Laboratory of Molecular Neuro Oncology

Laboratory of, United States

Laboratory of Molecular Neuro Oncology

Laboratory of, United States
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Liu Z.,Diana Helis Henry Medical Research Foundation | Liu Z.,Sun Yat Sen University | Zhao X.,Laboratory of Molecular Neuro oncology | Zhao X.,Texas Childrens Hospital | And 27 more authors.
Neuro-Oncology | Year: 2013

BackgroundSeneca Valley virus (SVV-001) is a nonpathogenic oncolytic virus that can be systemically administered and can pass through the blood-brain barrier. We examined its therapeutic efficacy and the mechanism of tumor cell infection in pediatric malignant gliomas.MethodsIn vitro antitumor activities were examined in primary cultures, preformed neurospheres, and self-renewing glioma cells derived from 6 patient tumor orthotopic xenograft mouse models (1 anaplastic astrocytoma and 5 GBM). In vivo therapeutic efficacy was examined by systemic treatment of preformed xenografts in 3 permissive and 2 resistant models. The functional role of sialic acid in mediating SVV-001 infection was investigated using neuraminidase and lectins that cleave or competitively bind to linkage-specific sialic acids.ResultsSVV-001 at a multiplicity of infection of 0.5 to 25 replicated in and effectively killed primary cultures, preformed neurospheres, and self-renewing stemlike single glioma cells derived from 4 of the 6 glioma models in vitro. A single i.v. injection of SVV-001 (5 × 1012 viral particles/kg) led to the infection of orthotopic xenografts without harming normal mouse brain cells, resulting in significantly prolonged survival in all 3 permissive and 1 resistant mouse models (P <. 05). Treatment with neuraminidase and competitive binding using lectins specific for α2,3-linked and/or α2,6-linked sialic acid significantly suppressed SVV-001 infectivity (P <. 01).ConclusionSVV-001 possesses strong antitumor activity against pediatric malignant gliomas and utilizes α2,3-linked and α2,6-linked sialic acids as mediators of tumor cell infection. Our findings support the consideration of SVV-001 for clinical trials in children with malignant glioma. © The Author(s) 2013. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved.

Zerrouqi A.,Laboratory of Molecular Neuro Oncology | Pyrzynska B.,Laboratory of Molecular Neuro Oncology | Pyrzynska B.,Medical University of Warsaw | Brat D.J.,Emory University | And 2 more authors.
Cancer Research | Year: 2014

How necrotic areas develop in tumors is incompletely understood but can impact progression. Recent findings suggest that the formation of vascular microthrombi contributes to tumor necrosis, prompting investigation of coagulation cascades. Here, we report that loss of tumor suppressor P14ARF can contribute to activating the clotting cascade in glioblastoma. P14ARF transcriptionally upregulated TFPI2, a Kunitz-type serine protease in the tissue factor pathway that inhibits the initiation of thrombosis reactions. P14ARF activation in tumor cells delayed their ability to activate plasma clotting. Mechanistically, P14ARF activated the TFPI2 promoter in a p53- independent manner that relied upon c-JUN, SP1, and JNK activity. Taken together, our results identify the critical signaling pathways activated by P14ARF to prevent vascular microthrombosis triggered by glioma cells. Stimulation of this pathway might be used as a therapeutic strategy to reduce aggressive phenotypes associated with necrotic tumors, including glioblastoma. © 2013 American Association for Cancer Research.

