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Research Articles: Therapeutics, Targets, and Development

p27^Kip1 expression inhibits glioblastoma growth, invasion, and tumor-induced neoangiogenesis

¹ Division of Experimental Oncology 2 and ² Division of Pathology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Aviano, Italy; ³ Division of Pathology, II Faculty of Medicine, University "La Sapienza," Ospedale Santo Andrea, Rome, Italy; and ⁴ Dipartimento di Scienze e Tecnologie Biomediche and ⁵ MATI Center of Excellence, University of Udine, Udine, Italy

Requests for reprints: Gustavo Baldassarre, Division of Experimental Oncology 2, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, Via Franco Gallini, 2 33081 Aviano, Italy. Phone: 39-434-659-233; Fax: 39-434-659-428. E-mail: gbaldassarre{at}cro.it

Abstract

The tumor suppressor gene CDKN1B encodes for a 27-kDa cyclin-dependent kinase inhibitory protein, p27^Kip1, which together with its well-established role in the inhibition of cell proliferation, displays additional activities in the control of gene transcription and cell motility. p27^Kip1 thus represents a good candidate for a gene therapy approach, especially in those cancers refractory to the conventional therapies, like human glioblastoma. Here, we show that overexpression of p27^Kip1 in glioblastoma cell lines induced cell cycle arrest and inhibition of cell motility through extracellular matrix substrates. The use of adenoviral vectors in the treatment of glioblastoma in vivo showed that p27^Kip1 was able to block not only cancer cell growth but also local invasion and tumor-induced neoangiogenesis. The latter effect was due to the ability of p27 to impair both endothelial cell growth and motility, thus preventing proper vessel formation in the tumor. The block of neoangiogenesis depended on cytoplasmic p27^Kip1 antimigratory activity and was linked to its ability to bind to and inhibit the microtubule-destabilizing protein stathmin. Our work provides the first evidence that a successful p27^Kip1-based gene therapy is linked to tumor microenvironment modification, thus opening new perspectives to the use of gene therapy approaches for the treatment of refractory cancers. [Mol Cancer Ther 2008;7(5):1164–75]

Grant support: Association for International Cancer Research (G. Baldassarre) and partially Associazione Italiana Ricerca sul Cancro (G. Baldassarre and A. Vecchione); Associazione Italiano Ricerca sul Cancro fellowship (F. Lovat) and Federazione Italiana Ricerca sul Cancro fellowship (S. Berton).

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.

Note: M. Schiappacassi and F. Lovat contributed equally to this work.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁷ Belletti et al., in preparation.

Received 10/ 1/07; revised 1/18/08; accepted 1/21/08.