneic GBM mouse model, we report that intratumoral virotherapy significantly modulates the tumor microenvironment. We found that intratumoral administration of an oncolytic adenovirus, AdCMVdelta24, decreased tumor-infiltrating CD4+ Foxp3+ regulatory T cells (Tregs) and increased IFNγ-producing CD8+ T cells in treated tumors, even in late stage disease in which a highly immunosuppressive tumor microenvironment is considered to be a significant barrier to immunotherapy. Importantly, intratumoral AdCMVdelta24 treatment augmented systemically transferred tumor-antigen-specific T cell therapy. Furthermore, mechanistic studies showed (1) downregulation of Foxp3 in Tregs that were incubated with media conditioned by virus-infected tumor cells, (2) downregulation of indoleamine 2,3 dioxygenase 1 (IDO) in glioma cells upon infection by AdCMVdelta24, and (3) reprograming of Tregs from an immunosuppressive to a stimulatory state. Taken together, our findings demonstrate the potency of intratumoral oncolytic adenoviral treatment in enhancing antitumor immunity through the regulation of multiple aspects of immune suppression in the context of glioma, supporting further clinical development of oncolytic adenovirus-based immune therapies for malignant brain cancer. PMID:26405578

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

    PubMed Central

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

    2015-01-01

    Background Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk. Methods The GICC contains detailed information on history of atopic conditions for 4533 cases and 4171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis odds ratios, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema. Results Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared to not having respiratory allergies (mOR: 0.72, 95% CI: 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma. Conclusions A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental. Impact As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biological mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. PMID:26908595

  11. An analysis of 170 glioma patients and systematic review to investigate the association between IDH-1 mutations and preoperative glioma-related epilepsy.

    PubMed

    Yang, Yuan; Mao, Qing; Wang, Xiang; Liu, Yanhui; Mao, Yunhe; Zhou, Qiao; Luo, Jiewen

    2016-09-01

    Seizure is a common presenting symptom of glioma, and many biomarkers have been suggested to be associated with preoperative seizure; however, the relationships between IDH (isocitrate dehydrogenase) mutations and glioma-related epilepsy only recently been studied. The authors aimed to examine the correlations between IDH mutations in glioma patients with preoperative seizures and tumor location. A series of 170 glioma samples were analyzed for IDH1 R132H mutations (amino acid change from arginine to histidine at codon 132) with immunohistochemistry (IHC) staining and for IDH mutations with direct DNA sequencing when the IHC results were negative. If either the IHC or direct DNA sequencing result was positive, the IDH status was defined as mutated. The results of the IDH mutation examinations were used to analyze the relationship between mutations and glioma-related epilepsy. The study population consisted of 64 (37.6%) World Health Organization (WHO) grade II gliomas, 58 (34.1%) grade III, and 48 (28.3%) grade IV gliomas. A total of 84 samples with IDH1 mutations were observed in our study, and 54 of these presented with seizures as the initial symptoms, whereas 28 of the patients with wild-type IDH status presented with seizures (p=0.043 for the WHO grade II gliomas, p=0.002 for the grade III gliomas and p=0.942 for the grade IV gliomas, chi-squared tests). Among the WHO grade II and III gliomas, IDH1 mutations were significantly associated with preoperative seizures, but no significant relationship between IDH mutations and preoperative seizures was found with glioblastoma multiforme.

  12. 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

  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

    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.

  14. An integrated transcriptomic and computational analysis for biomarker identification in human glioma.

    PubMed

    Xing, Wenli; Zeng, Chun

    2016-06-01

    Malignant glioma is one of the most common primary brain tumors and is among the deadliest of human cancers. The molecular mechanism for human glioma is poorly understood. Early prognosis of this disease and early treatment are vital. Thus, it is crucial to target the key genes controlling pathogenesis in the early stage of glioma. In this study, differentially expressed genes in human glioma and paired peritumoral tissues were detected by transcriptome microarray analysis. Following gene microarray analysis, the gene expression profile in the differential grade glioma was further validated by bioinformatic analyses, co-expression network construction. Microarray analysis revealed that 1725 genes were differentially expressed and classified into different glioma stage. The analysis revealed 14 genes that were significantly associated with survival with a false discovery rate. Among these genes, macrophage capping protein (CAPG), a member of the actin-regulatory protein, was the key gene in a 20-gene network that modulates cell motility by interacting with the cytoskeleton. Furthermore, the prognostic impact of CAPG was validated by use of quantitative real-time polymerase chain reaction (qPCR) and immunohistochemistry on human glioma tissue. CAPG protein was significantly upregulated in clinical high-grade glioblastoma as compared with normal brain tissues. Overexpression of CAPG levels also predict shorter overall survival of glioma patients. These data demonstrated CAPG protein expression in human glioma was associated with tumorigenesis and may be a biomarker for identification of the pathological grade of glioma.

  15. Circulating tumor cell is a common property of brain glioma and promotes the monitoring system

    PubMed Central

    Gao, Faliang; Cui, Yong; Jiang, Haihui; Sui, Dali; Wang, Yonggang; Jiang, Zhongli; Zhao, Jizong; Lin, Song

    2016-01-01

    Brain glioma is the most common primary intracranial tumor characterized by dismal prognosis and frequent recurrence, yet a real-time and reliable biological approach to monitor tumor response and progression is still lacking. Recently, few studies have reported that circulating tumor cells (CTCs) could be detected in glioblastoma multiform (GBM), providing the possibility of its application in brain glioma monitoring system. But its application limits still exist, because the detection rate of CTCs is still low and was exclusively limited to high- grade gliomas. Here, we adopted an advanced integrated cellular and molecular approach of SE-iFISH to detect CTCs in the peripheral blood (PB) of patients with 7 different subtypes of brain glioma, uncovering the direct evidences of glioma migration. We identified CTCs in the PB from 24 of 31 (77%) patients with glioma in all 7 subtypes. No statistical difference of CTC incidence and count was observed in different pathological subtypes or WHO grades of glioma. Clinical data revealed that CTCs, to some extent, was superior to MRI in monitoring the treatment response and differentiating radionecrosis from recurrence of glioma. Conclusively, CTCs is a common property of brain gliomas of various pathological subtypes, which has provided an ultimate paradox for the hypothesis “soil and seed”. It can be used to monitor the microenvironment of gliomas dynamically, which will be a meaningful complement to radiographic imaging. PMID:27517490

  16. Alphaxalone inhibits growth, migration and invasion of rat C6 malignant glioma cells.

    PubMed

    Sun, Huawei; Zheng, Xiaoke; Zhou, Yuehan; Zhu, Wenbo; Ou, Yanqiu; Shu, Minfeng; Gao, Xiuren; Leng, Tiandong; Qiu, Pengxin; Yan, Guangmei

    2013-10-01

    Malignant gliomas are the most devastating and aggressive brain tumors affecting the central nervous system. The insidious growth and infiltration are the most prominent characteristics of malignant gliomas, which render the current therapies for malignant gliomas including surgery, radiation and chemotherapy unsuccessful. Inhibition of infiltration as well as proliferation in combination with surgery might be more effective in the treatment of malignant gliomas. In the current study, we demonstrate the alphaxalone (3-hydroxypregnane-11,20-dione) could effectively inhibit the proliferation of C6 glioma cells in a concentration dependent manner. Moreover, this compound could also suppress the migration and invasion of C6 glioma cells at a concentration without causing significant cytotoxicity. Except the in vitro anti-glioma activity, alphaxalone effectively delayed the growth of rat C6 malignant glioma xenografts in vivo. Together, these findings suggest alphaxalone might be a promising candidate for the treatment of malignant gliomas and may also provide helpful clues for anti-glioma drugs development in future.

  17. 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.

  18. Diffusion kurtosis imaging can efficiently assess the glioma grade and cellular proliferation.

    PubMed

    Jiang, Rifeng; Jiang, Jingjing; Zhao, Lingyun; Zhang, Jiaxuan; Zhang, Shun; Yao, Yihao; Yang, Shiqi; Shi, Jingjing; Shen, Nanxi; Su, Changliang; Zhang, Ju; Zhu, Wenzhen

    2015-12-08

    Conventional diffusion imaging techniques are not sufficiently accurate for evaluating glioma grade and cellular proliferation, which are critical for guiding glioma treatment. Diffusion kurtosis imaging (DKI), an advanced non-Gaussian diffusion imaging technique, has shown potential in grading glioma; however, its applications in this tumor have not been fully elucidated. In this study, DKI and diffusion weighted imaging (DWI) were performed on 74 consecutive patients with histopathologically confirmed glioma. The kurtosis and conventional diffusion metric values of the tumor were semi-automatically obtained. The relationships of these metrics with the glioma grade and Ki-67 expression were evaluated. The diagnostic efficiency of these metrics in grading was further compared. It was demonstrated that compared with the conventional diffusion metrics, the kurtosis metrics were more promising imaging markers in distinguishing high-grade from low-grade gliomas and distinguishing among grade II, III and IV gliomas; the kurtosis metrics also showed great potential in the prediction of Ki-67 expression. To our best knowledge, we are the first to reveal the ability of DKI to assess the cellular proliferation of gliomas, and to employ the semi-automatic method for the accurate measurement of gliomas. These results could have a significant impact on the diagnosis and subsequent therapy of glioma.

  19. HOXB1 Is a Tumor Suppressor Gene Regulated by miR-3175 in Glioma

    PubMed Central

    Han, Liang; Liu, Dehua; Li, Zhaohui; Tian, Nan; Han, Ziwu; Wang, Guang; Fu, Yao; Guo, Zhigang; Zhu, Zifeng

    2015-01-01

    The HOXB1 gene plays a critical role as an oncogene in diverse tumors. However, the functional role of HOXB1 and the mechanism regulating HOXB1 expression in glioma are not fully understood. A preliminary bioinformatics analysis showed that HOXB1 is ectopically expressed in glioma, and that HOXB1 is a possible target of miR-3175. In this study, we investigated the function of HOXB1 and the relationship between HOXB1 and miR-3175 in glioma. We show that HOXB1 expression is significantly downregulated in glioma tissues and cell lines, and that its expression may be closely associated with the degree of malignancy. Reduced HOXB1 expression promoted the proliferation and invasion of glioma cells, and inhibited their apoptosis in vitro, and the downregulation of HOXB1 was also associated with worse survival in glioma patients. More importantly, HOXB1 was shown experimentally to be a direct target of miR-3175 in this study. The downregulated expression of miR-3175 inhibited cell proliferation and invasion, and promoted apoptosis in glioma. The oncogenicity induced by low HOXB1 expression was prevented by an miR-3175 inhibitor in glioma cells. Our results suggest that HOXB1 functions as a tumor suppressor, regulated by miR-3175 in glioma. These results clarify the pathogenesis of glioma and offer a potential target for its treatment. PMID:26565624

  20. Convection-enhanced Delivery of Therapeutics for Malignant Gliomas

    PubMed Central

    SAITO, Ryuta; TOMINAGA, Teiji

    2017-01-01

    Convection-enhanced delivery (CED) circumvents the blood–brain barrier by delivering agents directly into the tumor and surrounding parenchyma. CED can achieve large volumes of distribution by continuous positive-pressure infusion. Although promising as an effective drug delivery method in concept, the administration of therapeutic agents via CED is not without challenges. Limitations of distribution remain a problem in large brains, such as those of humans. Accurate and consistent delivery of an agent is another challenge associated with CED. Similar to the difficulties caused by immunosuppressive environments associated with gliomas, there are several mechanisms that make effective local drug distribution difficult in malignant gliomas. In this review, methods for local drug application targeting gliomas are discussed with special emphasis on CED. Although early clinical trials have failed to demonstrate the efficacy of CED against gliomas, CED potentially can be a platform for translating the molecular understanding of glioblastomas achieved in the laboratory into effective clinical treatments. Several clinical studies using CED of chemotherapeutic agents are ongoing. Successful delivery of effective agents should prove the efficacy of CED in the near future. PMID:27980285

  1. [Gliomas and BRCA genes mutations: fortuitous association or imputability?].

    PubMed

    Girardstein-Boccara, Laura; Mari, Véronique; Met-Domestici, Marie; Burel-Vandenbos, Fanny; Berthet, Pascaline; Paquis, Philippe; Frenay, Marc Paul; Lebrun-Frenay, Christine

    2014-09-01

    BRCA is a tumor suppressor gene implicated in the major mechanisms of cellular stability in every type of cell. Its mutations are described in numerous cancers, mainly breast and ovarian in women. It was also found an increase of lifetime risk of pancreas, colon, prostate cancer or lymphoma in men carriers. We report the cases of two female patients aged 40 and 58-years-old female patients and one 35-years-old male patient, with brain or medullar gliomas, carriers of a germline mutation of BRCA gene. Those gliomas were particularly aggressive and were not responding to the standard treatment, with chemo and radiotherapy. The very unusual characteristics in location and evolutive profile of these central nervous system tumors raise the question of a genetical underlying mechanism, maybe linked to the BRCA gene mutation that carry these patients. In addition, a non-fortuitous association between germline mutation of BRCA and occurrence of a glioma can be evoked according to the embryological, epidemiological and biomolecular findings noted in the literature. Other clinical and experimental studies are necessary to precise the physiopathological link existing between BRCA mutations and the occurrence of a glioma; this could have therapeutical and clinical implications in the future.

  2. [Dendritic cells and gliomas: a hope in immunotherapy?].

    PubMed

    Jouanneau, E; Poujol, D; Caux, C; Belin, M-F; Blay, J-Y; Puisieux, I

    2006-12-01

    Immunotherapy has been explored for several decades to try to improve the prognosis of gliomas, but until recently no therapeutic benefit has been achieved. The discovery of dendritic cells, the most potent professional antigen presenting cells to initiate specific immune response, and the possibility of producing them ex vivo gave rise to new protocols of active immunotherapy. In oncology, promising experimental and clinical therapeutic results were obtained using these dendritic cells loaded with tumor antigen. Patients bearing gliomas have deficit antigen presentation making this approach rational. In several experimental glioma models, independent research teams have showed specific antitumor responses using these dendritic cells. Phase I/II clinical trials have demonstrated the feasibility and the tolerance of this immunotherapeutic approach. In neuro-oncology, the efficiency of such an approach remains to be established, similarly in oncology where positive phase III studies are missing. Nevertheless, dendritic cells comprise a complex network which is only partially understood and capable of generating either immunotolerance or immune response. Numerous parameters remain to be explored before any definitive conclusion about their utility as an anticancer weapon can be drawn. It seems however logical that immunotherapy with dendritic cells could prevent or delay tumor recurrence in patients with minor active disease. A review on glioma and dendritic cells is presented.

  3. Critical Neural Networks in Awake Surgery for Gliomas

    PubMed Central

    KINOSHITA, Masashi; MIYASHITA, Katsuyoshi; TSUTSUI, Taishi; FURUTA, Takuya; NAKADA, Mitsutoshi

    2016-01-01

    From the embarrassing character commonly infiltrating eloquent brain regions, the surgical resection of glioma remains challenging. Owing to the recent development of in vivo visualization techniques for the human brain, white matter regions can be delineated using diffusion tensor imaging (DTI) as a routine clinical practice in neurosurgery. In confirmation of the results of DTI tractography, a direct electrical stimulation (DES) substantially influences the investigation of cortico-subcortical networks, which can be identified via specific symptoms elicited in the concerned white matter tracts (eg., the arcuate fascicle, superior longitudinal fascicles, inferior fronto-occipital fascicle, inferior longitudinal fascicle, frontal aslant tract, sensori-motor tracts, optic radiation, and so forth). During awake surgery for glioma using DES, it is important to identify the anatomo-functional structure of white matter tracts to identify the surgical boundaries of brain regions not only to achieve maximal resection of the glioma but also to maximally preserve quality of life. However, the risk exists that neurosurgeons may be misled by the inability of DTI to visualize the actual anatomy of the white matter fibers, resulting in inappropriate decisions regarding surgical boundaries. This review article provides information of the critical neuronal network that is necessary to identify and understand in awake surgery for glioma, with special references to white matter tracts and the author’s experiences. PMID:27250817

  4. A combined preclinical therapy of cannabinoids and temozolomide against glioma.

    PubMed

    Torres, Sofía; Lorente, Mar; Rodríguez-Fornés, Fátima; Hernández-Tiedra, Sonia; Salazar, María; García-Taboada, Elena; Barcia, Juan; Guzmán, Manuel; Velasco, Guillermo

    2011-01-01

    Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ(9)-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM.

  5. Interrelationship between differentiation and malignancy-associated properties in glioma.

    PubMed

    Frame, M C; Freshney, R I; Vaughan, P F; Graham, D I; Shaw, R

    1984-03-01

    The phenotypic expression of cells derived from human anaplastic astrocytomas, rat glioma, normal human adult and foetal brain tissue have been examined for differentiated and malignancy-associated properties. Glial fibrillary acidic protein (GFAP), high affinity glutamate and gamma-amino butyric acid (GABA) uptake and glutamine synthetase were used as indicators of astroglial differentiation. Plasminogen activator and tumour angiogenesis factor were the malignancy-associated markers. The normal adult brain-derived lines showed some differentiated astroglial features and expressed low levels of the malignancy-associated properties. The foetal cultures contained highly differentiated astroglia while the glioma lines showed considerable phenotypic heterogeneity from highly differentiated to undifferentiated. The least differentiated glioma cells exhibited the highest plasminogen activator activities. The density-dependent control of phenotypic expression was also investigated. High affinity GABA uptake, and GFAP in rat C6 glioma cultures, increased with increasing monolayer cell density, events probably mediated by an increase in the formation of cell-cell contacts at confluence. Plasminogen activator activity decreased with increasing cell density.

  6. Interrelationship between differentiation and malignancy-associated properties in glioma.

    PubMed Central

    Frame, M. C.; Freshney, R. I.; Vaughan, P. F.; Graham, D. I.; Shaw, R.

