Article

Ovarian cancer side population defines cells with stem-like characteristics and Mullerian Inhibiting Substance responsiveness

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 08/2006; 103(30):11154-9. DOI: 10.1073/pnas.0603672103
Source: PubMed

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.

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Available from: Rosemary Foster, Jan 05, 2015
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    • "Several groups were able to later identify ABCG2 as a key contributor to Hoechst 33342 efflux and an important side population marker56575859. Since then, the Hoechst 33342 efflux assay has been used to successfully isolate a number of normal stem-like populations, such as retinal stem cells [60] and primitive neural cells [61], as well as CSC-like populations in lung cancer cell lines [62], head and neck cancer cell lines [63], hepatocellular carcinoma cell lines [64], a glioma cell line [65], primary neuroblastoma cultures [66], ovarian cancer cell lines [67] , and in ascites cells from patients with ovarian can- cer [67]. ABCG2 is often associated with CSCs because of the presence of ABCG2-positive cells in the side population identified by dye efflux assays. "
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    • "Subsequently CSCs were also observed in a wide variety of solid tumors viz. lung cancer (Kim et al., 2005), colon cancer (O'Brien et al., 2006), prostate cancer (Collins et al., 2005), ovarian cancer (Szotek et al., 2006), brain cancer (Piccirillo et al., 2006), melanoma (Fang et al., 2005) and others. The stem cell hypothesis is thus, different from earlier stochastic model, wherein all the tumor cells are considered to have potential for tumor development (Gugjoo et al., 2013). "
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    • "Subsequently CSCs were also observed in a wide variety of solid tumors viz. lung cancer (Kim et al., 2005), colon cancer (O'Brien et al., 2006), prostate cancer (Collins et al., 2005), ovarian cancer (Szotek et al., 2006), brain cancer (Piccirillo et al., 2006), melanoma (Fang et al., 2005) and others. The stem cell hypothesis is thus, different from earlier stochastic model, wherein all the tumor cells are considered to have potential for tumor development (Gugjoo et al., 2013). "
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