The Role of White Matter Progenitors in Glioma Formation and Progression

Summary

Principal Investigator: Peter D Canoll
Abstract: DESCRIPTION (provided by applicant): The adult brain contains several distinct populations of cycling cells. Prominent among these is a large and widely distributed population of oligodendrocyte progenitor cells that express platelet derived growth factor receptor alpha (PDGFR1). Normally these cells are non-migratory and slowly proliferating. However, they can be induced to proliferate massively when stimulated with PDGF. We have shown that infecting glial progenitors in the adult subcortical white matter with retroviruses that express PDGF-B will induce the formation of brain tumors that have the histological features of malignant gliomas. These tumors are composed of a mixture of retrovirus infected progenitors and reactive progenitors that have been driven to proliferate by PDGF stimulation. Furthermore, genetically deleting tumor suppressor genes PTEN or p53 greatly facilitates PDGF driven proliferation and glioma formation. The goal of this proposal is to characterize the role(s) of adult glial progenitors play in the formation and progression of gliomas, both as genetically transformed cells and as reactive cells in the tumor environment. We believe these studies will provide important insight into the basic mechanism that drive gliomagenesis. PUBLIC HEALTH RELEVANCE: Oligodendrocyte progenitors are one of the largest populations of cycling cells in the adult brain. These cells have an inherent capacity to proliferate massively when stimulated with platelet derived growth factor (PDGF) and genetic deletion of the tumor suppressor genes PTEN and p53 greatly facilitate their responsiveness to PDGF. Our goal is to characterize the role that adult oligodendrocyte progenitors play in the formation and progression of malignant gliomas.
Funding Period: 2010-02-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. ncbi Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation
    Kenta Masui
    Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
    Glia 58:1050-65. 2010
  2. pmc PDGF-B-mediated downregulation of miR-21: new insights into PDGF signaling in glioblastoma
    Pedro M Costa
    CNC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004 517, Portugal
    Hum Mol Genet 21:5118-30. 2012
  3. pmc MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma
    Pedro M Costa
    CNC Center for Neuroscience and Cell Biology, University of Coimbra, 3004 517 Coimbra, Portugal
    Hum Mol Genet 22:904-18. 2013
  4. pmc Convection-enhanced delivery for targeted delivery of antiglioma agents: the translational experience
    Jonathan Yun
    Gabriele Bartoli Brain Tumor Laboratory, Departments of Neurosurgery, Columbia University Medical Center, 1130 St Nicholas Avenue Room 1001, New York, NY 10032, USA
    J Drug Deliv 2013:107573. 2013
  5. pmc Murine cell line model of proneural glioma for evaluation of anti-tumor therapies
    Adam M Sonabend
    Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University Medical Center, 1130 St Nicholas Ave Rm 1001, New York, NY 10032, USA
    J Neurooncol 112:375-82. 2013
  6. pmc Tumor-associated macrophages in glioma: friend or foe?
    Benjamin C Kennedy
    The Gabriele Bartoli Brain Tumor Research Laboratory, Department of Neurological Surgery, The Neurological Institute, Columbia University College of Physicians and Surgeons, New York City, NY 10032, USA
    J Oncol 2013:486912. 2013
  7. ncbi Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R
    Vattoly J Majo
    Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University College of Physicians and Surgeons, NY, USA
    Bioorg Med Chem Lett 23:4191-4. 2013
  8. pmc A secreted PTEN phosphatase that enters cells to alter signaling and survival
    Benjamin D Hopkins
    Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA
    Science 341:399-402. 2013
  9. pmc The integrated landscape of driver genomic alterations in glioblastoma
    Véronique Frattini
    1 Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA 2
    Nat Genet 45:1141-9. 2013
  10. pmc Inhibition of caveolin-1 restores myeloid cell function in human glioblastoma
    Shinji Shimato
    Department of Neurosurgery, Gabriele Bartoli Brain Tumor Research Laboratory, Columbia University, New York, New York, United States of America
    PLoS ONE 8:e77397. 2013

Research Grants

  1. Validation of microRNA Targets in Glioma
    Anna M Krichevsky; Fiscal Year: 2013
  2. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013