    1984-01-01

    The phenotypic expression of cells derived from human anaplastic astrocytomas, rat glioma, normal human adult and foetal brain tissue have been examined for differentiated and malignancy-associated properties. Glial fibrillary acidic protein (GFAP), high affinity glutamate and gamma-amino butyric acid (GABA) uptake and glutamine synthetase were used as indicators of astroglial differentiation. Plasminogen activator and tumour angiogenesis factor were the malignancy-associated markers. The normal adult brain-derived lines showed some differentiated astroglial features and expressed low levels of the malignancy-associated properties. The foetal cultures contained highly differentiated astroglia while the glioma lines showed considerable phenotypic heterogeneity from highly differentiated to undifferentiated. The least differentiated glioma cells exhibited the highest plasminogen activator activities. The density-dependent control of phenotypic expression was also investigated. High affinity GABA uptake, and GFAP in rat C6 glioma cultures, increased with increasing monolayer cell density, events probably mediated by an increase in the formation of cell-cell contacts at confluence. Plasminogen activator activity decreased with increasing cell density. Images Figure 2 Figure 6 PMID:6200130

  7. Extracellular matrix protein CCN1 limits oncolytic efficacy in glioma.

    PubMed

    Haseley, Amy; Boone, Sean; Wojton, Jeffrey; Yu, Lianbo; Yoo, Ji Young; Yu, Jianhua; Kurozumi, Kazuhiko; Glorioso, Joseph C; Caligiuri, Michael A; Kaur, Balveen

    2012-03-15

    Oncolytic viral therapy has been explored widely as an option for glioma treatment but its effectiveness has remained limited. Cysteine rich 61 (CCN1) is an extracellular matrix (ECM) protein elevated in cancer cells that modulates their adhesion and migration by binding cell surface receptors. In this study, we examined a hypothesized role for CCN1 in limiting the efficacy of oncolytic viral therapy for glioma, based on evidence of CCN1 induction that occurs in this setting. Strikingly, we found that exogenous CCN1 in glioma ECM orchestrated a cellular antiviral response that reduced viral replication and limited cytolytic efficacy. Gene expression profiling and real-time PCR analysis revealed a significant induction of type-I interferon responsive genes in response to CCN1 exposure. This induction was accompanied by activation of the Jak/Stat signaling pathway, consistent with induction of an innate antiviral cellular response. Both effects were mediated by the binding of CCN1 to the cell surface integrin α6β1, activating its signaling and leading to rapid secretion of interferon-α, which was essential for the innate antiviral effect. Together, our findings reveal how an integrin signaling pathway mediates activation of a type-I antiviral interferon response that can limit the efficacy of oncolytic viral therapy. Furthermore, they suggest therapeutic interventions to inhibit CCN1-integrin α6 interactions to sensitize gliomas to viral oncolysis.

  8. [Anaplastic glioma. Neuropathology, molecular diagnostics and current study concepts].

    PubMed

    Wick, W; Weller, M

    2010-08-01

    According to the current WHO classification anaplastic gliomas comprise pure astrocytomas and oligodendrogliomas and mixed tumors. This review summarizes findings, discusses problems and defines new questions from the phase III trials on anaplastic gliomas. The molecular subgroup analyses of the NOA-04 trial identified three molecular parameters, which predict longer progression-free and overall survival independent from the mode of therapy, radiotherapy or alkylating chemotherapy-. These are 1p/19q codeletion, methylation of the promoter of the O(6)-methylguanyl methyltransferase (MGMT) gene and hot-spot mutations in the isocitrate dehydrogenase 1 (IDH1) gene. The prognostic relevance of these markers is not lower than that of histopathological subclassification but determination is potentially more robust. Therefore, marker profiles should be included into the next WHO brain tumor classification. The current standard of care for first-line treatment in anaplastic gliomas is radiotherapy or chemotherapy. The next steps, e.g. within the international CATNON trial, are to define the role and optimal sequencing of combined modality treatment focusing on radiotherapy and temozolomide. Inclusion in this trial is already based on the WHO grade and the 1p/19q status and not on the histopathological subtype. Furthermore, anaplastic gliomas are an important group of brain tumors for developing future molecular targeted therapies and should therefore be in the main focus of academic and industrial drug development, which aims at improved efficacy and avoiding long-term side-effects.

  9. Mutant tristetraprolin: a potent inhibitor of malignant glioma cell growth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Malignant gliomas rely on the production of certain critical growth factors including VEGF, interleukin (IL)-6 and IL-8, to fuel rapid tumor growth, angiogenesis, and treatment resistance. Post-transcriptional regulation through adenine and uridine-rich elements of the 3' untranslated region is one ...

  10. Myosin VI contributes to malignant proliferation of human glioma cells

    PubMed Central

    Xu, Rong; Fang, Xu-hao

    2016-01-01

    Previously characterized as a backward motor, myosin VI (MYO6), which belongs to myosin family, moves toward the minus end of the actin track, a direction opposite to all other known myosin members. Recent researches have illuminated the role of MYO6 in human cancers, particularly in prostate cancer. However, the role of MYO6 in glioma has not yet been determined. In this study, to explore the role of MYO6 in human glioma, lentivirus-delivered short hairpin RNA (shRNA) targeting MYO6 was designed to stably down-regulate its endogenous expression in glioblastoma cells U251. Knockdown of MYO6 signifi cantly inhibited viability and proliferation of U251 cells in vitro. Moreover, the cell cycle of U251 cells was arrested at G0/G1 phase with the absence of MYO6, which could contribute to the suppression of cell proliferation. In conclusion, we firstly identified the crucial involvement of MYO6 in human glioma. The inhibition of MYO6 by shRNA might be a potential therapeutic method in human glioma. PMID:26937209

  11. 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.

  12. 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…

  13. Insulator dysfunction and oncogene activation in IDH mutant gliomas.

    PubMed

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

    2016-01-07

    Gain-of-function IDH mutations are initiating events that define major clinical and prognostic classes of gliomas. Mutant IDH protein produces a new onco-metabolite, 2-hydroxyglutarate, which interferes with iron-dependent hydroxylases, including the TET family of 5'-methylcytosine hydroxylases. TET enzymes catalyse a key step in the removal of DNA methylation. IDH mutant gliomas thus manifest a CpG island methylator phenotype (G-CIMP), although the functional importance of this altered epigenetic state remains unclear. Here we show that human IDH mutant gliomas exhibit hypermethylation at cohesin and CCCTC-binding factor (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 interact aberrantly with the receptor tyrosine kinase gene PDGFRA, a prominent glioma oncogene. Treatment of IDH mutant gliomaspheres with a demethylating agent partially restores insulator function and downregulates PDGFRA. Conversely, CRISPR-mediated disruption of the CTCF motif in IDH wild-type gliomaspheres upregulates 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.

  14. Growth hormone and cancer: GH production and action in glioma?

    PubMed

    Lea, Robert W; Dawson, Timothy; Martinez-Moreno, Carlos G; El-Abry, Nasra; Harvey, Steve

    2015-09-01

    The hypersecretion of pituitary growth hormone (GH) is associated with an increased risk of cancer, while reducing pituitary GH signaling reduces this risk. Roles for pituitary GH in cancer are therefore well established. The expression of the GH gene is, however, not confined to the pituitary gland and it is now known to occur in many extrapituitary tissues, in which it has local autocrine or paracrine actions, rather than endocrine function. It is, for instance, expressed in cancers of the prostate, lung, skin, endometrium and colon. The oncogenicity of autocrine GH may also be greater than that induced by endocrine or exogenous GH, as higher concentrations of GHR antagonists are required to inhibit its actions. This may reflect the fact that autocrine GH is thought to act at intracellular receptors directly after synthesis, in compartments not readily accessible to endocrine (or exogenous) GH. The roles and actions of extrapituitary GH in cancer may therefore differ from those of pituitary GH. The possibility that GH may be expressed and act in glioma tumors was therefore examined by immunohistochemistry. These results demonstrate, for the first time, the presence of abundant GH- and GH receptor (GHR-) immunoreactivity in glioma, in which they were co-localized in cytoplasmic but not nuclear compartments. These results demonstrate that glioma differs from most cancers in lacking nuclear GHRs, but GH is nevertheless likely to have autocrine or paracrine actions in the induction and progression of glioma.

  15. 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

  16. EXPLORING THE ANTITUMOR EFFECT OF VIRUS IN MALIGNANT GLIOMA

    PubMed Central

    Saha, Dipongkor; Ahmed, Seemin S.; Rabkin, Samuel D.

    2016-01-01

    SUMMARY Malignant gliomas are the most common type of primary malignant brain tumor with no effective treatments. Current conventional therapies (surgical resection, radiation therapy, temozolomide (TMZ), and bevacizumab administration) typically fail to eradicate the tumors resulting in the recurrence of treatment-resistant tumors. Therefore, novel approaches are needed to improve therapeutic outcomes. Oncolytic viruses (OVs) are excellent candidates as a more effective therapeutic strategy for aggressive cancers like malignant gliomas since OVs have a natural preference or have been genetically engineered to selectively replicate in and kill cancer cells. OVs have been used in numerous preclinical studies in malignant glioma, and a large number of clinical trials using OVs have been completed or are underway that have demonstrated safety, as well as provided indications of effective antiglioma activity. In this review, we will focus on those OVs that have been used in clinical trials for the treatment of malignant gliomas (herpes simplex virus, adenovirus, parvovirus, reovirus, poliovirus, Newcastle disease virus, measles virus, and retrovirus) and OVs examined preclinically (vesicular stomatitis virus and myxoma virus), and describe how these agents are being used. PMID:26855472

  17. 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.

  18. [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.

  19. Comparative permeability of different glioma models to horseradish peroxidase.

    PubMed

    Groothuis, D R; Fischer, J M; Vick, N A; Bigner, D D

    1981-01-01

    Seven different experimental glioma models were studied to determine their capillary permeability to horseradish peroxidase. The models were the autochthonous ASV-viral model, intracerebral (ic) and (sc) injections of rat 9L and RG-2 tumor cell lines, the sc rat S-69C15 tumor cell line, and human glioblastoma cell lines in nude mice. The ASV-viral model showed an average HRP permeability of 63% of tumor volume, the ic RG-2 tumors were 100% permeable, and the ic 9L tumors were 41% permeable. The permeability of the marginal zone (brain-tumor interface) showed similar variation from group to group. In contrast, all of the sc tumors were 100% permeable regardless of the cell line used to create the tumors. Our results show the variability between these glioma models, and suggest that RG-2 ic gliomas and all sc gliomas should be optimal to assess the tumoricidal effect of drugs, because access to the tumor compartment from the vascular compartment is complete.

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

    PubMed Central

    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.

    2016-01-01

    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. PMID:26871599

  1. Exploiting macrophages as targeted carrier to guide nanoparticles into glioma

    PubMed Central

    Pang, Liang; Qin, Jing; Han, Limei; Zhao, Wenjie; Liang, Jianming; Xie, Zhongyi; Yang, Pei; Wang, Jianxin

    2016-01-01

    The restriction of anti-cancer drugs entry to tumor sites in the brain is a major impediment to the development of new strategies for the treatment of glioma. Based on the finding that macrophages possess an intrinsic homing property enabling them to migrate to tumor sites across the endothelial barriers in response to the excretion of cytokines/chemokines in the diseased tissues, we exploited macrophages as ‘Trojan horses’ to carry drug-loading nanoparticles (NPs), pass through barriers, and offload them into brain tumor sites. Anticancer drugs were encapsulated in nanoparticles to avoid their damage to the cells. Drug loading NPs was then incubated with RAW264.7 cells in vitro to prepare macrophage-NPs (M-NPs). The release of NPs from M-NPs was very slow in medium of DMEM and 10% FBS and significantly accelerated when LPS and IFN-γ were added to mimic tumor inflammation microenvironment. The viability of macrophages was not affected when the concentration of doxorubicin lower than 25 μg/ml. The improvement of cellular uptake and penetration into the core of glioma spheroids of M-NPs compared with NPs was verified in in vitro studies. The tumor-targeting efficiency of NPs was also significantly enhanced after loading into macrophages in nude mice bearing intracranial U87 glioma. Our results provided great potential of macrophages as an active biocarrier to deliver anticancer drugs to the tumor sites in the brain and improve therapeutic effects of glioma. PMID:27213597

  2. Effect of pterostilbene on glioma cells and related mechanisms

    PubMed Central

    Yu, Liang; Zhong, Zhendong; Sun, Hongbin; Yan, Linxia; He, Baomin; Li, Supin; Ma, Shuai; Yang, Lili; Huang, Yulan

    2016-01-01

    Neuroglioma is the most common primary malignant tumor in neurosurgery. Due to unfavorable life quality of patients, the treatment of glioma is a major challenge in clinics. The search for effect treatment drugs thus benefits patient prognosis. As one derivative of resveratrol, pterostilbene has a wide spectrum of pharmaceutical functions, especially with the anti-tumor effects. This study thus investigated the effect of pterostilbene on neuroglioma and related mechanisms. U87 glioma cell line was divided into control, normal culture and different dosages of pterostilbene groups, which received 5 mM or 10 mM pterostilbene for 48 h. MTT assay was used to detect U87 cell proliferation, while invasion assay was employed to test the effect of pterostilbene on cell invasion, followed by flow cytometry assay for analyzing U87 cell apoptosis. Real-time PCR was used to test mRNA expression of Bcl-2 and Bax in glioma cells under the effect of pterostilbene, while Western blotting was used to detect alternation of Bcl-2 and Bax protein levels. Pterostilbene significantly inhibited proliferation and invasion abilities of glioma cells compared to those in control group (P<0.05). It can also enhance cell apoptosis, decrease mRNA and protein of Bcl-2 expression, and increase mRNA and protein expressions of Bax (P<0.05 compared to control group) in a dose-dependent manner. Pterostilbene can facilitate apoptosis of glioma cells, and inhibit their proliferation and invasion via mediating apoptotic/anti-apoptotic homeostasis. PMID:28077996

  3. Association between Prediagnostic Allergy-Related Serum Cytokines and Glioma.

    PubMed

    Schwartzbaum, Judith; Seweryn, Michal; Holloman, Christopher; Harris, Randall; Handelman, Samuel K; Rempala, Grzegorz A; Huang, Ruo-Pan; Burkholder, Brett; Brandemihl, Adam; Kallberg, Henrik; Johannesen, Tom Borge; Ahlbom, Anders; Feychting, Maria; Grimsrud, Tom K

    2015-01-01

    Allergy is inversely related to glioma risk. To determine whether prediagnostic allergy-related serum proteins are associated with glioma, we conducted a nested case-control study of seven cytokines (IL4, IL13, IL5, IL6, IL10, IFNG, TGFB2), two soluble cytokine receptors (sIL4RA, sIL13RA2) and three allergy-related transcription factors (FOXP3, STAT3, STAT6) using serum specimens from the Janus Serum Bank Cohort in Oslo, Norway. Blood donors subsequently diagnosed with glioma (n = 487) were matched to controls (n = 487) on age and date of blood draw and sex. We first estimated individual effects of the 12 serum proteins and then interactions between IL4 and IL13 and their receptors using conditional logistic regression. We next tested equality of case-control inter-correlations among the 12 serum proteins. We found that TGFB2 is inversely related to glioblastoma (Odds Ratio (OR) = 0.87, 95% Confidence Interval (CI)) = 0.76, 0.98). In addition, ≤ 5 years before diagnosis, we observed associations between IL4 (OR = 0.82, 95% CI = 0.66, 1.01), sIL4RA (OR = 0.80, 95% CI = 0.65, 1.00), their interaction (OR = 1.06, 95% CI = 1.01, 1.12) and glioblastoma. This interaction was apparent > 20 years before diagnosis (IL4-sIL4RA OR = 1.20, 95% CI = 1.05, 1.37). Findings for glioma were similar. Case correlations were different from control correlations stratified on time before diagnosis. Five years or less before diagnosis, correlations among case serum proteins were weaker than were those among controls. Our findings suggest that IL4 and sIL4RA reduce glioma risk long before diagnosis and early gliomagenesis affects circulating immune function proteins.

  4. Lactate dehydrogenase A silencing in IDH mutant gliomas

    PubMed Central

    Chesnelong, Charles; Chaumeil, Myriam M.; Blough, Michael D.; Al-Najjar, Mohammad; Stechishin, Owen D.; Chan, Jennifer A.; Pieper, Russell O.; Ronen, Sabrina M.; Weiss, Samuel; Luchman, H. Artee; Cairncross, J. Gregory

    2014-01-01

    Background Mutations of the isocitrate dehydrogenase 1 and 2 gene (IDH1/2) were initially thought to enhance cancer cell survival and proliferation by promoting the Warburg effect. However, recent experimental data have shown that production of 2-hydroxyglutarate by IDH mutant cells promotes hypoxia-inducible factor (HIF)1α degradation and, by doing so, may have unexpected metabolic effects. Methods We used human glioma tissues and derived brain tumor stem cells (BTSCs) to study the expression of HIF1α target genes in IDH mutant (mt) and IDH wild-type (wt) tumors. Focusing thereafter on the major glycolytic enzyme, lactate dehydrogenase A (LDHA), we used standard molecular methods and pyrosequencing-based DNA methylation analysis to identify mechanisms by which LDHA expression was regulated in human gliomas. Results We found that HIF1α-responsive genes, including many essential for glycolysis (SLC2A1, PDK1, LDHA, SLC16A3), were underexpressed in IDHmt gliomas and/or derived BTSCs. We then demonstrated that LDHA was silenced in IDHmt derived BTSCs, including those that did not retain the mutant IDH1 allele (mIDHwt), matched BTSC xenografts, and parental glioma tissues. Silencing of LDHA was associated with increased methylation of the LDHA promoter, as was ectopic expression of mutant IDH1 in immortalized human astrocytes. Furthermore, in a search of The Cancer Genome Atlas, we found low expression and high methylation of LDHA in IDHmt glioblastomas. Conclusion To our knowledge, this is the first demonstration of downregulation of LDHA in cancer. Although unexpected findings, silencing of LDHA and downregulation of several other glycolysis essential genes raise the intriguing possibility that IDHmt gliomas have limited glycolytic capacity, which may contribute to their slow growth and better prognosis. PMID:24366912

  5. Differential response of glioma cells to FOXO1-directed therapy.

    PubMed

    Lau, Cara J; Koty, Zaf; Nalbantoglu, Josephine

    2009-07-01

    Gliomas are the most common adult primary brain tumors, and the most malignant form, glioblastoma multiforme, is invariably fatal. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is altered in most glioblastoma multiforme. PTEN, an important negative regulator of the PI3K-Akt pathway, is also commonly mutated in glioma, leading to constitutive activation of Akt. One ultimate consequence is phosphorylation and inactivation of FOXO forkhead transcription factors that regulate genes involved in apoptosis, cell cycle arrest, nutrient availability, DNA repair, stress, and angiogenesis. We tested the ability of a mutant FOXO1 factor that is not subject to Akt phosphorylation to overcome dysregulated PI3K-Akt signaling in two PTEN-null glioma cell lines, U87 and U251. Adenovirus-mediated gene transfer of the mutant FOXO1 successfully restored cell cycle arrest and induced cell death in vitro and prolonged survival in vivo in xenograft models of human glioma (33% survival at 1 year of animals bearing U251 tumors). However, U87 were much more resistant than U251 to mutant FOXO1-induced death, showing evidence of increased nuclear export and Akt-independent phosphorylation of FOXO1 at S249. A cyclin-dependent kinase 2 inhibitor decreased phosphorylation of S249 and rendered U87 cells significantly more susceptible to mutant FOXO1-induced death. Our results indicate that targeting FOXO1, which is at the convergence point of several growth factor receptor tyrosine kinase pathways, can effectively induce glioma cell death and inhibit tumor growth. They also highlight the importance of Akt-independent phosphorylation events in the nuclear export of FOXO1.

