title: Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian Inhibiting Substance responsiveness.
abstract: 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.
authors.affiliation: Pediatric Surgical Research Laboratories, Department of Surgery, Harvard Medical School, 185 Cambridge Street, Boston, MA 02114, USA.
authors.forename: Paul P
authors.initials: PP
authors.lastname: Szotek
authors.forename: Rafael
authors.initials: R
authors.lastname: Pieretti-Vanmarcke
authors.forename: Peter T
authors.initials: PT
authors.lastname: Masiakos
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Dinulescu
authors.forename: Denise
authors.initials: D
authors.lastname: Connolly
authors.forename: Rosemary
authors.initials: R
authors.lastname: Foster
authors.forename: David
authors.initials: D
authors.lastname: Dombkowski
authors.forename: Frederic
authors.initials: F
authors.lastname: Preffer
authors.forename: David T
authors.initials: DT
authors.lastname: Maclaughlin
authors.forename: Patricia K
authors.initials: PK
authors.lastname: Donahoe
mesh_terms: D000818:Animals; D054304:Anti-Mullerian Hormone; D000970:Antineoplastic Agents / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D005260:Female; D005456:Fluorescent Dyes / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*; D013735:Testicular Hormones / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D005456:Fluorescent Dyes; D006023:Glycoproteins; D013735:Testicular Hormones; D054304:Anti-Mullerian Hormone; D014700:Verapamil; C017807:bisbenzimide ethoxide trihydrochloride