Detail Information

Publications26

  1. ncbi Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation
    Kenta Masui
    Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
    Glia 58:1050-65. 2010
    ..Together, these findings are the first implications regarding the cell-of-origin and the gliomagenesis in the brainstem...
  2. pmc PDGF-B-mediated downregulation of miR-21: new insights into PDGF signaling in glioblastoma
    Pedro M Costa
    CNC Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra 3004 517, Portugal
    Hum Mol Genet 21:5118-30. 2012
    ..Overall, our findings suggest that, besides its role in inducing GBM tumorigenesis, PDGF-B may enhance tumor proliferation by modulating the expression of oncomiRs and tumor suppressor miRNAs in U87 human GBM cells...
  3. pmc MicroRNA-21 silencing enhances the cytotoxic effect of the antiangiogenic drug sunitinib in glioblastoma
    Pedro M Costa
    CNC Center for Neuroscience and Cell Biology, University of Coimbra, 3004 517 Coimbra, Portugal
    Hum Mol Genet 22:904-18. 2013
    ..Overall, our results provide evidence that miR-21 is uniformly overexpressed in GBM and constitutes a highly promising target for multimodal therapeutic approaches toward GBM...
  4. pmc Convection-enhanced delivery for targeted delivery of antiglioma agents: the translational experience
    Jonathan Yun
    Gabriele Bartoli Brain Tumor Laboratory, Departments of Neurosurgery, Columbia University Medical Center, 1130 St Nicholas Avenue Room 1001, New York, NY 10032, USA
    J Drug Deliv 2013:107573. 2013
    ....
  5. pmc Murine cell line model of proneural glioma for evaluation of anti-tumor therapies
    Adam M Sonabend
    Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Columbia University Medical Center, 1130 St Nicholas Ave Rm 1001, New York, NY 10032, USA
    J Neurooncol 112:375-82. 2013
    ....
  6. pmc Tumor-associated macrophages in glioma: friend or foe?
    Benjamin C Kennedy
    The Gabriele Bartoli Brain Tumor Research Laboratory, Department of Neurological Surgery, The Neurological Institute, Columbia University College of Physicians and Surgeons, New York City, NY 10032, USA
    J Oncol 2013:486912. 2013
    ....
  7. ncbi Synthesis and in vitro evaluation of [18F]BMS-754807: a potential PET ligand for IGF-1R
    Vattoly J Majo
    Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University College of Physicians and Surgeons, NY, USA
    Bioorg Med Chem Lett 23:4191-4. 2013
    ..These studies indicate that [(18)F]1 can be a potential PET tracer for monitoring IGF-1R. ..
  8. pmc A secreted PTEN phosphatase that enters cells to alter signaling and survival
    Benjamin D Hopkins
    Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029, USA
    Science 341:399-402. 2013
    ..As an exogenous agent, PTEN-Long antagonized PI3K signaling and induced tumor cell death in vitro and in vivo. By providing a means to restore a functional tumor-suppressor protein to tumor cells, PTEN-Long may have therapeutic uses. ..
  9. pmc The integrated landscape of driver genomic alterations in glioblastoma
    Véronique Frattini
    1 Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA 2
    Nat Genet 45:1141-9. 2013
    ..These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention. ..
  10. pmc Inhibition of caveolin-1 restores myeloid cell function in human glioblastoma
    Shinji Shimato
    Department of Neurosurgery, Gabriele Bartoli Brain Tumor Research Laboratory, Columbia University, New York, New York, United States of America
    PLoS ONE 8:e77397. 2013
    ..Our group has previously demonstrated using complementary in vitro and in vivo approaches that GBM tumor cells polarize tumor-associated myeloid cells (TAMs) and suppress their immunostimulatory function...
  11. pmc The transcriptional regulatory network of proneural glioma determines the genetic alterations selected during tumor progression
    Adam M Sonabend
    Authors Affiliations Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery Department of Pathology and Cell Biology, Columbia University Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center Departments of Systems Biology and Biomedical Informatics Center for Computational Biology and Bioinformatics Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York Department of Molecular and Cellular Biochemistry, The Ohio State University Medical Center, Columbus and Brain Tumor and Neuro Oncology Center, Cleveland Clinic, Cleveland, Ohio
    Cancer Res 74:1440-51. 2014
    ....
  12. pmc The cellular origin for malignant glioma and prospects for clinical advancements
    Hui Zong
    Institute of Molecular Biology, University of Oregon, Eugene, OR 97403, USA
    Expert Rev Mol Diagn 12:383-94. 2012
    ..Further studies with multidisciplinary approaches are needed to link each subtype to a particular cell of origin, and to develop effective therapies that target the signaling network within these cells...
  13. pmc A multi-cancer mesenchymal transition gene expression signature is associated with prolonged time to recurrence in glioblastoma
    Wei yi Cheng
    Center for Computational Biology and Bioinformatics, Columbia University, New York, New York, United States of America
    PLoS ONE 7:e34705. 2012
    ....
  14. pmc Magnetic resonance imaging characteristics of glioblastoma multiforme: implications for understanding glioma ontogeny