  6. Thyroid hormone transport in a human glioma cell line.

    PubMed

    Goncalves, E; Lakshmanan, M; Pontecorvi, A; Robbins, J

    1990-03-05

    The uptake of 3,5,3'-triiodothyronine (T3) and thyroxine (T4) was studied in human glioma cells (Hs 683) and compared with that in several other neural cell lines. At 25 degrees C or 37 degrees C, total cell uptake rose rapidly and reached equilibrium within 60 min. The glioma cells had the highest uptake: 47.6 fmol of L-T3 and 43.4 fmol of L-T4 per 10(6) cells at 37 degrees C. These were inhibited 77% and 72%, respectively, by excess unlabeled hormone. Uptake in the nuclei reached equilibrium between 90 and 120 min and was also highest in glioma cells: 1.46 fmol of L-T3 and 0.49 fmol of L-T4 per 10(6) cells. When expressed as percent of total cell uptake, however, glioma cells had the lowest values (3.1% for L-T3 and 1.1% for L-T4). Also in contrast to other cell lines, glioma cells transported L-T4 almost as effectively as L-T3. D-T3 and D-T4 total cell uptake was 86% and 96% lower than that of the respective L-isomers, and the nuclear uptake as a fraction of the cell uptake was similar. Kinetic analysis of the initial rate of cell uptake gave Vmax values for D-T3 and D-T4 that were 97% and 98% lower than for the L-isomers. Antimycin and monodansylcadaverine decreased the Vmax as well as the equilibrium cell and nuclear uptake of the L-isomers. The apparent nuclear affinity constant for L-T4 in intact cells was inhibited 90% in the presence of antimycin, whereas no effect was observed in isolated nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)

  7. 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.

  8. Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

    PubMed

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

    2016-01-28

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

  9. HLF/miR-132/TTK axis regulates cell proliferation, metastasis and radiosensitivity of glioma cells.

    PubMed

    Chen, Shu; Wang, Yang; Ni, Chunxia; Meng, Ge; Sheng, Xiaofang

    2016-10-01

    Glioma is a malignant cancer with high mortality. A key prognostic factor of glioma is radiosensitivity. It has also been known that microRNAs (miR) significantly contribute to the development of glioma. miR-132 has been previously reported to inhibit tumor growth in some cancers, but not well studied in glioma. It is necessary to understand the association between miR-132 and glioma, including miR-132 expression in glioma, effects of miR-132 on cancer metastasis and radiosensitivity, and the involved molecular mechanism. We first explored the expression levels of miR-132 in human normal and glioma tissues, then correlated the expression levels with different stages of glioma. Utilizing human glioma U87 cells, lentiviral transduction technique, luciferase reporter assay, wound healing assay, transwell invasion assay and clonogenic assay, we investigated the effects of hepatic leukemia factor (HLF), miR-132 and TTK protein kinase (TTK) on cancer cell viability, proliferation, migration, invasion and radiosensitivity. The expression of miR-132 was low in human glioma tissues, and the downregulated expression was associated with advanced glioma grades. HLF directly bound to the BS1 site of miR-132 promoter to enhance the expression of miR-132. HLF-mediated miR-132 was able to directly target and inhibit a downstream factor TTK, which had an oncogenic role. Overexpression of TTK could reverse the inhibitory effects of either miR-132 or HLF on cancer cell proliferation, metastasis and radioresistance. TTK acts as an oncogene in glioma. HLF-mediated miR-132 directly suppresses TTK expression, thus exerting inhibitory effects on cancer cell proliferation, metastasis and radioresistance.

  10. 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…

  11. 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

  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

    2015-12-08

    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.

  13. 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.

  14. Adhesion molecules and the extracellular matrix as drug targets for glioma.

    PubMed

    Shimizu, Toshihiko; Kurozumi, Kazuhiko; Ishida, Joji; Ichikawa, Tomotsugu; Date, Isao

    2016-04-01

    The formation of tumor vasculature and cell invasion along white matter tracts have pivotal roles in the development and progression of glioma. A better understanding of the mechanisms of angiogenesis and invasion in glioma will aid the development of novel therapeutic strategies. The processes of angiogenesis and invasion cause the production of an array of adhesion molecules and extracellular matrix (ECM) components. This review focuses on the role of adhesion molecules and the ECM in malignant glioma. The results of clinical trials using drugs targeted against adhesion molecules and the ECM for glioma are also discussed.

  15. The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.

    PubMed

    Yin, Haoyuan; Shao, Ying; Chen, Xuan

    2017-01-01

    To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P < 0.05). Downregulated the expression of CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

  16. Plerixafor After Radiation Therapy and Temozolomide in Treating Patients With Newly Diagnosed High Grade Glioma

    ClinicalTrials.gov

    2016-11-08

    Adult Ependymoblastoma; Adult Giant Cell Glioblastoma; Adult Glioblastoma; Adult Gliosarcoma; Adult Medulloblastoma; Adult Mixed Glioma; Adult Oligodendroglial Tumors; Adult Pineoblastoma; Adult Supratentorial Primitive Neuroectodermal Tumor (PNET)

  17. Radiation combined with temozolomide contraindicated for young adults diagnosed with anaplastic glioma

    PubMed Central

    Cai, Jinquan; You, Gan; Wang, Yinyan; Qiu, Xiaoguang; Li, Shouwei; Wu, Chenxing; Yao, Kun; Li, Wenbin; Peng, Xiaoxia; Zhang, Wei; Jiang, Tao

    2016-01-01

    Purpose Age is a major prognostic factor for malignant gliomas. However, few studies have investigated the management of gliomas in young adults. We determined the role of survival and treatment in young adults with advanced gliomas in a large population from the Chinese Glioma Genome Atlas (CGGA). Methods This study included 726 adults (age ≥ 18) with histologically proven anaplastic glioma or glioblastoma multiforme (GBM). The overall and progression-free survival was determined in young (age < 50) and older groups (age ≥ 50). Results The study included an older group (OP) of 264 patients and a younger group (YP) of 462patients. In the OP group with GBM and anaplastic glioma, patients treated with RT combined with temozolomide (TMZ) manifested significantly longer OS and PFS compared with patients assigned to RT alone (P < 0.05). In contrast, the YP group diagnosed with anaplastic glioma failed to show any survival advantage with RT plus TMZ compared with RT alone. Conclusions We observed no survival benefit in young adults (age < 50) with anaplastic glioma when treated with TMZ combined with RT. Our findings warrant further investigation of younger patients diagnosed with anaplastic glioma treated with radiotherapy plus TMZ chemotherapy. PMID:27590514

  18. Erlotinib Hydrochloride and Isotretinoin in Treating Patients With Recurrent Malignant Glioma

    ClinicalTrials.gov

    2017-02-20

    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

  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. 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

  1. 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

  2. Targeted Therapy for MAPK Alterations in Pediatric Gliomas

    PubMed Central

    Truong, AY; Nicolaides, TP

    2015-01-01

    Although the mitogen-activated protein kinase (MAPK) pathway helps promote normal cell development, the pathway is known to contribute to the initiation and growth of many types of cancers. Tumorigenesis can result from mutations in a number of the pathway’s key proteins, including but not limited to RAS, any one of the three RAF kinases, or MEK1/2. Moreover, by discovering and understanding the biology of oncogenic mutations, scientists can develop novel targeted therapies. This review describes the general history of such targeted therapies in the context of pediatric gliomas. We first describe the biology of gliomas and oncogenic mutations in the MAPK pathway and then summarize notable pre-clinical data and clinical trials for these targeted therapies. PMID:26525348

  3. 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

  4. SVM-based glioma grading: Optimization by feature reduction analysis.

    PubMed

    Zöllner, Frank G; Emblem, Kyrre E; Schad, Lothar R

    2012-09-01

    We investigated the predictive power of feature reduction analysis approaches in support vector machine (SVM)-based classification of glioma grade. In 101 untreated glioma patients, three analytic approaches were evaluated to derive an optimal reduction in features; (i) Pearson's correlation coefficients (PCC), (ii) principal component analysis (PCA) and (iii) independent component analysis (ICA). Tumor grading was performed using a previously reported SVM approach including whole-tumor cerebral blood volume (CBV) histograms and patient age. Best classification accuracy was found using PCA at 85% (sensitivity=89%, specificity=84%) when reducing the feature vector from 101 (100-bins rCBV histogram+age) to 3 principal components. In comparison, classification accuracy by PCC was 82% (89%, 77%, 2 dimensions) and 79% by ICA (87%, 75%, 9 dimensions). For improved speed (up to 30%) and simplicity, feature reduction by all three methods provided similar classification accuracy to literature values (∼87%) while reducing the number of features by up to 98%.

  5. 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

  6. 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

  7. Intratumoral heterogeneity of malignant gliomas measured in vitro

    SciTech Connect

    Allam, A.; Taghian, A.; Gioioso, D.; Duffy, M.; Suit, H.D. )

    1993-09-20

    The purpose of the study was to evaluate the extent of intratumoral heterogeneity of radiation sensitivity in malignant gliomas, by comparing the intrinsic radiation sensitivity of different glioma sublines derived from the same tumor. The study was performed on five early established malignant gliomas (passage 3-10). Each specimen was quickly cut into three equal pieces (except for one specimen, where only two pieces were obtained). Each piece was processed independently, disintegrated into single cell suspension using a cocktail of enzymes. Survival curve assays, using colony formation as an end-point, were performed for each subline. Comparison between the intrinsic radiation sensitivity of sublines was calculated using the surviving fraction at 2 Gy and the mean inactivation dose as the measured parameters. The DNA content of the cell lines as well as their cell cycle analysis was determined using flow cytometry. The mean calculated surviving fraction at 2 Gy of all the sublines was 0.37, the mean mean inactivation dose was 1.98. The intertumoral coefficient of variation for the calculated surviving fraction at a statistically significant difference in the surviving fraction at 2 Gy and mean inactivation dose values of their sublines. This difference in radiation sensitivity between sublines of the same tumor was not attributed to a difference either in the ploidy status or in the distribution of cells in the cell cycle. There is a significant intratumoral heterogeneity of radiation sensitivity in some malignant gliomas. This heterogeneity may limit the predictive power of surviving fraction at 2 Gy or mean inactivation dose, especially when their values are based upon a single measurement/single biopsy. In the meantime, this heterogeneity may be a factor in the discrepancy between unexpectedly sensitive tumor cell lines in vitro and their high clinical radiation resistance. 20 refs., 3 figs., 2 tabs.

  8. Integrin inhibition promotes atypical anoikis in glioma cells

    PubMed Central

    Silginer, M; Weller, M; Ziegler, U; Roth, P

    2014-01-01

    Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation and motility. They are expressed by glioma cells and may contribute to their malignant phenotype. Integrin inhibition may therefore represent a promising therapeutic strategy. GL-261 and SMA-560 glioma cells grown under standard conditions uniformly detached and formed large cell clusters after integrin gene silencing or pharmacological inhibition using EMD-121974, a synthetic Arg-Gly-Asp-motif peptide, or GLPG0187, a nonpeptidic integrin inhibitor. After 120 h, the clusters induced by integrin inhibition decayed and cells died. In contrast, when cells were cultured under stem cell (sphere) conditions, no disaggregation became apparent upon integrin inhibition, and cell death was not observed. As poly-HEMA-mediated detachment had similar effects on cell viability as integrin inhibition, we postulated that cell death may result from detachment alone, which was confirmed using various permissive and nonpermissive substrates. No surrogate markers of apoptosis were detected and electron microscopy confirmed that necrosis represents the dominant morphology of detachment-induced cell death. In addition, integrin inhibition resulted in the induction of autophagy that represents a survival signal. When integrins were inhibited in nonsphere glioma cells, the TGF-β pathway was strongly impaired, whereas no such effect was observed in glioma cells cultured under sphere conditions. Cell death induced by integrin inhibition was rescued by the addition of recombinant transforming growth factor-β (TGF-β) and accelerated by exposure to the TGF-β receptor inhibitor, SD-208. In summary, cell death following integrin inhibition is detachment mediated, represents an atypical form of anoikis involving necrosis as well as autophagy, and is modulated by TGF-β pathway activity. PMID:24457956

  9. Long noncoding RNA FTX is upregulated in gliomas and promotes proliferation and invasion of glioma cells by negatively regulating miR-342-3p.

    PubMed

    Zhang, Weiguang; Bi, Yunke; Li, Jianhua; Peng, Fei; Li, Hui; Li, Chenguang; Wang, Laizang; Ren, Fubin; Xie, Chen; Wang, Pengwei; Liang, Weiwei; Wang, Zhi; Zhu, Dan

    2017-04-01

    Gliomas remain a major public health challenge, posing a high risk for brain tumor-related morbidity and mortality. However, the mechanisms that drive the development of gliomas remain largely unknown. Emerging evidence has shown that long noncoding RNAs are key factors in glioma pathogenesis. qRT-PCR analysis was used to assess the expression of FTX and miR-342-3p in the different stages of gliomas in tissues. Bioinformatics tool DIANA and TargetSCan were used to predict the targets of FTX and miR-342-3p, respectively. Pearson's correlation analysis was performed to test the correlation between the expression levels of FTX, miR-342-3p, and astrocyte-elevated gene-1 (AEG-1). To examine the role of FTX in regulating proliferation and invasion of glioma cells, specific siRNA was used to knockdown FTX, and MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) and transwell assays were performed. Furthermore, rescue experiments were performed to further confirm the regulation of miR-342-3p by FTX. We then found that the expression of FTX and miR-342-3p was associated with progression of gliomas. FTX directly inhibited the expression of miR-342-3p, which subsequently regulates the expression of AEG-1. Collectively, FTX is critical for proliferation and invasion of glioma cells by regulating miR-342-3p and AEG-1. Our findings indicate that FTX and miR-342-3p may serve as a biomarker of glioma diagnosis, and offer potential novel therapeutic targets of treatment of gliomas.

  10. Pre-clinical evaluation of voltage-gated calcium channel blockers derived from the spider P. nigriventer in glioma progression.

    PubMed

    Nicoletti, Natália Fontana; Erig, Thaís Cristina; Zanin, Rafael Fernandes; Roxo, Marcelo Ricardo; Ferreira, Nelson Pires; Gomez, Marcus Vinicius; Morrone, Fernanda Bueno; Campos, Maria Martha

    2017-04-01

    This study investigated the effects of P/Q- and N-type voltage-gated calcium channel (VGCC) blockers derived from P. nigriventer in glioma progression, by means of in vitro and in vivo experiments. Glioma cells M059J, U-138MG and U-251MG were used to evaluate the antiproliferative effects of P/Q- and N-type VGCC inhibitors PhTx3-3 and Phα1β from P. nigriventer (0.3-100 pM), in comparison to MVIIC and MVIIA from C. magus (0.3-100 pM), respectively. The toxins were also analyzed in a glioma model induced by implantation of GL261 mouse cells. PhTx3-3, Phα1β and MVIIA displayed significant inhibitory effects on the proliferation and viability of all tested glioma cell lines, and evoked cell death mainly with apoptosis characteristics, as indicated by Annexin V/propidium iodide (PI) positivity. The antiproliferative effects of toxins were confirmed by flow cytometry using Ki67 staining. None of the tested toxins altered the proliferation rates of the N9 non-tumor glial cell line. Noteworthy, the administration of the preferential N-type VGCC inhibitors, Phα1β (50 pmol/site; i.c.v.), its recombinant form CTK 01512-2 (50 pmol/site; i.c.v. and i.t.), or MVIIA (10 pmol/site; i.c.v.) caused significant reductions of tumor areas in vivo. N-type VGCC inhibition by Phα1β, CTK 01512-2, and MVIIA led to a marked increase of GFAP-activated astrocytes, and Iba-1-positive microglia, in the peritumoral region, which might explain, at least in part, the inhibitory effects of the toxins in tumor development. This study provides novel evidence on the potential effects of P. nigriventer-derived P/Q-, and mainly, N-type VGCC inhibitors, in glioma progression.

