Type-3 metabotropic glutamate receptors negatively modulate bone morphogenetic protein receptor signaling and support the tumourigenic potential of glioma-initiating cells

Ruggero De Maria Marchiano, Roberto Pallini, Gerardo Battaglia, Fabio Santoro, Fabrizio Nicoletti, C. Ciceroni, A. Arcella, P. Mosillo, G. Battaglia, E. Mastrantoni, M. A. Oliva, G. Carpinelli, F. Santoro, P. Sale, L. Ricci-Vitiani, F. Giangaspero, F. Nicoletti, D. Melchiorri

Risultato della ricerca: Contributo in rivistaArticolo in rivista

32 Citazioni (Scopus)

Abstract

Targeted-therapies enhancing differentiation of glioma-initiating cells (GICs) are potential innovative approaches to the treatment of malignant gliomas. These cells support tumour growth and recurrence and are resistant to radiotherapy and chemotherapy. We have found that GICs express mGlu3 metabotropic glutamate receptors. Activation of these receptors sustained the undifferentiated state of GICs in culture by negatively modulating the action of bone morphogenetic proteins, which physiologically signal through the phosphorylation of the transcription factors, Smads. The cross-talk between mGlu3 receptors and BMP receptors was mediated by the activation of the mitogen-activated protein kinase pathway. Remarkably, pharmacological blockade of mGlu3 receptors stimulated the differentiation of cultured GICs into astrocytes, an effect that appeared to be long lasting, independent of the growth conditions, and irreversible. In in vivo experiments, a 3-month treatment with the brain-permeant mGlu receptor antagonist, LY341495 limited the growth of infiltrating brain tumours originating from GICs implanted into the brain parenchyma of nude mice. While clusters of tumour cells were consistently found in the brain of control mice, they were virtually absent in a large proportion of mice treated with LY341495. These findings pave the way to a new non-cytotoxic treatment of malignant gliomas based on the use of mGlu3 receptor antagonists. © 2008 Elsevier Ltd. All rights reserved.
Lingua originaleEnglish
pagine (da-a)568-576
Numero di pagine9
RivistaNeuropharmacology
Volume55
DOI
Stato di pubblicazionePubblicato - 2008

Keywords

  • Amino Acids
  • Animals
  • Bone Morphogenetic Protein Receptors
  • Brain Neoplasms
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cell Differentiation
  • Cell Line, Tumor
  • Cellular and Molecular Neuroscience
  • Disease Models, Animal
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • Glioblastoma
  • Glioma
  • Glioma-initiating cells
  • Glutamate
  • Humans
  • Magnetic Resonance Imaging
  • Mice
  • Mitogen-Activated Protein Kinases
  • Nerve Tissue Proteins
  • Pharmacology
  • Phosphorylation
  • Receptors, Metabotropic Glutamate
  • Signal Transduction
  • Xanthenes
  • mGlu3 receptor

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