    Leif Erik Bohman
    Department of Neurological Surgery, Columbia University College of Physicians and Surgeons, New York, New York, USA
    Neurosurgery 67:1319-27; discussion 1327-8. 2010
    ..However, conflicting evidence suggests that SVZ-like cells are not uniquely gliomagenic but this capacity may be shared by cycling progenitors distributed throughout the subcortical white matter (SCWM)...
  15. pmc Persistent roles of signal transduction of platelet-derived growth factor B in genesis, growth, and anaplastic transformation of gliomas in an in-vivo serial transplantation model
    Rina Torisu
    Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, 3 1 1 Maidashi, Higashi ku, Fukuoka 812 8582, Japan
    Brain Tumor Pathol 28:33-42. 2011
    ..This model would be useful for investigation of the long-term effects of PDGFB stimulation in glioma tissues on anaplastic evolution...
  16. pmc Glioblastoma models reveal the connection between adult glial progenitors and the proneural phenotype
    Liang Lei
    Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America
    PLoS ONE 6:e20041. 2011
    ..In addition, it is unclear how different genetic alterations interact with cells of origin in determining tumor heterogeneity. This issue cannot be addressed by studying end-stage human tumors...
  17. pmc Retroviral delivery of platelet-derived growth factor to spinal cord progenitor cells drives the formation of intramedullary gliomas
    Jason A Ellis
    Department of Neurological Surgery, Columbia University Medical Center, New York, New York 10032, USA
    Neurosurgery 70:198-204; discussion 204. 2012
    ..The transforming effects of platelet-derived growth factor (PDGF) on spinal cord glial progenitor cells may play an important role in the development of these tumors...
  18. pmc Platelet-derived growth factor receptor (PDGFR) expression in primary spinal cord gliomas
    Jason A Ellis
    Department of Neurological Surgery, Neurological Institute of New York, Columbia University Medical Center, 710 West 168th Street, New York, NY 10032, USA
    J Neurooncol 106:235-42. 2012
    ..Further studies investigating the prognostic significance of PDGFR expression as well as the role of PDGF signaling on the development of intramedullary spinal cord gliomas are warranted...
  19. pmc MADM gives new insights into gliomagenesis
    Liang Lei
    Department of Pathology and Cell Biology, Columbia University, NY 10032, USA
    J Mol Cell Biol 3:273-5. 2011
    ..They also provide new insights, and raise new questions, regarding where, when, and how malignant gliomas form...
  20. pmc Human cancer cells express Slug-based epithelial-mesenchymal transition gene expression signature obtained in vivo
    Dimitris Anastassiou
    Center for Computational Biology and Bioinformatics, Columbia University, New York, NY, USA
    BMC Cancer 11:529. 2011
    ..The biological mechanisms underlying cancer cell motility and invasiveness remain unclear, although it has been hypothesized that they involve some type of epithelial-mesenchymal transition (EMT)...
  21. pmc Direct inhibition of myosin II effectively blocks glioma invasion in the presence of multiple motogens
    Sanja Ivkovic
    Department of Neurology, Columbia University, New York, NY 10032, USA
    Mol Biol Cell 23:533-42. 2012
    ..Our results thus support our hypothesis that myosin II represents a point of convergence for signal transduction pathways that drive glioma invasion and that its inhibition cannot be overcome by other motility mechanisms...
  22. pmc Glial progenitor cell recruitment drives aggressive glioma growth: mathematical and experimental modelling
    Susan Christine Massey
    Department of Pathology, University of Washington, Box 357470, Seattle, WA 98195, USA
    J R Soc Interface 9:1757-66. 2012
    ....
  23. pmc The addition of Sunitinib to radiation delays tumor growth in a murine model of glioblastoma
    Randy D'Amico
    Department of Biophysics, Columbia University Medical Center, New York, USA
    Neurol Res 34:252-61. 2012
    ..However, the effects of these treatments on glioma growth and progression are poorly understood...
  24. pmc E2F1 coregulates cell cycle genes and chromatin components during the transition of oligodendrocyte progenitors from proliferation to differentiation
    Laura Magri
    Departments of Neuroscience, Genetics and Genomics, and Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, Center for Neuroscience Research, Children s National Medical Center, George Washington University, Washington, DC 20010 2970, and Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York 10032
    J Neurosci 34:1481-93. 2014
    ..Together, these data identify E2F1 as a key transcription factor modulating the expression of chromatin components in OPC during the transition from proliferation to differentiation. ..

Research Grants30

  1. Validation of microRNA Targets in Glioma
    Anna M Krichevsky; Fiscal Year: 2013
    ..The proposed work on microRNAs holds promises to advance our understanding of brain tumors and may open the door to novel treatments. ..
  2. Processing of Complex Lesions in the Mammalian Genome
    Randy J Legerski; Fiscal Year: 2013
    ..These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation. ..