  11. Decreased Expression of miR-15b in Human Gliomas Is Associated with Poor Prognosis

    PubMed Central

    Sun, Guan; Yan, Shushan; Shi, Lei; Wan, Zhengqiang; Jiang, Nan; Li, Min

    2015-01-01

    Abstract MicroRNA-15b (miR-15b) has been demonstrated to suppress proliferation by arresting cell cycle progression and inducing apoptosis in glioma cells. However, the prognostic value of miR-15b expression in human gliomas remains unclear. In the present study, the authors examined the expression profile in glioma specimens and the prognostic value of miR-15b in patients with gliomas. Real-time polymerase chain reaction assay was employed to detect the expression levels of miR-15b in 92 glioma tissues categorized by World Health Organization (WHO) histopathological grades. However, the prognostic value of miR-15b in human glioma has not been evaluated yet. MiR-15b expression in human glioma tissues was distinctly lower than in normal brain tissues. Furthermore, the expression of miR-15b notably decreased with the ascending histopathological grade of gliomas. Additionally, Kaplan–Meier survival analysis showed that low miR-15b expression was associated with poor overall survival in patients with gliomas. Similarly, miR-15b reduction occurred with increasing frequency in glioma patients with lower Karnofsky performance scale (KPS) scores than in those with higher KPS scores. No significant difference was observed between miR-15b expression and gender, age, and tumor location. These findings revealed that a lower expression level of miR-15b was closely related to a shorter overall survival, suggesting that miR-15b could be an intrinsic factor that plays an important role in the malignant progression of gliomas. PMID:25811315

  12. Joint effects between five identified risk variants, allergy, and autoimmune conditions on glioma risk.

    PubMed

    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

    2013-10-01

    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.

  13. Altered Resting-State Functional Connectivity in the Hand Motor Network in Glioma Patients.

    PubMed

    Mallela, Arka N; Peck, Kyung K; Petrovich-Brennan, Nicole M; Zhang, Zhigang; Lou, William; Holodny, Andrei I

    2016-08-22

    To examine the functional connectivity of the primary and supplementary motor areas (SMA) in glioma patients using resting-state functional MRI (rfMRI). To correlate rfMRI data with tumor characteristics and clinical information to characterize functional reorganization of resting-state networks (RSN) and the limitations of this method. This study was IRB approved and in compliance with Health Insurance Portability and Accountability Act. Informed consent was waived in this retrospective study. We analyzed rfMRI in 24 glioma patients and 12 age- and sex-matched controls. We compared global activation, interhemispheric connectivity, and functional connectivity in the hand motor RSNs using hemispheric voxel counts, pairwise Pearson correlation, and pairwise total spectral coherence. We explored the relationship between tumor grade, volume, location, and the patient's clinical status to functional connectivity. Global network activation and interhemispheric connectivity were reduced in gliomas (p < 0.05). Functional connectivity between the bilateral motor cortices and the SMA was reduced in gliomas (p < 0.01). High-grade gliomas had lower functional connectivity than low-grade gliomas (p < 0.05). Tumor volume and distance to ipsilateral motor cortex demonstrated no association with functional connectivity loss. Functional connectivity loss is associated with motor deficits in low-grade gliomas, but not in high-grade gliomas. Global reduction in resting-state connectivity in areas distal to tumor suggests that radiological tumor boundaries underestimate areas affected by glioma. Association between motor deficits and rfMRI suggests that rfMRI may accurately reflect functional changes in low-grade gliomas. Lack of association between rfMRI and clinical motor deficits implies decreased sensitivity of rfMRI in high-grade gliomas, possibly due to neurovascular uncoupling.

  14. 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

  15. Repetitive 5-aminolevulinic acid mediated photodynamic therapy of rat glioma

    NASA Astrophysics Data System (ADS)

    Hirschberg, Henry; Madsen, Steen J.; Angell-Petersen, Even; Peng, Qian; Sioud, Mouldy; Sun, Chung-Ho; Sorensen, Dag R.

    2004-07-01

    The probability of achieving local control with current single-shot, intraoperative PDT treatments of intracerebral gliomas seems improbable due to the length of time required to deliver adequate light fluences to depths of 1 - 2 cm in the resection margin. The results of in vitro experiments indicated that PDT, repeated at weekly intervals, was substantially more effective at inhibiting glioma spheriod growth than single treatment regimes. This prompted the initiation of in vivo studies of repetitive PDT in a rat glioma model. BT4C cell line tumors were established in the brains of inbred BD-IX rats. Three days following tumor induction, the animals were injected with 250 mg/kg ALA i.p. and four hours later, after the introduction of an optical fiber, light treatment at various radiant energies was given over a 10- to 30-minute interval. Two additional treatments were given at weekly intervals. In vitro experiments verified that spheroids derived from the cell line were sensitive to ALA PDT. Microfluorometry of frozen tissue sections showed that PpIX is produced with a 10 - 20:1 tumor to normal tissue selectivity ratio four hours after 250 mg/kg ALA i.p. Toxic radiant energy levels for ALA PDT have been determined.

  16. Oncolytic Virotherapy for the Treatment of Malignant Glioma.

    PubMed

    Foreman, Paul M; Friedman, Gregory K; Cassady, Kevin A; Markert, James M

    2017-03-06

    Malignant glioma is the most common primary brain tumor and carries a grim prognosis, with a median survival of just over 14 months. Given the poor outcomes with standard-of-care treatments, novel treatment strategies are needed. The concept of virotherapy for the treatment of malignant tumors dates back more than a century and can be divided into replication-competent oncolytic viruses and replication-deficient viral vectors. Oncolytic viruses are designed to selectively target, infect, and replicate in tumor cells, while sparing surrounding normal brain. A host of oncolytic viruses has been evaluated in early phase human trials with promising safety results, but none has progressed to phase III trials. Despite the 25 years that has passed since the initial publication of genetically engineered oncolytic viruses for the treatment of glioma, much remains to be learned about the use of this therapy, including its mechanism of action, optimal treatment paradigm, appropriate targets, and integration with adjuvant agents. Oncolytic viral therapy for glioma remains promising and will undoubtedly impact the future of patient care.

  17. 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).

  18. Metabolomics of Human Cerebrospinal Fluid Identifies Signatures of Malignant Glioma*

    PubMed Central

    Locasale, Jason W.; Melman, Tamar; Song, Susan; Yang, Xuemei; Swanson, Kenneth D.; Cantley, Lewis C.; Wong, Eric T.; Asara, John M.

    2012-01-01

    Cerebrospinal fluid is routinely collected for the diagnosis and monitoring of patients with neurological malignancies. However, little is known as to how its constituents may change in a patient when presented with a malignant glioma. Here, we used a targeted mass-spectrometry based metabolomics platform using selected reaction monitoring with positive/negative switching and profiled the relative levels of over 124 polar metabolites present in patient cerebrospinal fluid. We analyzed the metabolic profiles from 10 patients presenting malignant gliomas and seven control patients that did not present malignancy to test whether a small sample size could provide statistically significant signatures. We carried out multiple unbiased forms of classification using a series of unsupervised techniques and identified metabolic signatures that distinguish malignant glioma patients from the control patients. One subtype identified contained metabolites enriched in citric acid cycle components. Newly diagnosed patients segregated into a different subtype and exhibited low levels of metabolites involved in tryptophan metabolism, which may indicate the absence of an inflammatory signature. Together our results provide the first global assessment of the polar metabolic composition in cerebrospinal fluid that accompanies malignancy, and demonstrate that data obtained from high throughput mass spectrometry technology may have suitable predictive capabilities for the identification of biomarkers and classification of neurological diseases. PMID:22240505

  19. 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.

  20. 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

  1. Genetic therapy in gliomas: historical analysis and future perspectives.

    PubMed

    Mattei, Tobias Alécio; Ramina, Ricardo; Miura, Flavio Key; Aguiar, Paulo Henrique; Valiengo, Leandro da Costa

    2005-03-01

    High-grade gliomas are relatively frequent in adults, and consist of the most malignant kind of primary brain tumor. Being resistant to standard treatment modalities such as surgery, radiation, and chemotherapy, it is fatal within 1 to 2 years of onset of symptoms. Although several gene therapy systems proved to be efficient in controlling or eradicating these tumors in animal models, the clinical studies performed so far were not equally successful. Most clinical studies showed that methodologies that increase tumor infection/transduction and, consequently confer more permanent activity against the tumor, will lead to enhanced therapeutic results. Due to the promising practical clinical benefits that can be expected for the near future, an exposition to the practicing neurosurgeon about the basic issues in genetic therapy of gliomas seems convenient. Among the main topics, we shall discuss anti-tumoral mechanisms of various genes that can be transfected, the advantages and drawbacks of the different vectors utilized, the possibilities of tumor targeting by modifications in the native tropism of virus vectors, as well as the different physical methods for vector delivery to the tumors. Along with the exposition we will also review of the history of the genetic therapy for gliomas, with special focus on the main problems found during the advancement of scientific discoveries in this area. A general analysis is also made of the present state of this promising therapeutic modality, with reference to the problems that still must be solved and the new paradigms for future research in this area.

  2. Implications of mitogen-activated protein kinase signaling in glioma.

    PubMed

    Pandey, Vimal; Bhaskara, Vasantha Kumar; Babu, Phanithi Prakash

    2016-02-01

    Gliomas are the most common primary central nervous system tumors. Gliomas originate from astrocytes, oligodendrocytes, and neural stem cells or their precursors. According to WHO classification, gliomas are classified into four different malignant grades ranging from grade I to grade IV based on histopathological features and related molecular aberrations. The induction and maintenance of these tumors can be attributed largely to aberrant signaling networks. In this regard, the mitogen-activated protein kinase (MAPK) network has been widely studied and is reported to be severely altered in glial tumors. Mutations in MAPK pathways most frequently affect RAS and B-RAF in the ERK, c-Jun N-terminal kinase (JNK), and p38 pathways leading to malignant transformation. Also, it is linked to both inherited and sequential accumulations of mutations that control receptor tyrosine kinase (RTK)-activated signal transduction pathways, cell cycle growth arrest pathways, and nonresponsive cell death pathways. Genetic alterations that modulate RTK signaling can also alter several downstream pathways, including RAS-mediated MAP kinases along with JNK pathways, which ultimately regulate cell proliferation and cell death. The present review focuses on recent literature regarding important deregulations in the RTK-activated MAPK pathway during gliomagenesis and progression.

  3. Progress in the application of molecular biomarkers in gliomas.

    PubMed

    Wang, Jing; Su, Hong-kai; Zhao, Hua-fu; Chen, Zhong-ping; To, Shing-shun Tony

    2015-09-11

    Gliomas are a common adult central nervous system tumor, and glioblastoma (GBM), which has a poor prognosis, is the most lethal of all gliomas. The overall survival of GBM patients is only 12-14 months after diagnosis. With progress in the precision of personal medication, therapeutic options for various tumors have become gradually dependent on the molecular profiles of patients. GBM is one of the tumors in which treatment response relies largely on the molecular characteristics of the tumor. Therefore, awareness of the genetic background of each patient will help decision-making regarding the best treatment strategy to use. In this review, a novel molecular classification of gliomas based on recent findings of their genetic characteristics is introduced. Representative molecular markers, such as IDH1 mutation, 1p19q co-deletion, MGMT promoter methylation and EGFRvIII amplification, are described. Furthermore, the development of non-coding RNAs and omics studies of GBM are briefly discussed. Finally, a novel concept for non-invasive detection that could facilitate both diagnosis and treatment monitoring is presented. There is no doubt that the use of molecular profiling by biomarkers will indeed improve the overall survival and quality of life of GBM patients.

  4. 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.

  5. ASYMMETRIC CELL DIVISION: IMPLICATIONS FOR GLIOMA DEVELOPMENT AND TREATMENT.

    PubMed

    Lewis, Kate Marie; Petritsch, Claudia

    2013-12-01

    Glioma is a heterogeneous disease process with differential histology and treatment response. It was previously thought that the histological features of glial tumors indicated their cell of origin. However, the discovery of continuous neuro-gliogenesis in the normal adult brain and the identification of brain tumor stem cells within glioma have led to the hypothesis that these brain tumors originate from multipotent neural stem or progenitor cells, which primarily divide asymmetrically during the postnatal period. Asymmetric cell division allows these cell types to concurrently self-renew whilst also producing cells for the differentiation pathway. It has recently been shown that increased symmetrical cell division, favoring the self-renewal pathway, leads to oligodendroglioma formation from oligodendrocyte progenitor cells. In contrast, there is some evidence that asymmetric cell division maintenance in tumor stem-like cells within astrocytoma may lead to acquisition of treatment resistance. Therefore cell division mode in normal brain stem and progenitor cells may play a role in setting tumorigenic potential and the type of tumor formed. Moreover, heterogeneous tumor cell populations and their respective cell division mode may confer differential sensitivity to therapy. This review aims to shed light on the controllers of cell division mode which may be therapeutically targeted to prevent glioma formation and improve treatment response.

  6. 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.

  7. Retinoids in the treatment of glioma: a new perspective

    PubMed Central

    Mawson, Anthony R

    2012-01-01

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

  8. Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients.

    PubMed

    Sun, Boqian; Chu, Dake; Li, Wei; Chu, Xiaodan; Li, Yunming; Wei, Dun; Li, Haiping

    2009-09-01

    The aim of the study was to examine the expression of NDRG1 gene in glioma samples with different WHO grades and its association with survival. About 168 glioma specimens and 21 normal control tissues were collected. Immunochemistry assay, quantitative real-time PCR and Western blot analysis were carried out to investigate the expression of NDRG1 and Myc. Kaplan-Meier method and Cox's proportional hazards model were used in survival analysis. Immunohistochemistry showed that Ndrg1 expression was reduced in glioma. NDRG1 mRNA and protein levels were lower in glioma compared to control on real-time PCR and Western blot analysis (P < 0.001). Its expression levels increase from grade IV to grade I glioma on real-time PCR, immunohistochemistry analysis (P < 0.001) and Western blot. On the contrary, the expression of Myc by real-time PCR and Western blot showed the opposite trend of NDRG1. The survival rate of Ndrg1-negative patients was lower than that of Ndrg1-positive patients. We confirmed that the loss of NDRG1 expression was a significant and independent prognostic indicator in glioma by multivariate analysis. NDRG1 may play an inhibitory role during the development of glioma and may be a potential prognosis predictor of glioma.

  9. Angiogenic Signalling Pathways Altered in Gliomas: Selection Mechanisms for More Aggressive Neoplastic Subpopulations with Invasive Phenotype

    PubMed Central

    Bulnes, Susana; Bengoetxea, Harkaitz; Ortuzar, Naiara; Argandoña, Enrike G.; Garcia-Blanco, Álvaro; Rico-Barrio, Irantzu; Lafuente, José V.

    2012-01-01

    The angiogenesis process is a key event for glioma survival, malignancy and growth. The start of angiogenesis is mediated by a cascade of intratumoural events: alteration of the microvasculature network; a hypoxic microenvironment; adaptation of neoplastic cells and synthesis of pro-angiogenic factors. Due to a chaotic blood flow, a consequence of an aberrant microvasculature, tissue hypoxia phenomena are induced. Hypoxia inducible factor 1 is a major regulator in glioma invasiveness and angiogenesis. Clones of neoplastic cells with stem cell characteristics are selected by HIF-1. These cells, called “glioma stem cells” induce the synthesis of vascular endothelial growth factor. This factor is a pivotal mediator of angiogenesis. To elucidate the role of these angiogenic mediators during glioma growth, we have used a rat endogenous glioma model. Gliomas induced by prenatal ENU administration allowed us to study angiogenic events from early to advanced tumour stages. Events such as microvascular aberrations, hypoxia, GSC selection and VEGF synthesis may be studied in depth. Our data showed that for the treatment of gliomas, developing anti-angiogenic therapies could be aimed at GSCs, HIF-1 or VEGF. The ENU-glioma model can be considered to be a useful option to check novel designs of these treatment strategies. PMID:22852079

  10. O6.09PROSTAGLANDIN E RECEPTOR-4 ACTIVATION REGULATES TRYPTOPHAN METABOLISM IN HUMAN MALIGNANT GLIOMAS

    PubMed Central

    Ochs, K.; Ott, M.; Rauschenbach, K.J.; Sahm, F.; Opitz, C.A.; von Deimling, A.; Wick, W.; Platten, M.

    2014-01-01

    Malignant gliomas generate a local immunosuppressive microenvironment as well as systemic immunosuppression. Tryptophan-2,3-dioxygenase (TDO)-mediated tryptophan metabolism and the production of immunosuppressive prostaglandins relevantly contribute to this inhibition of anti-glioma immune responses. We now connect these two critical immunosuppressive pathways by demonstrating that prostaglandins enhance TDO expression and enzymatic activity in malignant gliomas via activation of prostaglandin E receptor-4 (EP4). Stimulation with prostaglandin E2 (PGE2) concentration-dependently upregulates TDO-mediated kynurenine release in human glioma cell lines, while knockdown of the PGE2 receptor EP4 inhibits TDO expression and activity. In tissue of human malignant gliomas expression of the PGE2-producing enzyme cyclooxygenase-2 (COX-2) and its receptor EP4 are associated with TDO expression both on transcript and protein level. Of clinical relevance, high expression of EP4 correlates with poor survival in patients with gliomas of the WHO grades III and IV. Importantly, treatment of glioma cells with an EP4 inhibitor decreased TDO expression and activity. In summary targeting EP4 may inhibit both immunosuppressive COX-2 signaling as well as tryptophan degradation and thus could provide a novel immunotherapeutic avenue for the treatment of malignant gliomas.

  11. 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

  12. The epidemiology of glioma in adults: a "state of the science" review.

    PubMed

    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

    2014-07-01

    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.

  13. Overexpression of SMC4 activates TGFβ/Smad signaling and promotes aggressive phenotype in glioma cells.

    PubMed

    Jiang, L; Zhou, J; Zhong, D; Zhou, Y; Zhang, W; Wu, W; Zhao, Z; Wang, W; Xu, W; He, L; Ma, Y; Hu, Y; Zhang, W; Li, J

    2017-03-13

    Overexpression of structural maintenance of chromosomes 4 (SMC4) has been reported to be involved in tumor cell growth, migration and invasion, and to be correlated with poor prognosis of cancer patient. However, its clinical significance and biological role in glioma remain unknown. Herein, we found that SMC4 expression at both mRNA and protein level was markedly increased in glioma cells and clinical tissues and that it correlated with poor prognosis. SMC4 overexpression markedly promoted the glioma cell proliferation rate and migration and invasive capability in vitro and in vivo, whereas SMC4 downregulation reduced it. Moreover, the transforming growth factor β (TGFβ)/Smad signaling pathway, which was activated in SMC4-transduced glioma cells and inhibited in SMC4-silenced glioma cells, contributed to SMC4-mediated glioma cell aggressiveness. Our results provide new insight into the oncofunction of SMC4 and the mechanism by which the TGFβ/Smad pathway is hyperactivated in gliomas, indicating that SMC4 is a valuable prognostic factor and a potential therapeutic target in gliomas.

