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Szotek PP , Pieretti-Vanmarcke R , Masiakos PT , Dinulescu DM , Connolly D , Foster R , Dombkowski D , Preffer F , Maclaughlin DT , Donahoe PK
Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness
Proc Natl Acad Sci U S A. 2006 Jul 25;103(30) :11154-9
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The recent identification of "side population" (SP) cells in a number of unrelated human cancers and their normal tissue sources has renewed interest in the hypothesis that cancers may arise from somatic stem/progenitor cells. The high incidence of recurrence attributable to multidrug resistance and the multiple histologic phenotypes indicative of multipotency suggests a stem cell-like etiology of ovarian cancer. Here we identify and characterize SP cells from two distinct genetically engineered mouse ovarian cancer cell lines. Differential efflux of the DNA-binding dye Hoechst 33342 from these cell lines defined a human breast cancer-resistance protein 1-expressing, verapamil-sensitive SP of candidate cancer stem cells. In vivo, mouse SP cells formed measurable tumors sooner than non-SP (NSP) cells when equal numbers were injected into the dorsal fat pad of nude mice. The presence of Mullerian Inhibiting Substance (MIS) signaling pathway transduction molecules in both SP and NSP mouse cells led us to investigate the efficacy of MIS against these populations in comparison with traditional chemotherapies. MIS inhibited the proliferation of both SP and NSP cells, whereas the lipophilic chemotherapeutic agent doxorubicin more significantly inhibited the NSP cells. Finally, we identified breast cancer-resistance protein 1-expressing verapamil-sensitive SPs in three of four human ovarian cancer cell lines and four of six patient primary ascites cells. In the future, individualized therapy must incorporate analysis of the stem cell-like subpopulation of ovarian cancer cells when designing therapeutic strategies for ovarian cancer patients.
Szotek, Paul P Pieretti-Vanmarcke, Rafael Masiakos, Peter T Dinulescu, Daniela M Connolly, Denise Foster, Rosemary Dombkowski, David Preffer, Frederic Maclaughlin, David T Donahoe, Patricia K 1P50CA105009/CA/United States NCI 5T32CA071345-10/CA/United States NCI CA17393/CA/United States NCI HD32112/HD/United States NICHD P50 CA083638/CA/United States NCI U01 CA084242/CA/United States NCI Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Proceedings of the National Academy of Sciences of the United States of America Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11154-9. Epub 2006 Jul 18.