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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)568-576
Number of pages9
JournalNeuropharmacology
Volume55
Issue number4
DOIs
Publication statusPublished - Sep 2008

Fingerprint

Bone Morphogenetic Protein Receptors
Glioma
LY 341495
Brain
Growth
Bone Morphogenetic Proteins
Metabotropic Glutamate Receptors
Therapeutics
metabotropic glutamate receptor 3
Mitogen-Activated Protein Kinases
Nude Mice
Brain Neoplasms
Astrocytes
Neoplasms
Transcription Factors
Radiotherapy
Cell Culture Techniques
Phosphorylation
Pharmacology
Recurrence

Keywords

  • Glioblastoma
  • Glioma-initiating cells
  • Glutamate
  • mGlu3 receptor

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Drug Discovery
  • Pharmacology

Cite this

Type-3 metabotropic glutamate receptors negatively modulate bone morphogenetic protein receptor signaling and support the tumourigenic potential of glioma-initiating cells. / Ciceroni, C.; Arcella, A.; Mosillo, P.; Battaglia, G.; Mastrantoni, E.; Oliva, M. A.; Carpinelli, G.; Santoro, F.; Sale, P.; Ricci-Vitiani, L.; De Maria, R.; Pallini, R.; Giangaspero, F.; Nicoletti, F.; Melchiorri, D.

In: Neuropharmacology, Vol. 55, No. 4, 09.2008, p. 568-576.

Research output: Contribution to journalArticle

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