  14. Transient receptor potential canonical channels are essential for chemotactic migration of human malignant gliomas.

    PubMed

    Bomben, Valerie C; Turner, Kathryn L; Barclay, Tia-Tabitha C; Sontheimer, Harald

    2011-07-01

    The majority of malignant primary brain tumors are gliomas, derived from glial cells. Grade IV gliomas, Glioblastoma multiforme, are extremely invasive and the clinical prognosis for patients is dismal. Gliomas utilize a number of proteins and pathways to infiltrate the brain parenchyma including ion channels and calcium signaling pathways. In this study, we investigated the localization and functional relevance of transient receptor potential canonical (TRPC) channels in glioma migration. We show that gliomas are attracted in a chemotactic manner to epidermal growth factor (EGF). Stimulation with EGF results in TRPC1 channel localization to the leading edge of migrating D54MG glioma cells. Additionally, TRPC1 channels co-localize with the lipid raft proteins, caveolin-1 and β-cholera toxin, and biochemical assays show TRPC1 in the caveolar raft fraction of the membrane. Chemotaxis toward EGF was lost when TRPC channels were pharmacologically inhibited or by shRNA knockdown of TRPC1 channels, yet without affecting unstimulated cell motility. Moreover, lipid raft integrity was required for gliomas chemotaxis. Disruption of lipid rafts not only impaired chemotaxis but also impaired TRPC currents in whole cell recordings and decreased store-operated calcium entry as revealed by ratiomeric calcium imaging. These data indicated that TRPC1 channel association with lipid rafts is essential for glioma chemotaxis in response to stimuli, such as EGF.

  15. Brain slice invasion model reveals genes differentially regulated in glioma invasion

    SciTech Connect

    Holtkamp, Nikola . E-mail: nikola.holtkamp@charite.de; Afanasieva, Anastasia; Elstner, Anja; Landeghem, Frank K.H. van; Koenneker, Matthias; Kuhn, Susanne A.; Kettenmann, Helmut; Deimling, Andreas von

    2005-11-04

    Invasion of tumor cells into adjacent brain areas is one of the major problems in treatment of glioma patients. To identify genes that might contribute to invasion, fluorescent F98 glioma cells were allowed to invade an organotypic brain slice. Gene expression analysis revealed 5 up-regulated and 14 down-regulated genes in invasive glioma cells as compared to non-invasive glioma cells. Two gene products, ferritin and cyclin B1, were verified in human gliomas by immunohistochemistry. Ferritin exhibited high mRNA levels in migratory F98 cells and also showed higher protein expression in the infiltrating edge of human gliomas. Cyclin B1 with high mRNA expression levels in stationary F98 cells showed marked protein expression in the central portions of gliomas. These findings are compatible with the concept of tumor cells either proliferating or migrating. Our study is the first to apply brain slice cultures for the identification of differentially regulated genes in glioma invasion.

  16. Smoothened is a poor prognosis factor and a potential therapeutic target in glioma

    PubMed Central

    Tu, Yiming; Niu, Mingshan; Xie, Peng; Yue, Chenglong; Liu, Ning; Qi, Zhenglei; Gao, Shangfeng; Liu, Hongmei; Shi, Qiong; Yu, Rutong; Liu, Xuejiao

    2017-01-01

    Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome. Our data suggest that GDC-0449 significantly inhibits the proliferation of glioma cells by inducing cell cycle arrest at the G1 phase. Our results demonstrate that GDC-0449 can effectively inhibit the migration and invasion of glioma cells. Furthermore, GDC-0449 treatment significantly suppressed glioma cell xenograft tumorigenesis. Mechanistically, GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli1 and Gli2). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. Taken together, our study suggests that smoothened could be used as a prognostic marker and molecular therapeutic target for glioma. PMID:28195165

  17. Smoothened is a poor prognosis factor and a potential therapeutic target in glioma.

    PubMed

    Tu, Yiming; Niu, Mingshan; Xie, Peng; Yue, Chenglong; Liu, Ning; Qi, Zhenglei; Gao, Shangfeng; Liu, Hongmei; Shi, Qiong; Yu, Rutong; Liu, Xuejiao

    2017-02-14

    Malignant gliomas are associated with a high mortality rate. Thus, there is an urgent need for the development of novel targeted therapeutics. Aberrant Hedgehog signaling has been directly linked to glioma. GDC-0449 is a novel small molecule inhibitor of Hedgehog signaling that blocks the activity of smoothened (Smo). In this study, we evaluated the in vitro and in vivo effects of the smoothened inhibitor GDC-0449 on cell proliferation in human gliomas. We found that high expression of smoothened in glioma is a predictor of short overall survival and poor patient outcome. Our data suggest that GDC-0449 significantly inhibits the proliferation of glioma cells by inducing cell cycle arrest at the G1 phase. Our results demonstrate that GDC-0449 can effectively inhibit the migration and invasion of glioma cells. Furthermore, GDC-0449 treatment significantly suppressed glioma cell xenograft tumorigenesis. Mechanistically, GDC-0449 treatment markedly decreases the expression levels of key Hedgehog pathway component genes (Shh, Patched-1, Patched-2, smoothened, Gli1 and Gli2). These results indicate that GDC-0449 works through targeting the Hedgehog pathway. Taken together, our study suggests that smoothened could be used as a prognostic marker and molecular therapeutic target for glioma.

  18. Fall of the Optical Wall: Freedom from the Tyranny of the Microscope Improves Glioma Risk Stratification.

    PubMed

    Ramaswamy, Vijay; Taylor, Michael D

    2016-02-08

    A recent study uses an integrated genomic approach to identify biologically defined subgroups of adult diffuse glioma. These results further lay the foundation for a pathological classification scheme for gliomas that incorporates both histology and molecular biomarkers, which appears far more robust than the current scheme, based solely on morphology.

  19. The evolving role of molecular markers in the diagnosis and management of diffuse glioma.

    PubMed

    Huse, Jason T; Aldape, Kenneth D

    2014-11-15

    While the classification of diffuse gliomas has relied on the examination of morphologic features supplemented with techniques such as immunohistochemistry, there is an increasing recognition of substantial biologic diversity within morphologically defined entities. High-throughput technologies, in particular studies that integrate genome-wide data from diverse molecular platforms, increasingly identify the existence of robust and distinct glioma subtypes. While treatment advances and improvement of outcomes for patients with diffuse glioma have been modest, there may be benefit to integrate findings from biologic studies into clinical practice to enhance the precision of treatment for these diseases. Recent examples such as the identification of mutations in IDH1 and IDH2 as an early genetic event that is predominantly in lower-grade gliomas (grades 2 and 3) underscore the importance of molecular discovery leading to the ability to develop subclassifications with prognostic and potentially therapeutic implications. In contrast, glioblastoma (grade 4), the most common and aggressive glioma, typically arises without IDH mutation, supporting the need for different therapeutic approaches. Additional genomic and epigenomic signatures are generally nonoverlapping between IDH-mutant and IDH wild-type diffuse glioma, and despite comparable histopathology, IDH-mutant gliomas can be considered as biologically distinct from IDH wild-type gliomas. In this CCR Focus article, we highlight and summarize the current understanding of recent molecular findings and the relationships of these findings to clinical trials and clinical management.

  20. Preclinical TSPO Ligand PET to Visualize Human Glioma Xenotransplants: A Preliminary Study

    PubMed Central

    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. PMID:26517124

  1. IL-10 and PRKDC polymorphisms are associated with glioma patient survival

    PubMed Central

    Hu, Mingjun; Du, Jieli; Cui, Lihong; Huang, Tingqin; Guo, Xiaoye; Zhao, Yonglin; Ma, Xudong; Jin, Tianbo; Li, Gang; Song, Jinning

    2016-01-01

    Interleukin-10 (IL-10) and DNA repair gene PRKDC mutations are implicated in the development of multiple human cancers, including glioma. We investigated associations between IL-10 and PRKDC gene polymorphisms and prognosis in low- and high-grade glioma patients. We analyzed the associations of one IL-10 and one PRKDC single nucleotide polymorphism with patient clinical factors in 481 glioma patients using Cox proportional hazard models and Kaplan-Meier curves. We also assessed associations between patient clinical characteristics and prognosis. Our data showed that the extent of tumor resection (gross-total resection) and application of chemotherapy were associated with improved patient outcomes in all glioma cases. Additionally, univariate (Log-rank p = 0.019) and multivariate Cox regression analyses (p = 0.022) showed that the IL-10 rs1800871 C/T genotype correlates with improved overall survival in cases of low-grade glioma, whereas the PRKDC rs7003908 C/C genotype correlated with reduced overall and progression-free survival in high-grade glioma patients in univariate (Log-rank p = 0.000 and p = 0.000, respectively) and multivariate Cox regression analyses (p = 0.001; p = 0.002, respectively). These results suggest that IL-10 rs1800871 and PRKDC rs7003908 may be useful biomarkers for predicting glioma patient outcome. Further functional studies are needed to evaluate the mechanisms by which these polymorphisms affect glioma progression. PMID:27811370

  2. Pontine glioma extending to the ipsilateral cavernous sinus and Meckel's cave: MR appearance.

    PubMed

    Yuh, W T; Nguyen, H D; Mayr, N A; Follett, K A

    1992-01-01

    The authors describe an exophytic glioma of the pons that grew into the Meckel's cave and cavernous sinus in a 75-year-old man. Pontine gliomas should be included in the differential diagnosis of a hyperintense, complex cystic mass seen along the distribution of cranial nerve V.

  3. Hyperbaric oxygen promotes malignant glioma cell growth and inhibits cell apoptosis.

    PubMed

    Wang, Yong-Gang; Zhan, Yi-Ping; Pan, Shu-Yi; Wang, Hai-Dong; Zhang, Dun-Xiao; Gao, Kai; Qi, Xue-Ling; Yu, Chun-Jiang

    2015-07-01

    Glioblastoma multiforme (GBM) is the most frequently diagnosed intracranial malignant tumor in adults. Clinical studies have indicated that hyperbaric oxygen may improve the prognosis and reduce complications in glioma patients; however, the specific mechanism by which this occurs remains unknown. The present study investigated the direct effects of hyperbaric oxygen stimulation on glioma by constructing an intracranial transplanted glioma model in congenic C57BL/6J mice. Bioluminescent imaging (BLI) was used to assess the growth of intracranial transplanted GL261-Luc glioma cells in vivo, while flow cytometric and immunohistochemical assays were used to detect and compare the expression of the biomarkers, Ki-67, CD34 and TUNEL, reflecting the cell cycle, apoptosis and angiogenesis. BLI demonstrated that hyperbaric oxygen promoted the growth of intracranially transplanted GL261-Luc glioma cells in vivo. Flow cytometric analysis indicated that hyperbaric oxygen promoted GL261-Luc glioma cell proliferation and also prevented cell cycle arrest. In addition, hyperbaric oxygen inhibited the apoptosis of the transplanted glioma cells. Immunohistochemical analysis also indicated that hyperbaric oxygen increased positive staining for Ki-67 and CD34, while reducing staining for TUNEL (a marker of apoptosis). The microvessel density was significantly increased in the hyperbaric oxygen treatment group compared with the control group. In conclusion, hyperbaric oxygen treatment promoted the growth of transplanted malignant glioma cells in vivo and also inhibited the apoptosis of these cells.

  4. Potential role of Shh-Gli1-BMI1 signaling pathway nexus in glioma chemoresistance.

    PubMed

    Shahi, M H; Farheen, S; Mariyath, M P M; Castresana, J S

    2016-11-01

    Chemoresistance is a common hurdle for the proper treatment of gliomas. The role of Shh-Gli1 signaling in glioma progression has been reported. However, its role in glioma chemoresistance has not been well studied yet. In this work, we found that Shh-Gli1 signaling regulates the expression of one stem cell marker, BMI1 (B cell-specific Moloney murine leukemia virus), in glioma. Interestingly, we also demonstrated high expression of MRP1 (multi-drug resistance protein 1) in glioma. MRP1 expression was decreased by BMI1 siRNA and Shh-Gli1 cell signaling specific inhibitor GANT61 in our experiments. GANT61 very efficiently inhibited cell colony growth in glioma cell lines, compared to temozolomide. Moreover, a synergic effect of GANT61 and temozolomide drastically decreased the LD50 of temozolomide in the cell colony experiments. Therefore, our results suggest that there is a potential nexus of Shh-Gli1-BMI1 cell signaling to regulate MRP1 and to promote chemoresistance in glioma. Henceforth, our study opens the possibility of facing new targets, Gli1 and BMI1, for the effective treatment of glioma suppression of chemoresistance with adjuvant therapy of GANT61 and temozolomide.

  5. Contributions of aryl hydrocarbon receptor genetic variants to the risk of glioma and PAH-DNA adducts.

    PubMed

    Gu, Aihua; Ji, Guixiang; Jiang, Tao; Lu, Ailin; You, Yongping; Liu, Ning; Luo, Chengzhang; Yan, Wei; Zhao, Peng

    2012-08-01

    The aryl hydrocarbon receptor (AHR) gene is involved in the response to polycyclic aromatic hydrocarbon (PAH) exposure. To investigate the hypothesis that the genetic variants in the AHR gene might be a causal genetic susceptibility to PAH-DNA adduct formation and glioma risk, we conducted a case-control study of 384 glioma cases and 384 cancer-free controls to explore the association between six common single-nucleotide polymorphisms of the AHR gene and glioma risk. Using PAH-DNA adducts as biomarkers, we then evaluated the association between PAH-DNA adduct levels and glioma risk based on a tissue microarray including 11 controls and 77 glioma patients. We further explored the contributions of the glioma risk-associated AHR polymorphisms to the levels of PAH-DNA adducts in glioma tissues based on 77 glioma patients. We found that PAH-DNA adduct staining existed in normal brain tissues and grades I-IV gliomas, and the staining intensity was significantly associated with the glioma grade. Two AHR polymorphisms (rs2066853 and rs2158041) demonstrated significant association with glioma risk. Intriguingly, we also found statistically significant associations between these two variants and PAH-DNA adduct levels in glioma tissue. These data suggest the contributions of AHR rs2066853 and rs2158041 to glioma risk and the PAH-DNA adduct levels, which shed new light on gene-environment interactions in the etiology of glioma. Further studies with a larger sample size and ethnically diverse populations are required to elucidate the potential biological mechanism for, as well as the impact of, the susceptibility to glioma due to genetic variants of AHR.

  6. Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas

    PubMed Central

    Zhao, Zheng; Meng, Fanlin; Wang, Wen; Wang, Zheng; Zhang, Chuanbao; Jiang, Tao

    2017-01-01

    Gliomas are the most common and lethal intracranial tumours. RNA sequencing technologies and advanced data analyses recently enabled the characterization of transcriptomic information, including protein-coding gene expression, non-coding gene expression, alternative splicing, and fusion gene detection, to facilitate detection of diseases and altered phenotypes. As a part of the Chinese Glioma Genome Atlas (CGGA) project, our aim was to delineate comprehensive transcriptome profiling in the malignant progression of human gliomas. Three hundred twenty five gliomas with different grades were collected over the past twelve years. Using the Illumina HiSeq 2,000 system, over 92 million high quality 101-bp paired-end reads were generated per sample, yielding a total of 30 billion reads. This comprehensive dataset will be useful to deepen the comprehensive understanding of gliomas, providing an opportunity to generate new therapies, diagnoses, and preventive strategies. PMID:28291232

  7. Molecular Mechanisms Involved in the Antitumor Activity of Cannabinoids on Gliomas: Role for Oxidative Stress

    PubMed Central

    Massi, Paola; Valenti, Marta; Solinas, Marta; Parolaro, Daniela

    2010-01-01

    Cannabinoids, the active components of Cannabis sativa, have been shown to exert antiproliferative and proapoptotic effects on a wide spectrum of tumor cells and tissues. Of interest, cannabinoids have displayed great potency in reducing the growth of glioma tumors, one of the most aggressive CNS tumors, either in vitro or in animal experimental models curbing the growth of xenografts generated by subcutaneous or intrathecal injection of glioma cells in immune-deficient mice. Cannabinoids appear to be selective antitumoral agents as they kill glioma cells without affecting the viability of non-transformed cells. This review will summarize the anti-cancer properties that cannabinoids exert on gliomas and discuss their potential action mechanisms that appear complex, involving modulation of multiple key cell signaling pathways and induction of oxidative stress in glioma cells. PMID:24281104

  8. Comprehensive RNA-seq transcriptomic profiling in the malignant progression of gliomas.

    PubMed

    Zhao, Zheng; Meng, Fanlin; Wang, Wen; Wang, Zheng; Zhang, Chuanbao; Jiang, Tao

    2017-03-14

    Gliomas are the most common and lethal intracranial tumours. RNA sequencing technologies and advanced data analyses recently enabled the characterization of transcriptomic information, including protein-coding gene expression, non-coding gene expression, alternative splicing, and fusion gene detection, to facilitate detection of diseases and altered phenotypes. As a part of the Chinese Glioma Genome Atlas (CGGA) project, our aim was to delineate comprehensive transcriptome profiling in the malignant progression of human gliomas. Three hundred twenty five gliomas with different grades were collected over the past twelve years. Using the Illumina HiSeq 2,000 system, over 92 million high quality 101-bp paired-end reads were generated per sample, yielding a total of 30 billion reads. This comprehensive dataset will be useful to deepen the comprehensive understanding of gliomas, providing an opportunity to generate new therapies, diagnoses, and preventive strategies.

