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NK Cells Recognize and Kill Human Glioblastoma Cells with Stem Cell-Like Properties¹

Roberta Castriconi^2,*, Antonio Daga^2,, Alessandra Dondero^*, Gianluigi Zona, Pietro Luigi Poliani, Alice Melotti^,¶, Fabrizio Griffero^,¶, Daniela Marubbi^,¶, Renato Spaziante, Francesca Bellora^*, Lorenzo Moretta^*,||,#, Alessandro Moretta^*,||, Giorgio Corte^2,,¶ and Cristina Bottino^2,*,#

^* Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy; Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Dipartimento di Neuroscienze, Oftalmologia e Genetica, Università degli Studi di Genova, Genova, Italy; I Servizio di Anatomia Patologica, Università di Brescia, Brescia, Italy; ^¶ Dipartimento di Oncologia, Biologia e Genetica, Università degli Studi di Genova, Genova, Italy; ^|| Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy; and ^# Istituto Giannina Gaslini, Genova, Italy

In this study, cancer cells were isolated from tumor specimens of nine glioblastoma patients. Glioblastoma cells, cultured under suitable culture conditions, displayed markers typical of neural stem cells, were capable of partial multilineage differentiation in vitro, and gave origin to infiltrating tumors when orthotopically injected in NOD/SCID mice. These cells, although resistant to freshly isolated NK cells, were highly susceptible to lysis mediated by both allogeneic and autologous IL-2 (or IL-15)-activated NK cells. Indeed, all stem cell-cultured glioblastoma cells analyzed did not express protective amounts of HLA class I molecules, while expressing various ligands of activating NK receptors that triggered optimal NK cell cytotoxicity. Importantly, glioblastoma stem cells expressed high levels of PVR and Nectin-2, the ligands of DNAM-1-activating NK receptor.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants awarded to R.C., Al.D., F.B., L.M., A.M., and C.B. by Associazione Italiana per la Ricerca sul Cancro, Istituto Superiore di Sanità, Ministero della Sanità, Ministero dell’Università e della Ricerca Scientifica e Tecnologica, European Union FP6, LSHB-CT-2004-503319-AlloStem (the European Commission is not liable for any use that may be made of the information contained), and Fondazione Compagnia di San Paolo (Torino, Italy). Al.D. is the recipient of a Fondo Incentivazione Ricerca di Base fellowship awarded by Ministero dell’Università e della Ricerca Scientifica e Tecnologica. An.D., G.Z., A.M., F.G., D.M., R.S., and G.C. were supported by grants awarded by Ministero della Sanità and Fondazione Cassa di Risparmio di Genova e Imperia, Genova, Italy.

² R.C., An.D., G.C., and C.B. equally contributed to this study.

³ Address correspondence and reprint requests to Dr. Cristina Bottino, Laboratory of Clinical and Experimental Immunology, Istituto Giannina Gaslini L.g. G, Gaslini J, 16148 Genova, Italy. E-mail address: Cristina.Bottino{at}unige.it

⁴ Abbreviations used in this paper: GBM, glioblastoma; KIR, killer Ig-like receptor; NCR, natural cytotoxicity receptor; NSC, neural stem cell; RT, room temperature.

⁵ The online version of this article contains supplemental material.