The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of glioblastoma. However, the molecular alterations that drive stem cell proliferation in these tumors remain unknown. In this study, we found that expression of the MET oncogene was associated with neurospheres expressing the gene signature of mesenchymal and proneural subtypes of glioblastoma. Met expression was almost absent from neurospheres expressing the signature of the classical subtype, and was mutually exclusive with amplification and expression of the epidermal growth factor receptor (EGFR) gene. Met-positive and Met-negative neurospheres displayed distinct growth factor requirements, differentiated along divergent pathways, and generated tumors with distinctive features. The Met(high) subpopulation within Met-pos neurospheres displayed clonogenic potential and long-term self-renewal ability in vitro, and enhanced growth kinetics in vivo. In Met(high) cells, the Met ligand HGF further sustained proliferation, clonogenicity, expression of self-renewal markers, migration, and invasion in vitro. Together, our findings suggest that Met is a functional marker of glioblastoma stem cells and a candidate target for identification and therapy of a subset of glioblastomas.

The MET oncogene is a functional marker of a glioblastoma stem cell subtype.

DE BACCO, FRANCESCA;MEDICO, Enzo;ORZAN, FRANCESCA NOEMI;ALBANO, Raffaella;LURAGHI, PAOLO;REATO, Gigliola;D'AMBROSIO, ANTONIO;COMOGLIO, Paolo;BOCCACCIO, Carla
2012

Abstract

The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of glioblastoma. However, the molecular alterations that drive stem cell proliferation in these tumors remain unknown. In this study, we found that expression of the MET oncogene was associated with neurospheres expressing the gene signature of mesenchymal and proneural subtypes of glioblastoma. Met expression was almost absent from neurospheres expressing the signature of the classical subtype, and was mutually exclusive with amplification and expression of the epidermal growth factor receptor (EGFR) gene. Met-positive and Met-negative neurospheres displayed distinct growth factor requirements, differentiated along divergent pathways, and generated tumors with distinctive features. The Met(high) subpopulation within Met-pos neurospheres displayed clonogenic potential and long-term self-renewal ability in vitro, and enhanced growth kinetics in vivo. In Met(high) cells, the Met ligand HGF further sustained proliferation, clonogenicity, expression of self-renewal markers, migration, and invasion in vitro. Together, our findings suggest that Met is a functional marker of glioblastoma stem cells and a candidate target for identification and therapy of a subset of glioblastomas.
72
17
4537
4550
http://cancerres.aacrjournals.org/content/72/17/4537.long
integrated genomic analysis; tumor-initiating cells; signal transduction; MALIGNANT GLIOMAS; invasive growth; brain cancer; EGFR; expression; Amplification; Receptors
De Bacco F;Casanova E;Medico E;Pellegatta S;Orzan F;Albano R;Luraghi P;Reato G;D'Ambrosio A;Porrati P;Patane M;Maderna E;Pollo B;Comoglio PM;Finocchiaro G;Boccaccio C
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/127216
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