  9. Characterization of Heparan Sulfate Proteoglycan-positive Recycling Endosomes Isolated from Glioma Cells

    PubMed Central

    A. PODYMA-INOUE, KATARZYNA; MORIWAKI, TAKUYA; R. RAJAPAKSHE, ANUPAMA; TERASAWA, KAZUE; HARA-YOKOYAMA, MIKI

    2016-01-01

    Background: Heparan sulfate proteoglycans (HSPGs)-dependent endocytic events have been involved in glioma progression. Thus, comprehensive understanding of the intracellular trafficking complexes formed in presence of HSPGs would be important for development of glioma treatments. Materials and Methods: Subcellular fractionation was used to separate vesicles containing HSPGs from the rat C6 glioma cell line. Isolated HSPG-positive vesicles were further characterized with liquid chromatography-mass spectrometry. Results: The HSPG-positive vesicular fractions, distinct from plasma membrane-derived material, were enriched in endocytic marker, Rab11. Proteomic analysis identified more than two hundred proteins to be associated with vesicular membrane, among them, over eighty were related to endosomal uptake, recycling or vesicular transport. Conclusion: Part of HSPGs in glioma cells is internalized through clathrin-dependent endocytosis and undergo recycling. The development of compounds regulating HSPG-mediated trafficking will likely enable design of effective glioma treatment. PMID:27807067

  10. 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.

  11. Gab3 overexpression in human glioma mediates Akt activation and tumor cell proliferation

    PubMed Central

    Gu, Weiting; Zhang, Weifeng

    2017-01-01

    This current study tested expression and potential biological functions of Gab3 in human glioma. Gab3 mRNA and protein expression was significantly elevated in human glioma tissues and glioma cells. Its level was however low in normal brain tissues and primary human astrocytes. In both established (U251MG cell line) and primary human glioma cells, Gab3 knockdown by shRNA/siRNA significantly inhibited Akt activation and cell proliferation. Reversely, forced Gab3 overexpression in U251MG cells promoted Akt activation and cell proliferation. In vivo, the growth of U251MG tumors in nude mice was inhibited following expressing Gab3 shRNA. Akt activation in cancer tissues was also suppressed by Gab3 shRNA. Together, we conclude that Gab3 overexpression in human glioma mediates Akt activation and cancer cell proliferation. PMID:28291820

  12. Silencing of WNK2 is associated with upregulation of MMP2 and JNK in gliomas

    PubMed Central

    Costa, Angela Margarida; Pinto, Filipe; Martinho, Olga; Oliveira, Maria José; Jordan, Peter; Reis, Rui Manuel

    2015-01-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade extracellular matrix (ECM), thus assisting invasion. Upregulation of MMPs, frequently reported in gliomas, is associated with aggressive behavior. WNK2 is a tumor suppressor gene expressed in normal brain, and silenced by promoter methylation in gliomas. Patients without WNK2 exhibited poor prognosis, and its downregulation was associated with increased glioma cell invasion. Here we showed that MMP2 expression and activity are increased in glioma cell lines that do not express WNK2. Also, WNK2 inhibited JNK, a process associated with decreasing levels of MMP2. Thus, WNK2 promoter methylation and silencing in gliomas is associated with increased JNK activation and MMP2 expression and activity, thus explaining in part tumor cell invasion potential. PMID:25596741

  13. Autologous glioma cell vaccine admixed with interleukin-4 gene transfected fibroblasts in the treatment of patients with malignant gliomas

    PubMed Central

    Okada, Hideho; Lieberman, Frank S; Walter, Kevin A; Lunsford, L Dade; Kondziolka, Douglas S; Bejjani, Ghassan K; Hamilton, Ronald L; Torres-Trejo, Alejandro; Kalinski, Pawel; Cai, Quan; Mabold, Jennifer L; Edington, Howard D; Butterfield, Lisa H; Whiteside, Theresa L; Potter, Douglas M; Schold, S Clifford; Pollack, Ian F

    2007-01-01

    Background The prognosis for malignant gliomas remains dismal. We addressed the safety, feasibility and preliminary clinical activity of the vaccinations using autologous glioma cells and interleukin (IL)-4 gene transfected fibroblasts. Methods In University of Pittsburgh Cancer Institute (UPCI) protocol 95-033, adult participants with recurrent glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) received gross total resection (GTR) of the recurrent tumors, followed by two vaccinations with autologous fibroblasts retrovirally transfected with TFG-IL4-Neo-TK vector admixed with irradiated autologous glioma cells. In UPCI 99-111, adult participants with newly diagnosed GBM or AA, following GTR and radiation therapy, received two intradermal vaccinations with the TFG-IL4-Neo-TK-transfected fibroblasts admixed with type-1 dendritic cells (DC) loaded with autologous tumor lysate. The participants were evaluated for occurrence of adverse events, immune response, and clinical response by radiological imaging. Results and Discussion In UPCI 95-033, only 2 of 6 participants received the vaccinations. Four other participants were withdrawn from the trial because of tumor progression prior to production of the cellular vaccine. However, both participants who received two vaccinations demonstrated encouraging immunological and clinical responses. Biopsies from the local vaccine sites from one participant displayed IL-4 dose-dependent infiltration of CD4+ as well as CD8+ T cells. Interferon (IFN)-γ Enzyme-Linked Immuno-SPOT (ELISPOT) assay in another human leukocyte antigen (HLA)-A2+ participant demonstrated systemic T-cell responses against an HLA-A2-restricted glioma-associated antigen (GAA) epitope EphA2883–891. Moreover, both participants demonstrated clinical and radiological improvement with no evidence of allergic encephalitis, although both participants eventually succumbed with the tumor recurrence. In 99-111, 5 of 6 enrolled participants received scheduled

  14. KCa3.1 inhibition switches the phenotype of glioma-infiltrating microglia/macrophages

    PubMed Central

    Grimaldi, A; D'Alessandro, G; Golia, M T; Grössinger, E M; Di Angelantonio, S; Ragozzino, D; Santoro, A; Esposito, V; Wulff, H; Catalano, M; Limatola, C

    2016-01-01

    Among the strategies adopted by glioma to successfully invade the brain parenchyma is turning the infiltrating microglia/macrophages (M/MΦ) into allies, by shifting them toward an anti-inflammatory, pro-tumor phenotype. Both glioma and infiltrating M/MΦ cells express the Ca2+-activated K+ channel (KCa3.1), and the inhibition of KCa3.1 activity on glioma cells reduces tumor infiltration in the healthy brain parenchyma. We wondered whether KCa3.1 inhibition could prevent the acquisition of a pro-tumor phenotype by M/MΦ cells, thus contributing to reduce glioma development. With this aim, we studied microglia cultured in glioma-conditioned medium or treated with IL-4, as well as M/MΦ cells acutely isolated from glioma-bearing mice and from human glioma biopsies. Under these different conditions, M/MΦ were always polarized toward an anti-inflammatory state, and preventing KCa3.1 activation by 1-[(2-Chlorophenyl)diphenylmethyl]-1H-pyrazole (TRAM-34), we observed a switch toward a pro-inflammatory, antitumor phenotype. We identified FAK and PI3K/AKT as the molecular mechanisms involved in this phenotype switch, activated in sequence after KCa3.1. Anti-inflammatory M/MΦ have higher expression levels of KCa3.1 mRNA (kcnn4) that are reduced by KCa3.1 inhibition. In line with these findings, TRAM-34 treatment, in vivo, significantly reduced the size of tumors in glioma-bearing mice. Our data indicate that KCa3.1 channels are involved in the inhibitory effects exerted by the glioma microenvironment on infiltrating M/MΦ, suggesting a possible role as therapeutic targets in glioma. PMID:27054329

  15. Circulating anti-filamin C autoantibody as a potential serum biomarker for low-grade gliomas

    PubMed Central

    2014-01-01

    Background Glioma is the most common primary malignant central nervous system tumor in adult, and is usually not curable due to its invasive nature. Establishment of serum biomarkers for glioma would be beneficial both for early diagnosis and adequate therapeutic intervention. Filamins are an actin cross-linker and filamin C (FLNC), normally restricted in muscle tissues, offers many signaling molecules an essential communication fields. Recently, filamins have been considered important for tumorigenesis in cancers. Methods We searched for novel glioma-associated antigens by serological identification of antigens utilizing recombinant cDNA expression cloning (SEREX), and found FLNC as a candidate protein. Tissue expressions of FLNC (both in normal and tumor tissues) were examined by immunohistochemistry and quantitative RT-PCR analyses. Serum anti-FLNC autoantibody level was measured by ELISA in normal volunteers and in the patients with various grade gliomas. Results FLNC was expressed in glioma tissues and its level got higher as tumor grade advanced. Anti-FLNC autoantibody was also detected in the serum of glioma patients, but its levels were inversely correlated with the tissue expression. Serum anti-FLNC autoantibody level was significantly higher in low-grade glioma patients than in high-grade glioma patients or in normal volunteers, which was confirmed in an independent validation set of patients’ sera. The autoantibody levels in the patients with meningioma or cerebral infarction were at the same level of normal volunteers, and they were significantly lower than that of low-grade gliomas. Total IgG and anti-glutatione S-transferase (GST) antibody level were not altered among the patient groups, which suggest that the autoantibody response was specific for FLNC. Conclusions The present results suggest that serum anti-FLNC autoantibody can be a potential serum biomarker for early diagnosis of low-grade gliomas while it needs a large-scale clinical study

  16. 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.

  17. FIBULIN-3 IS UNIQUELY UPREGULATED IN MALIGNANT GLIOMAS AND PROMOTES TUMOR CELL MOTILITY AND INVASION

    PubMed Central

    Hu, Bin; Thirtamara-Rajamani, Keerthi K.; Sim, Hosung; Viapiano, Mariano S.

    2013-01-01

    Malignant gliomas are highly invasive tumors with an almost invariably rapid and lethal outcome. Surgery and chemoradiotherapy fail to remove resistant tumor cells that disperse within normal tissue, which are a major cause for disease progression and therapy failure. Infiltration of the neural parenchyma is a distinctive property of malignant gliomas compared to other solid tumors. Thus, glioma cells are thought to produce unique molecular changes that remodel the neural extracellular matrix and form a microenvironment permissive for their motility. Here we describe the unique expression and pro-invasive role of fibulin-3, a mesenchymal matrix protein specifically upregulated in gliomas. Fibulin-3 is downregulated in peripheral tumors and thought to inhibit tumor growth. However, we found fibulin-3 highly upregulated in gliomas and cultured glioma cells, although the protein was undetectable in normal brain or cultured astrocytes. Overexpression and knockdown experiments revealed that fibulin-3 did not seem to affect glioma cell morphology or proliferation, but enhanced substrate-specific cell adhesion and promoted cell motility and dispersion in organotypic cultures. Moreover, orthotopic implantation of fibulin-3-overexpressing glioma cells resulted in diffuse tumors with increased volume and rostrocaudal extension compared to controls. Tumors and cultured cells overexpressing fibulin-3 also showed elevated expression and activity of matrix metalloproteases, such as MMP-2/9 and ADAMTS-5. Taken together, our results suggest that fibulin-3 has a unique expression and pro-tumoral role in gliomas, and could be a potential target against tumor progression. Strategies against this glioma-specific matrix component could disrupt invasive mechanisms and restrict dissemination of these tumors. PMID:19887559

  18. 68Ga-PRGD2 PET/CT in the Evaluation of Glioma: A Prospective Study

    PubMed Central

    2015-01-01

    Integrin αvβ3 is overexpressed in both neovasculature and glioma cells. We aimed to evaluate 68gallium-BNOTA-PRGD2 (68Ga-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 68Ga-PRGD2 PET/CT and 18F-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 68Ga-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, 68Ga-PRGD2 PET/CT was able to evaluate the glioma demarcation more specifically than 18F-FDG PET/CT. The maximum standardized uptake values (SUVmax) of 68Ga-PRGD2, rather than those of 18F-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 68Ga-PRGD2 seemed to be more superior to 18F-FDG in differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Moreover, 68Ga-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. PMID:25093246

  19. 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.

  20. Sequential imaging and volumetric analysis of an intracerebral C6 glioma by means of a clinical MRI system.

    PubMed

    Raila, F A; Bowles, A P; Perkins, E; Terrell, A

    1999-05-01

    In this study, using high resolution coils; implanted growing rat brain tumors were imaged sequentially with 3-D volume measurements generated by means of a clinical magnetic resonance imaging system (CMRI) and commercially available wrist coil. Ten female Sprague-Dawley rats were used, eight were implanted with C6 rat glioma cells and two served as controls. The images that were used for the three-dimensional (3-D) measurements were obtained from T1 weighted post contrast sequences. A commercially available computer work station with 3-D image analysis software was used to generate the tumor volumes. In addition to the rat studies a mouse was included to see if the resolution would be adequate for imaging very small brains. Six rats had brain tumor growth after transplantation and two rats did not have any tumor growth, however, their images were similar to the controls animals. Tumor volumes varied widely among the implanted rats. The number of implanted tumor cells had no direct relationship to developing tumor volumes. This study demonstrates that high resolution images of a rat brain tumor can be obtained from a CMRI system using a commercially available wrist coil which is capable of imaging two rats at the same time or even a mouse brain. A commercially available computer work station was able to generate the tumor volumes. The ability to image brain tumor and generate volume measurements over time has potential for animal research.

  1. IKBKE is over-expressed in glioma and contributes to resistance of glioma cells to apoptosis via activating NF-κB.

    PubMed

    Guan, Hongyu; Zhang, Heng; Cai, Junchao; Wu, Jueheng; Yuan, Jie; Li, Jun; Huang, Zhengsong; Li, Mengfeng

    2011-02-01

    IκB kinase-ε (IKBKE), a member of the IκB kinase (IKK) family, has been identified as an oncogenic protein and found to be up-regulated in breast cancer, ovarian cancer and prostate cancer. Nonetheless, the expression status and functional significance of IKBKE in human glioma remain unexplored. For the first time, we have demonstrated that mRNA and protein levels of IKBKE were robustly up-regulated in glioma cell lines and human primary glioma tissues. Immunohistochemistry analysis revealed that 53.5% (38/71) paraffin-embedded archived glioma specimens exhibited high levels of IKBKE expression. Intriguingly, there was no significant difference in IKBKE expression among different grades of glioma. To understand the biological function of IKBKE in the development and progression of human glioma, glioma cells lines ectopically over-expressing IKBKE were established and tested for their responsiveness to apoptotic inducers. Our data showed that IKBKE over-expression inhibited cell apoptosis induced by UV irradiation or adriamycin and, in contrast, shRNAi-mediated suppression of IKBKE increased the sensitivity of glioma cells to the apoptotic inducers. Importantly, we found that up-regulated IKBKE could induce the expression of Bcl-2 through activating NF-κB signalling, and that, specifically, we identified IκB as a critical component for this signalling cascade. The current study suggests that up-regulation of IKBKE may represent an important molecular hallmark that is biologically and clinically relevant to the development and progression, as well as the chemo- and radio-resistance, of the disease.

  2. Genetically Engineered Mouse Model of Diffuse Intrinsic Pontine Glioma as a Preclinical Tool

    DTIC Science & Technology

    2014-11-01

    sagittal orientation. Sections were rehydrated in PBS-T (0.1% Triton-X100) and blocked in PBS-T with 10% normal goat serum . Pri- mary antibodies were...acquired from previously published data [4,9,11,48]. Human BSG and CG samples with expression data available from Necker- Sick Children [5] were...100 units/mL penicillin and 100 μg/mL streptomycin at 37°C and 5% CO2, and pas- saged a maximum of 3 times for experiments. Cells were plated in clear 6

  3. Probing the Bi-directional Interaction Between Microglia and Gliomas in a Tumor Microenvironment on a Microdevice.

    PubMed

    Gu, Rui; Zhang, Xu; Zhang, Ge; Tao, Tingting; Yu, Haibo; Liu, Lianqing; Dou, Ying; Li, Aiping; Qin, Jianhua

    2017-02-24

    It has been proven that microglia are involved in both early and late stages of glioma progression and contribute substantially to the tumor mass of gliomas. Because no appropriate in vitro or in vivo investigative approach is available, the dynamic interaction between microglia and gliomas during tumor formation remains unclear. In this study, three types of microfluidic assay were developed to examine the outcomes of the dynamic interaction between microglia and gliomas. Co-migration assay and two-dimensional cell co-culture assay have been used to show that microglial BV-2 cells migrate toward C6 glioma cells and inhibit tumor growth during the early stage of tumorigenesis. However, in three-dimensional cell spheres (three-dimensional cell co-culture assay) that contain a large amount of glioma cells, mimicking the late stage of glioma growth, the phagocytosis of microglia was suppressed, which suggests that glioma cells could reeducate classically activated microglia into a tumor-promoting state at some point during tumor progression. Notably, we found that microglia could contribute to tumor invasion and acquisition of the epithelial-mesenchymal transition phenotype in the glioma microenvironment during the early stage and the late stage of tumor progression. In conclusion, we have developed a potential quantitative method for in vitro study of glioma immunity and provided evidence for the duality of glioma-associated microglia.

  4. Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility

    PubMed Central

    Baskin, Rebekah; Woods, Nicholas T.; Mendoza-Fandiño, Gustavo; Forsyth, Peter; Egan, Kathleen M.; Monteiro, Alvaro N.A.

