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-per-meant 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. (C) 2008 Elsevier Ltd. All rights reserved.

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; Mosillo, Paola; Battaglia, Giuseppe; Mastrantoni, Elisa; M. A., Oliva; G., Carpinelli; F., Santoro; Sale, Patrizio; L., Ricci Vitiani; R., De Maria; R., Pallini; Giangaspero, Felice; Nicoletti, Ferdinando; Melchiorri, Daniela. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 55:4(2008), pp. 568-576. [10.1016/j.neuropharm.2008.06.064]

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

MOSILLO, PAOLA;BATTAGLIA, Giuseppe;MASTRANTONI, ELISA;SALE, PATRIZIO;GIANGASPERO, FELICE;NICOLETTI, Ferdinando;MELCHIORRI, Daniela
2008

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-per-meant 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. (C) 2008 Elsevier Ltd. All rights reserved.
2008
glioblastoma; glioma-initiating cells; glutamate; mglu3 receptor
01 Pubblicazione su rivista::01a Articolo in rivista
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; Mosillo, Paola; Battaglia, Giuseppe; Mastrantoni, Elisa; M. A., Oliva; G., Carpinelli; F., Santoro; Sale, Patrizio; L., Ricci Vitiani; R., De Maria; R., Pallini; Giangaspero, Felice; Nicoletti, Ferdinando; Melchiorri, Daniela. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 55:4(2008), pp. 568-576. [10.1016/j.neuropharm.2008.06.064]
File allegati a questo prodotto
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/358545
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 19
  • Scopus 38
  • ???jsp.display-item.citation.isi??? 38
social impact