Thomas S.L.,Ford Motor Company | Schultz C.R.,Ford Motor Company | Mouzon E.,Ford Motor Company | Golembieski W.A.,Ford Motor Company | And 7 more authors.
Brain Pathology | Year: 2015

Both the induction of SPARC expression and the loss of the p53 tumor suppressor gene are changes that occur early in glioma development. Both SPARC and p53 regulate glioma cell survival by inverse effects on apoptotic signaling. Therefore, during glioma formation, the upregulation of SPARC may cooperate with the loss of p53 to enhance cell survival. This study determined whether the loss of Sparc in astrocytes that are null for p53 would result in reduced cell survival and tumor formation and increased tumor immunogenicity in an in vivo xenograft brain tumor model. In vitro, the loss of Sparc in p53-null astrocytes resulted in an increase in cell proliferation, but a loss of tumorigenicity. At 7 days after intracranial implantation, Sparc-null tumors had decreased tumor cell survival, proliferation and reduced tumor size. The loss of Sparc promoted microglia/macrophage activation and phagocytosis of tumor cells. Our results indicate that the loss of p53 by deletion/mutation in the early stages of glioma formation may cooperate with the induction of SPARC to potentiate cancer cell survival and escape from immune surveillance. © 2014 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

Szabo E.,Laboratory of Molecular Neuro Oncology | Schneider H.,Laboratory of Molecular Neuro Oncology | Seystahl K.,Laboratory of Molecular Neuro Oncology | Rushing E.J.,University of Zürich | And 3 more authors.
Neuro-Oncology | Year: 2016

Background Although the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) system has become a prime target for antiangiogenic treatment, its biological role in glioblastoma beyond angiogenesis has remained controversial. Methods Using neutralizing antibodies to VEGF or placental growth factor (PlGF) or the tyrosine kinase inhibitor, cediranib, or lentiviral gene silencing, we delineated autocrine signaling in glioma cell lines. The in vivo effects of VEGFR1 and VEGFR2 depletion were evaluated in orthotopic glioma xenograft models. Results VEGFR1 and VEGFR2 modulated glioma cell clonogenicity, viability, and invasiveness in vitro in an autocrine, cell-line-specific manner. VEGFR1 silencing promoted mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, whereas VEGFR2 silencing resulted in cell-type dependent activation of the protein kinase B (PKB)/AKT and MAPK/ERK pathways. These responses may represent specific escape mechanisms from VEGFR inhibition. The survival of orthotopic glioma-bearing mice was prolonged upon VEGFR1 silencing in the LNT-229, LN-308, and U87MG models and upon VEGFR2 silencing in LN-308 and U87MG. Disruption of VEGFR1 and VEGFR2 signaling was associated with decreased tumor size, increased tumor necrosis, or loss of matrix metalloproteinase 9 (MMP9) immunoreactivity. Neutralizing VEGF and PlGF by specific antibodies was superior to either antibody treatment alone in the VEGFR1-dependent LNT-229 model. Conclusions Differential dependence on autocrine signaling through VEGFR1 and VEGFR2 suggests a need for biomarker-stratified VEGF(R)-based therapeutic approaches to glioblastoma. © 2016 The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

Nduom E.K.-E.,Emory University | Hadjipanayis C.G.,Emory University | Van Meir E.G.,Emory University | Van Meir E.G.,Laboratory of Molecular Neuro oncology
Cancer Journal | Year: 2012

Glioblastoma remains one of the deadliest forms of cancer. Infiltrating cancer cells in the surrounding brain prevent complete resection, and tumor cell resistance to chemoradiation results in the poor prognosis of the glioblastoma (GBM) patient. Much research has been devoted over the years to the pathogenesis and treatment of GBM. The tumor stem cell hypothesis, which was initially described in hematopoietic cell malignancies, may explain the resistance of these tumors to conventional therapies. In this model, a certain subset of tumor cells, with characteristics similar to normal stem cells, is capable of producing the variety of cell types, which constitute the bulk of a tumor. As these tumor cells have properties distinct from those constituting the bulk of the tumor, a different approach may be required to eradicate these residual cells within the brain. Here we outline the history behind the theory of GBM cancer stem-like cells, as they are now referred to. We will also discuss the implications of their existence on commonly held beliefs about GBM pathogenesis and how they might influence future treatment strategies. © 2012 by Lippincott Williams & Wilkins.

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