    2015-01-01

    Glioma is the most common malignant primary brain tumor and is associated with poor prognosis. Genetic factors contributing to glioma risk have recently been investigated through genome-wide association studies (GWAS), implicating seven independent glioma risk loci in six chromosomal regions. Here, we performed an in-depth functional analysis of the risk locus proximal to the PHLDB1 gene on 11q23.3. We retrieved all SNPs in linkage disequilibrium (r2 ≥ 0.2) with the glioma-associated SNP (rs498872) and performed a comprehensive bioinformatics and experimental functional analysis for the region. After testing candidate SNPs for allele-specific activity in a luciferase-based enhancer scanning assay, we established a subset of 10 functional SNPs in the promoters of PHLDB1 and DDX6, and in a putative enhancer element. Chromatin conformation capture (3C) identified a physical interaction between the enhancer element containing a functional SNP (rs73001406) and the promoter of the DDX6 gene. Knockdown experiments in cell culture and 3D assays to evaluate the role of PHLDB1 and DDX6 suggest that both genes may contribute to the phenotype. These studies reveal the functional landscape of the 11q23.3 glioma susceptibility locus and identify a network of functional SNPs in regulatory elements and two target genes as a possible mechanism driving glioma risk association. PMID:26610392

  5. Functional analysis of the 11q23.3 glioma susceptibility locus implicates PHLDB1 and DDX6 in glioma susceptibility.

    PubMed

    Baskin, Rebekah; Woods, Nicholas T; Mendoza-Fandiño, Gustavo; Forsyth, Peter; Egan, Kathleen M; Monteiro, Alvaro N A

    2015-11-27

    Glioma is the most common malignant primary brain tumor and is associated with poor prognosis. Genetic factors contributing to glioma risk have recently been investigated through genome-wide association studies (GWAS), implicating seven independent glioma risk loci in six chromosomal regions. Here, we performed an in-depth functional analysis of the risk locus proximal to the PHLDB1 gene on 11q23.3. We retrieved all SNPs in linkage disequilibrium (r(2) ≥ 0.2) with the glioma-associated SNP (rs498872) and performed a comprehensive bioinformatics and experimental functional analysis for the region. After testing candidate SNPs for allele-specific activity in a luciferase-based enhancer scanning assay, we established a subset of 10 functional SNPs in the promoters of PHLDB1 and DDX6, and in a putative enhancer element. Chromatin conformation capture (3C) identified a physical interaction between the enhancer element containing a functional SNP (rs73001406) and the promoter of the DDX6 gene. Knockdown experiments in cell culture and 3D assays to evaluate the role of PHLDB1 and DDX6 suggest that both genes may contribute to the phenotype. These studies reveal the functional landscape of the 11q23.3 glioma susceptibility locus and identify a network of functional SNPs in regulatory elements and two target genes as a possible mechanism driving glioma risk association.

  6. AKT Axis, miR-21, and RECK Play Pivotal Roles in Dihydroartemisinin Killing Malignant Glioma Cells

    PubMed Central

    Shao, Ying-Ying; Zhang, Tao-Lan; Wu, Lan-Xiang; Zou, He-Cun; Li, Shuang; Huang, Jin; Zhou, Hong-Hao

    2017-01-01

    Dihydroartemisinin (DHA), a semi-synthetic derivative of artemisinin, is known to play important roles in inhibiting proliferation rate, inducing apoptosis, as well as hindering the metastasis and invasion of glioma cells, but the underlying mechanisms are still unclear so far. In this study, methyl thiazolyl tetrazolium (MTT), colony-forming, wound healing, invasion, and apoptosis assays were performed to investigate the effect of DHA on malignant glioma cells. Results showed that DHA induced apoptosis of malignant glioma cells through Protein Kinase B (AKT) axis, induced death of malignant glioma cells by downregulating miR-21, and inhibited the invasion of malignant glioma cells corresponding with up-regulation of the reversion-inducing-cysteine-rich protein with kazal motifs (RECK). These results revealed that AKT axis, miR-21, and RECK play pivotal roles in DHA killing malignant glioma cells, suggesting that DHA is a potential agent for treating glioma. PMID:28208619

  7. Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models

    PubMed Central

    Olaciregui, Nagore G.; Barton, Kelly L.; Ehteda, Anahid; Chitranjan, Arjanna; Chang, Cecilia; Gifford, Andrew J.; Tsoli, Maria; Ziegler, David S.; Carcaboso, Angel M.; Becher, Oren J.

    2017-01-01

    Background Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG. Methods A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. Results In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. Conclusion Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation. PMID

  8. PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells.

    PubMed

    Rahme, Gilbert J; Zhang, Zhonghua; Young, Alison L; Cheng, Chao; Bivona, Eric J; Fiering, Steven N; Hitoshi, Yasuyuki; Israel, Mark A

    2016-05-15

    Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1 Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling. Cancer Res; 76(10); 2964-76. ©2016 AACR.

  9. Control of glioma cell migration and invasiveness by GDF-15.

    PubMed

    Codó, Paula; Weller, Michael; Kaulich, Kerstin; Schraivogel, Daniel; Silginer, Manuela; Reifenberger, Guido; Meister, Gunter; Roth, Patrick

    2016-02-16

    Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-β family of proteins. GDF-15 levels are increased in the blood and cerebrospinal fluid of glioblastoma patients. Using a TCGA database interrogation, we demonstrate that high GDF-15 expression levels are associated with poor survival of glioblastoma patients. To elucidate the role of GDF-15 in glioblastoma in detail, we confirmed that glioma cells express GDF-15 mRNA and protein in vitro. To allow for a detailed functional characterization, GDF-15 expression was silenced using RNA interference in LNT-229 and LN-308 glioma cells. Depletion of GDF-15 had no effect on cell viability. In contrast, GDF-15-deficient cells displayed reduced migration and invasion, in the absence of changes in Smad2 or Smad1/5/8 phosphorylation. Conversely, exogenous GDF-15 stimulated migration and invasiveness. Large-scale expression profiling revealed that GDF-15 gene silencing resulted in minor changes in the miRNA profile whereas several genes, including members of the plasminogen activator/inhibitor complex, were deregulated at the mRNA level. One of the newly identified genes induced by GDF-15 gene silencing was the serpin peptidase inhibitor, clade E nexin group 1 (serpine1) which is induced by TGF-β and known to inhibit migration and invasiveness. However, serpine1 down-regulation alone did not mediate GDF-15-induced promotion of migration and invasiveness. Our findings highlight the complex contributions of GDF-15 to the invasive phenotype of glioma cells and suggest anti-GDF-15 approaches as a promising therapeutic strategy.

  10. Control of glioma cell migration and invasiveness by GDF-15

    PubMed Central

    Codó, Paula; Weller, Michael; Kaulich, Kerstin; Schraivogel, Daniel; Silginer, Manuela; Reifenberger, Guido; Meister, Gunter; Roth, Patrick

    2016-01-01

    Growth and differentiation factor (GDF)-15 is a member of the transforming growth factor (TGF)-β family of proteins. GDF-15 levels are increased in the blood and cerebrospinal fluid of glioblastoma patients. Using a TCGA database interrogation, we demonstrate that high GDF-15 expression levels are associated with poor survival of glioblastoma patients. To elucidate the role of GDF-15 in glioblastoma in detail, we confirmed that glioma cells express GDF-15 mRNA and protein in vitro. To allow for a detailed functional characterization, GDF-15 expression was silenced using RNA interference in LNT-229 and LN-308 glioma cells. Depletion of GDF-15 had no effect on cell viability. In contrast, GDF-15-deficient cells displayed reduced migration and invasion, in the absence of changes in Smad2 or Smad1/5/8 phosphorylation. Conversely, exogenous GDF-15 stimulated migration and invasiveness. Large-scale expression profiling revealed that GDF-15 gene silencing resulted in minor changes in the miRNA profile whereas several genes, including members of the plasminogen activator/inhibitor complex, were deregulated at the mRNA level. One of the newly identified genes induced by GDF-15 gene silencing was the serpin peptidase inhibitor, clade E nexin group 1 (serpine1) which is induced by TGF-β and known to inhibit migration and invasiveness. However, serpine1 down-regulation alone did not mediate GDF-15-induced promotion of migration and invasiveness. Our findings highlight the complex contributions of GDF-15 to the invasive phenotype of glioma cells and suggest anti-GDF-15 approaches as a promising therapeutic strategy. PMID:26741507

  11. 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

  12. 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.

  13. Molecular classification of low-grade diffuse gliomas.

    PubMed

    Kim, Young-Ho; Nobusawa, Sumihito; Mittelbronn, Michel; Paulus, Werner; Brokinkel, Benjamin; Keyvani, Kathy; Sure, Ulrich; Wrede, Karsten; Nakazato, Yoichi; Tanaka, Yuko; Vital, Anne; Mariani, Luigi; Stawski, Robert; Watanabe, Takuya; De Girolami, Umberto; Kleihues, Paul; Ohgaki, Hiroko

    2010-12-01

    The current World Health Organization classification recognizes three histological types of grade II low-grade diffuse glioma (diffuse astrocytoma, oligoastrocytoma, and oligodendroglioma). However, the diagnostic criteria, in particular for oligoastrocytoma, are highly subjective. The aim of our study was to establish genetic profiles for diffuse gliomas and to estimate their predictive impact. In this study, we screened 360 World Health Organization grade II gliomas for mutations in the IDH1, IDH2, and TP53 genes and for 1p/19q loss and correlated these with clinical outcome. Most tumors (86%) were characterized genetically by TP53 mutation plus IDH1/2 mutation (32%), 1p/19q loss plus IDH1/2 mutation (37%), or IDH1/2 mutation only (17%). TP53 mutations only or 1p/19q loss only was rare (2 and 3%, respectively). The median survival of patients with TP53 mutation ± IDH1/2 mutation was significantly shorter than that of patients with 1p/19q loss ± IDH1/2 mutation (51.8 months vs. 58.7 months, respectively; P = 0.0037). Multivariate analysis with adjustment for age and treatment confirmed these results (P = 0.0087) and also revealed that TP53 mutation is a significant prognostic marker for shorter survival (P = 0.0005) and 1p/19q loss for longer survival (P = 0.0002), while IDH1/2 mutations are not prognostic (P = 0.8737). The molecular classification on the basis of IDH1/2 mutation, TP53 mutation, and 1p/19q loss has power similar to histological classification and avoids the ambiguity inherent to the diagnosis of oligoastrocytoma.

  14. Treatment of paediatric pontine glioma with oral trophosphamide and etoposide

    PubMed Central

    Wolff, J E A; Westphal, S; Mölenkamp, G; Gnekow, A; Warmuth-Metz, M; Rating, D; Kuehl, J

    2002-01-01

    To evaluate the overall survival of paediatric patients with pontine gliomas treated with oral trophosphamide and etoposide. Patients between 3 and 17 years of age with either typical diffuse pontine glioma on MRI or histologically proven anaplastic astrocytoma/glioblastoma multiforme located in the pons, were eligible. Treatment consisted of oral trophosphamide 100 mg m−2 day−1 combined with oral etoposide at 25 mg m−2 day−1 starting simultaneously with conventional radiation. Twenty patients were enrolled (median age 6 years, male : female=9 : 11). Surgical procedures included: no surgery: five, open biopsy: three, stereotactic biopsy: six, partial resection: three, and sub-total resection: three. Histological diagnoses included pilocytic astrocytoma: one, astrocytoma with no other specification: three, anaplastic astrocytoma: three, glioblastoma multiforme: eight, no histology: five. The most frequent side effects were haematologic and gastrointestinal. There was no toxic death. The response to combined treatment in 12 evaluable patients was: complete response: 0, partial response: three, stable disease: four, and progressive disease: five. All tumours progressed locally and all patients died. The overall median survival was 8 months. The overall survival rates at 1 and 4 years were: 0.4 and 0.05 respectively. This was not different from a control group of patients documented in the same population. Oral trophosphamide in combination with etoposide did not improve survival of pontine glioma patients. The treatment was well tolerated and should be evaluated for more chemoresponsive paediatric malignancies. British Journal of Cancer (2002) 87, 945–949. doi:10.1038/sj.bjc.6600552 www.bjcancer.com © 2002 Cancer Research UK PMID:12434281

  15. Radiosurgical boost for primary high-grade gliomas.

    PubMed

    Prisco, Flavio E; Weltman, Eduardo; de Hanriot, Rodrigo M; Brandt, Reynaldo A

    2002-04-01

    The purpose of this study was to retrospectively evaluate the survival of patients with high-grade gliomas treated with external beam radiotherapy with or without radiosurgical boost. From July 1993 to April 1998, 32 patients were selected, 15 of which received radiosurgery. Inclusion criteria were age > 18 years, histological confirmation of high-grade glioma, primary tumor treatment with curative intent, unifocal tumor and supratentorial location. All patients were found to be in classes III-VI, according to the recursive partitioning analysis proposed by the Radiation Therapy Oncology Group. The median interval between radiotherapy and radiosurgery was 5 weeks (range 1-13). Treatment volumes ranged from 2.9 to 70.3 cc (median 15.0 cc). Prescribed radiosurgery doses varied from 8.0 to 12.5 Gy (median 10.0 Gy). Radiosurgery and control groups were well balanced with respect to prognostic factor distributions. Median actuarial survival time in radiosurgery and control groups was 21.4 months and 11.6 months, respectively (p = 0.0254). Among patients with KPS > 80, median survival time was 11.0 months and 53.9 months in the control and radiosurgery groups, respectively (p = 0.0103). Radiosurgery was the single factor correlated with survival on Cox model analysis (p = 0.0362) and was associated with a 2.76 relative reduction in the risk of cancer death (95% confidence interval (CI) 1.07-7.13). Our results suggest that radiosurgery may confer a survival advantage for patients in RPA classes III-VI, especially for those with Karnofsky performance status >80. The definitive role of radiosurgical boost for patients with high-grade gliomas awaits the results of randomized trials.

  16. Genetically engineered rat gliomas: PDGF-driven tumor initiation and progression in tv-a transgenic rats recreate key features of human brain cancer

    PubMed Central

    Stokum, Jesse A.; Schneider, Craig S.; Ozawa, Tatsuya; Xu, Su; Galisteo, Rebeca; Castellani, Rudolph J.; Kim, Anthony J.; Simard, J. Marc; Winkles, Jeffrey A.; Holland, Eric C.; Woodworth, Graeme F.

    2017-01-01

    Previously rodent preclinical research in gliomas frequently involved implantation of cell lines such as C6 and 9L into the rat brain. More recently, mouse models have taken over, the genetic manipulability of the mouse allowing the creation of genetically accurate models outweighed the disadvantage of its smaller brain size that limited time allowed for tumor progression. Here we illustrate a method that allows glioma formation in the rat using the replication competent avian-like sarcoma (RCAS) virus / tumor virus receptor-A (tv-a) transgenic system of post-natal cell type-specific gene transfer. The RCAS/tv-a model has emerged as a particularly versatile and accurate modeling technology by enabling spatial, temporal, and cell type-specific control of individual gene transformations and providing de novo formed glial tumors with distinct molecular subtypes mirroring human GBM. Nestin promoter-driven tv-a (Ntv-a) transgenic Sprague-Dawley rat founder lines were created and RCAS PDGFA and p53 shRNA constructs were used to initiate intracranial brain tumor formation. Tumor formation and progression were confirmed and visualized by magnetic resonance imaging (MRI) and spectroscopy. The tumors were analyzed using histopathological and immunofluorescent techniques. All experimental animals developed large, heterogeneous brain tumors that closely resembled human GBM. Median survival was 92 days from tumor initiation and 62 days from the first point of tumor visualization on MRI. Each tumor-bearing animal showed time dependent evidence of malignant progression to high-grade glioma by MRI and neurological examination. Post-mortem tumor analysis demonstrated the presence of several key characteristics of human GBM, including high levels of tumor cell proliferation, pseudopalisading necrosis, microvascular proliferation, invasion of tumor cells into surrounding tissues, peri-tumoral reactive astrogliosis, lymphocyte infiltration, presence of numerous tumor

  17. Hypofractionated stereotactic radiotherapy combined with topotecan in recurrent malignant glioma

    SciTech Connect

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

    2006-11-15

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

  18. 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

  19. Language outcomes after resection of dominant inferior parietal lobule gliomas.

    PubMed

    Southwell, Derek G; Riva, Marco; Jordan, Kesshi; Caverzasi, Eduardo; Li, Jing; Perry, David W; Henry, Roland G; Berger, Mitchel S

    2017-01-06

    OBJECTIVE The dominant inferior parietal lobule (IPL) contains cortical and subcortical regions essential for language. Although resection of IPL tumors could result in language deficits, little is known about the likelihood of postoperative language morbidity or the risk factors predisposing to this outcome. METHODS The authors retrospectively examined a series of patients who underwent resections of gliomas from the dominant IPL. Postoperative language outcomes were characterized across the patient population. To identify factors associated with postoperative language morbidity, the authors then compared features between those patients who experienced postoperative deficits and those who experienced no postoperative language dysfunction. RESULTS Twenty-four patients were identified for analysis. Long-term language deficits occurred in 29.2% of patients (7 of 24): 3 of these patients had experienced preoperative language deficits, whereas new long-term language deficits occurred in 4 patients (16.7%; 4 of 24). Of those patients who exhibited preoperative language deficits, 62.5% (5 of 8) experienced long-term resolution of their language deficits with surgical treatment. All patients underwent intraoperative brain mapping by direct electrical stimulation. Awake, intraoperative cortical language mapping was performed on 17 patients (70.8%). Positive cortical language sites were identified in 23.5% of these patients (4 of 17). Awake, intraoperative subcortical language mapping was performed in 8 patients (33.3%). Positive subcortical language sites were identified in 62.5% of these patients (5 of 8). Patients with positive cortical language sites exhibited a higher rate of long-term language deficits (3 of 4, 75%), compared with those who did not (1 of 13, 7.7%; p = 0.02). Although patients with positive subcortical language sites exhibited a higher rate of long-term language deficits than those who exhibited only negative sites (40.0% vs 0.0%, respectively), this

  20. NDRG1 overexpressing gliomas are characterized by reduced tumor vascularization and resistance to antiangiogenic treatment.

    PubMed

    Broggini, Thomas; Wüstner, Marie; Harms, Christoph; Stange, Lena; Blaes, Jonas; Thomé, Carina; Harms, Ulrike; Mueller, Susanne; Weiler, Markus; Wick, Wolfgang; Vajkoczy, Peter; Czabanka, Marcus

    2016-10-01

    Hypoxia-regulated molecules play an important role in vascular resistance to antiangiogenic treatment. N-myc downstream-regulated-gene 1 (NDRG1) is significantly upregulated during hypoxia in glioma. It was the aim of the present study to analyze the role of NDRG1 on glioma angiogenesis and on antiangiogenic treatment. Orthotopically implanted NDRG1 glioma showed reduced tumor growth and vessel density compared to controls. RT-PCR gene array analysis revealed a 30-fold TNFSF15 increase in NDRG1 tumors. Consequently, the supernatant from NDRG1 transfected U87MG glioma cells resulted in reduced HUVEC proliferation, migration and angiogenic response in tube formation assays in vitro. This effect was provoked by increased TNFSF15 promoter activity in NDRG1 cells. Mutations in NF-κB and AP-1 promoter response elements suppressed TNFSF15 promoter activity. Moreover, U87MG glioma NDRG1 knockdown supernatant contained multiple proangiogenic proteins and increased HUVEC spheroid sprouting. Sunitinib treatment of orhotopically implanted mice reduced tumor volume and vessel density in controls; in NDRG1 overexpressing cells no reduction of tumor volume or vessel density was observed. NDRG1 overexpression leads to reduced tumor growth and angiogenesis in experimental glioma via upregulation of TNFSF15. In NDRG1 overexpressing glioma antiangiogenic treatment does not yield a therapeutic response.

