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The Side Population of Ovarian Cancer Cells Is a Primary Target of IFN- Antitumor Effects

Departments of ¹ Oncology and Surgical Sciences, ² Pediatrics, and ³ Information Engineering, University of Padova; ⁴ Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua, Italy; and ⁵ Department of Experimental Oncology, Unit of Molecular Therapies, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy

Requests for reprints: Stefano Indraccolo, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, via Gattamelata 64, 35128 Padua, Italy. Phone: 39-49-8215875; Fax: 30-49-8072854; E-mail: stefano.indraccolo{at}unipd.it.

Key Words: side population • ovarian cancer • stem cells • IFN • transcriptional signature

Note:

The side population (SP), recently identified in several normal tissues and in a variety of tumors based on its ability to extrude some fluorescent dyes, may comprise cells endowed with stem cell features. In this study, we investigated the presence of SP in epithelial ovarian cancer and found it in 9 of 27 primary tumor samples analyzed, as well as in 4 of 6 cultures from xenotransplants. SP cells from one xenograft bearing a large SP fraction were characterized in detail. SP cells had higher proliferation rates, were much less apoptotic compared with non-SP cells, and generated tumors more rapidly than non-SP cells. We also investigated the effects of IFN-, a cytokine that has widely been used to treat solid tumors, on epithelial ovarian cancer cells and observed that IFN- exerted marked antiproliferative and proapoptotic effects on primary cultures containing high numbers of SP cells. In vitro, IFN- treatment invariably caused a dramatic reduction in SP size in tumor cell lines of different origins; moreover, IFN- treatment of purified SP cells was associated with a distinctive change in their transcriptional profile. Gene therapy with human IFN- resulted in regression of established tumors bearing a large SP fraction, which was not observed when tumors bearing low SP levels were treated. These findings could have relevant clinical implications because they imply that tumors bearing large SP numbers, albeit rare, could be sensitive to IFN- treatment. [Cancer Res 2008;68(14):5658–68]