  1. Oncolytic virotherapy for malignant glioma: translating laboratory insights into clinical practice.

    PubMed

    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.

  2. Deubiquitinase USP9X deubiquitinates β-catenin and promotes high grade glioma cell growth

    PubMed Central

    Wang, Zhihao; Yang, Chunxu; Ouyang, Wen; Zhou, Fuxiang; Zhou, Yunfeng; Xie, Conghua

    2016-01-01

    β-catenin is a crucial signal transduction molecule in the Wnt/β-catenin signal pathway, and increased β-catenin expression has consistently been found in high grade gliomas. However, the mechanisms responsible for β-catenin overexpression have remained elusive. Here we show that the deubiquitinase USP9X stabilizes β-catenin and thereby promotes high grade glioma cell growth. USP9X binds β-catenin and removes the Lys 48-linked polyubiquitin chains that normally mark β-catenin for proteasomal degradation. Increased USP9X expression correlates with increased β-catenin protein in high grade glioma tissues. Moreover, patients with high grade glioma overexpressing USP9X have a poor prognosis. Knockdown of USP9X suppresses cell proliferation, inhibits G1/S phase conversion, and induces apoptosis in U251 and A172 cells. Interestingly, c-Myc and cyclinD1, which are important downstream target genes in the Wnt/β-catenin signal pathway, also show decreased expression in cells with siRNA-mediated down-regulation of USP9X. Down-regulation of USP9X also consistently inhibits the tumorigenicity of primary glioma cells in vivo. In summary, these results indicate that USP9X stabilizes β-catenin and activates Wnt/β-catenin signal pathway to promote glioma cell proliferation and survival. USP9X could also potentially be a novel therapeutic target for high grade gliomas. PMID:27783990

  3. 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

  4. Glioma-Derived ADAM10 Induces Regulatory B Cells to Suppress CD8+ T Cells

    PubMed Central

    Li, Wen-sheng; Luo, Lun; Huang, Zhen-chao; Guo, Ying

    2014-01-01

    CD8+ T cells play an important role in the anti-tumor activities of the body. The dysfunction of CD8+ T cells in glioma is unclear. This study aims to elucidate the glioma cell-derived ADAM10 (A Disintegrin and metalloproteinase domain-containing protein 10) in the suppression of CD8+ effector T cells by the induction of regulatory B cells. In this study, glioma cells were isolated from surgically removed glioma tissue and stimulated by Phorbol myristate acetage (PMA) in the culture. The levels of ADAM10 in the culture were determined by enzyme-linked immunosorbent assay. Immune cells were assessed by flow cytometry. The results showed that the isolated glioma cells express ADAM10, which was markedly up regulated after stimulated with PMA. The glioma-derived ADAM10 induced activated B cells to differentiate into regulatory B cells, the later suppressed CD8+ T cell proliferation as well as the induced regulatory T cells, which also showed the immune suppressor effect on CD8+ effector T cell proliferation. In conclusion, glioma cells produce ADAM10 to induce Bregs; the latter suppresses CD8+ T cells and induces Tregs. PMID:25127032

  5. 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.

  6. 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.

  7. Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell.

    PubMed

    Ding, Hong; Shen, Jinglian; Yang, Yang; Che, Yuqin

    2015-01-01

    Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p < 0.05). The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated.

  8. Saw Palmetto Extract Inhibits Metastasis and Antiangiogenesis through STAT3 Signal Pathway in Glioma Cell

    PubMed Central

    Ding, Hong; Shen, Jinglian; Yang, Yang; Che, Yuqin

    2015-01-01

    Signal transducer and activator of transcription factor 3 (STAT3) plays an important role in the proliferation and angiogenesis in human glioma. Previous research indicated that saw palmetto extract markedly inhibited the proliferation of human glioma cells through STAT3 signal pathway. But its effect on tumor metastasis and antiangiogenesis is not clear. This study is to further clear the impact of saw palmetto extract on glioma cell metastasis, antiangiogenesis, and its mechanism. TUNEL assay indicated that the apoptotic cells in the saw palmetto treated group are higher than that in the control group (p < 0.05). The apoptosis related protein is detected and the results revealed that saw palmetto extract inhibits the proliferation of human glioma. Meanwhile pSTAT3 is lower in the experimental group and CD34 is also inhibited in the saw palmetto treated group. This means that saw palmetto extract could inhibit the angiogenesis in glioma. We found that saw palmetto extract was an important phytotherapeutic drug against the human glioma through STAT3 signal pathway. Saw palmetto extract may be useful as an adjunctive therapeutic agent for treatment of individuals with glioma and other types of cancer in which STAT3 signaling is activated. PMID:26788112

  9. Lower expression of Nrdp1 in human glioma contributes tumor progression by reducing apoptosis.

    PubMed

    Shi, Hengliang; Du, Jin; Wang, Lei; Zheng, Bao; Gong, Hui; Wu, Yuxuan; Tang, Yuan; Gao, Yong; Yu, Rutong

    2014-10-01

    Ubiquitin ligase Nrdp1 (neuregulin receptor degradation protein 1) plays important roles in multiple physiological process because it can ubiquitinate various substrates such as ErbB3, BRUCE, MyD88, C/EBPβ, and Parkin, and so forth. In addition to the physiological function, it was also found to be involved in tumor progression. It has been shown that loss of Nrdp1 enhances breast cancer cell growth. Up to now, the role of Nrdp1 in glioma has not been elucidated. Here, we reported that Nrdp1 as well as cleaved caspase 3 was lower expressed in human glioma tissues comparing with the nontumorous. And then we found that the expression of Nrdp1 and cleaved caspase 3 was increased in the treatment of Temozolomide (TMZ), a drug for glioma chemotherapy. Further investigation indicated that transient transfection of Nrdp1 significantly promoted cell apoptosis by aggravating the degradation of BRUCE and activation of caspase 3. In addition, overexpression of Nrdp1 augmented TMZ induced apoptosis by evaluating the degradation of BRUCE and the activation of caspase 3, while silencing of Nrdp1 reduced the sensitivity to the TMZ by inhibiting the degradation of BRUCE and the activation of caspase 3 in human glioma cells. These observations show that Nrdp1 is a pro-apoptotic protein in human glioma and lower expression of Nrdp1 in human glioma may promote tumor progression by reducing apoptosis, suggesting that Nrdp1 may be an important regulator in the development of human glioma.

  10. MicroRNA-217 inhibits cell proliferation and invasion by targeting Runx2 in human glioma

    PubMed Central

    Zhu, Yonggang; Zhao, Hongguang; Feng, Li; Xu, Songbai

    2016-01-01

    MircroRNA-217 (miR-217) has been showed to involve in the initiation and development of human cancers, and is recognize as a tumor suppressor miRNA in several tumors. However, the clinical significance and its underlying role in human glioma remain unclear. Herein, we found that the expression of miR-217 was significantly down-regulated in glioma tissues as compared with adjacent normal brain tissues. Clinical association analysis disclosed that low-expression of miR-217 was evidently negative associated with advanced tumor stage (grade III + IV) in glioma. Further function assays showed that miR-217 inhibited proliferation, colony formation, invasion and migration of glioma cells. Notably, runt-related transcription factors 2 (Runx2) was identified as a functional target of miR-217 in glioma. Furthermore, an inverse correlation between miR-217 and Runx2 expression was observed in glioma tissues. Downregulation of Runx2 has similar with inhibition effect of overexpression of miR-217, and upregulation of Runx2 reversed the effects of overexpressing of miR-217. Taken together, these results suggest a critical role of miR-217 in suppressing proliferation, migration, and invasion of glioma by targeting Runx2. PMID:27186274

  11. Anticancer effect of eupatilin on glioma cells through inhibition of the Notch-1 signaling pathway

    PubMed Central

    WANG, YAWEI; HOU, HONGWEI; LI, MING; YANG, YANG; SUN, LAN

    2016-01-01

    Eupatilin, one of the major flavonoids in Artemisia asiatica Nakai (Asteraceae), has been reported to possess antitumor properties. However, thus far there have been no reports regarding the effects of eupatilin on glioma. Therefore, in the current study the effects of eupatilin on glioma and the underlying molecular mechanism were explored. The effect of eupatilin on cell viability was detected by the MTT assay. Cell invasion and migration were performed with Transwell assays and cell apoptosis was determined by flow cytometric analysis. Notch-1 knockdown cells were established by transfection with Notch-1 small interfering RNA (siRNA). The expression levels of Notch-1 were detected by quantitative reverse transcription-polymerase chain reaction and western blotting. The results of the present study indicated that eupatilin exhibits an anticancer effect on glioma cells. Eupatilin inhibited proliferation, reduced cell invasion and migration, and promoted the apoptosis of glioma cells. Additionally, it suppressed Notch-1 expression. Knockdown of Notch-1 by siRNA contributed to the inhibitory effect of eupatilin on proliferation and invasion of glioma cells. In conclusion, eupatilin had an inhibitory effect on proliferation, invasion and migration, and promoted apoptosis of glioma cells through suppression of the Notch-1 signaling pathway. Therefore, eupatilin may have potential as an effective agent for the treatment of glioma. PMID:26676446

  12. Overexpression of FZD7 promotes glioma cell proliferation by upregulating TAZ

    PubMed Central

    Tian, Tian

    2016-01-01

    Gliomas are the most prevalent type of primary brain tumors in adults, accounting for more than 40% of neoplasm in the central nervous system. Frizzled-7 (FZD7) is a seven-pass trans-membrane Wnt receptor that plays a critical role in the development of various tumors. In this study, we detected high-level FZD7 expression in glioma and its overexpression was associated with advanced tumor stage. In vitro functional assays showed that forced overexpression of FZD7 promoted proliferation of gliomas cells, whereas knockdown of endogenous FZD7 significantly suppressed proliferation ability of these cells. In a xenograft assay, FZD7 was also found to promote the growth of glioma cells. We further found that FZD7 could activate transcriptional coactivator with PDZ-binding motif (TAZ), and TAZ was required for FZD7 to promote cell proliferation in glioma. Furthermore, the univariate analysis of survival shows that glioma patients with high FZD7 expression have a shorter survival. In conclusion, our findings demonstrate that FZD7 may promote glioma cell proliferation via upregulation of TAZ. PMID:27852064

  13. c-Fos over-expression promotes radioresistance and predicts poor prognosis in malignant glioma

    PubMed Central

    Feng, Guokai; Chen, Furong; Tu, Ziwei; Liu, Guiyun; Zhao, Yu; Peng, Ming-Jing; He, Zheng-Wen; Chen, Xiao-Yan; Lindsay, Holly; Xia, Yun-Fei; Li, Xiao-Nan

    2016-01-01

    c-Fos is a major component of activator protein (AP)-1 complex. It has been implicated in cell differentiation, proliferation, angiogenesis, invasion, and metastasis. To investigate the role of c-Fos in glioma radiosensitivity and to understand the underlying molecular mechanisms, we downregulated c-Fos gene expression by lentivirus-mediated shRNA in glioma cell lines and subsequently analyzed the radiosensitivity, DNA damage repair capacity, and cell cycle distribution. Finally, we explored its prognostic value in 41 malignant glioma patients by immunohistochemistry. Our results showed that silencing c-Fos sensitized glioma cells to radiation by increasing radiation-induced DNA double strand breaks (DSBs), disturbing the DNA damage repair process, promoting G2/M cell cycle arrest, and enhancing apoptosis. c-Fos protein overexpression correlated with poor prognosis in malignant glioma patients treated with standard therapy. Our findings provide new insights into the mechanism of radioresistance in malignant glioma and identify c-Fos as a potentially novel therapeutic target for malignant glioma patients. PMID:27602752

  14. 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

  15. Genetic variants of SOX9 contribute to susceptibility of gliomas among Chinese population

    PubMed Central

    Wang, Zhen; Xu, Xiaoshan; Qi, Jing; Ren, Dongni; Zhang, Pengxing; Zhang, Yongsheng; Tu, Yanyang

    2016-01-01

    Gliomas make up about 80% of all malignant brain tumors, and cause serious public health problem. Genetic factors and environmental factors jointly caused the development of gliomas, and understanding of the genetic basis is a key component of preventive oncology. However, most genetic factors underlying carcinogenesis of gliomas remain largely unclear. In current study, we systematically evaluated whether genetic variants of SOX9 gene, a transcription factor that plays a central role in the development and differentiation of tumors, contribute to susceptibility of gliomas among Chinese population using a two-stage, case–control study. Results showed that SOX9 rs1042667 was significant associated with increased gliomas risk after adjusted by age, gender, family history of cancer, smoking status and alcohol status (Allele C vs A: OR=1.25; 95% CI=1.11-1.40; P=1.2×10−4). Compared with the carriers of genotype AA, both those of genotype AC (OR=1.37; 95% CI=1.13-1.66) and CC (OR=1.53; 95% CI=1.22-1.91) had significantly increased gliomas risk. This should be the first genetic association study which aims to evaluated the association between genetic variants of SOX9 and susceptibility of gliomas. Additional functional and association studies with different ethnic groups included are needed to further confirm our results. PMID:27589569

  16. Tetrandrine Exerts a Radiosensitization Effect on Human Glioma through Inhibiting Proliferation by Attenuating ERK Phosphorylation

    PubMed Central

    Ma, Ji-wei; Zhang, Yong; Ye, Ji-cheng; Li, Ru; Wen, Yu-Lin; Huang, Jian-xian; Zhong, Xue-yun

    2017-01-01

    Tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has been reported to have a radiosensitization effect on tumors. However, its effects on human glioma and the specific molecular mechanisms of these effects remain unknown. In this study, we demonstrated that Tet has a radiosensitization effect on human glioma cells. It has been hypothesized that Tet has a radiosensitization effect on glioma cells by affecting the glioma cell cycle and DNA repair mechanism and that ERK mediates these activities. Therefore, we conducted detailed analyses of the effects of Tet on the cell cycle by performing flow cytometric analysis and on DNA repair by detecting the expression of phosphorylated H2AX by immunofluorescence. We used western blot analysis to investigate the role of ERK in the effect of Tet on the cell cycle and DNA repair. The results revealed that Tet exerts its radiosensitization effect on glioma cells by inhibiting proliferation and decreasing the expression of phosphorylated ERK and its downstream proteins. In summary, our data indicate that ERK is involved in Tet-induced radiosensitization of glioma cells via inhibition of glioma cell proliferation or of the cell cycle at G0/G1 phase. PMID:27829269

  17. Magnetic resonance imaging biomarkers for clinical routine assessment of microvascular architecture in glioma.

    PubMed

    Stadlbauer, Andreas; Zimmermann, Max; Heinz, Gertraud; Oberndorfer, Stefan; Doerfler, Arnd; Buchfelder, Michael; Rössler, Karl

    2017-02-01

    Knowledge about the topological and structural heterogeneity of the microvasculature is important for diagnosis and monitoring of glioma. A vessel caliber and type-dependent temporal shift in the magnetic resonance imaging signal forms the basis for vascular architecture mapping. This study introduced a clinically feasible approach for assessment of vascular pathologies in gliomas using vascular architecture mapping. Sixty consecutive patients with known or suspected gliomas were examined using vascular architecture mapping as part of the routine magnetic resonance imaging protocol. Maps of microvessel radius and density, which adapted to the vasculature-dependent temporal shift phenomenon, were calculated using a costume-made software tool. Microvessel radius and density were moderately to severely elevated in a heterogeneous, inversely correlated pattern within high-grade gliomas. Additionally, three new imaging biomarkers were introduced: Microvessel type indicator allowing differentiation between supplying arterial and draining venous microvasculature in high-grade gliomas. Vascular-induced bolus peak time shift may presumably be sensitive for early neovascularization in the infiltration zone. Surprisingly, curvature showed significant changes in peritumoral vasogenic edema which correlated with neovascularization in the tumor core of high-grade gliomas. These new magnetic resonance imaging biomarkers give insights into complexity and heterogeneity of vascular changes in glioma; however, histological validations in more well-defined patient populations are required.

  18. DNA repair gene XRCC3 variants are associated with susceptibility to glioma in a Chinese population.

    PubMed

    Huang, J Y; Yang, J F; Qu, Q; Qu, J; Liu, F; Liu, F E; Xiong, T; Lu, S H

    2015-09-08

    The susceptibility to glioma is not well understood. It has been suggested that the X-ray cross complementing group 3 (XRCC3) gene influences the capacity to repair DNA damage, leading to increased glioma susceptibility. In this study, we evaluated the relationship between XRCC3 mutations and glioma risk. Genotypes were assessed in 389 Chinese glioma patients and 358 healthy controls. XRCC3 Thr241Met (rs861539) and 2 additional polymorphisms, rs3212112 (c.774+19T>G) and rs1799796 (c.562-14A>G), were directly sequenced. The frequency of the rs861539 T allele was significantly lower in the glioma group than in healthy controls [11.1 vs 17.7%, odds ratio = 0.62 (0.48-0.80), P < 0.001]; the frequencies of the CT or CT+TT genotypes differed between groups (18.5 vs 31%, 20.3 vs 33.2%, respectively). The frequency of the rs3212112 G allele was significantly higher in the glioma group than in healthy controls [15.8 vs 5.3%, odds ratio = 2.94 (2.07-4.17), P < 0.001]. The frequencies of the GT or TG+GG genotypes differed between groups (25.4 vs 7.8%, 28.5 vs 9.2%, respectively). This study demonstrates that the rs861539 and rs3212112 polymorphisms in the XRCC3 gene may influence the risk of glioma development in Chinese populations.

  19. 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

    2014-10-07

    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