Ovulation induces cyclic rupture and regenerative repair of the ovarian coelomic epithelium. This process of repeated disruption and repair accompanied by complex remodeling typifies a somatic stem/progenitor cell-mediated process. Using BrdU incorporation and doxycycline inducible histone2B-green fluorescent protein pulse–chase techniques, we identify a label-retaining cell population in the coelomic epithelium of the adult mouse ovary as candidate somatic stem/progenitor cells. The identified population exhibits quiescence with asymmetric label retention, functional response to estrous cycling in vivo by proliferation, enhanced growth characteristics by in vitro colony formation, and cytoprotective mechanisms by enrichment for the side population. Together, these characteristics identify the label-retaining cell population as a candidate for the putative somatic stem/progenitor cells of the coelomic epithelium of the mouse ovary.
Cancer stem cells are proposed to be tumor-initiating cells capable of tumorigenesis, recurrence, metastasis, and drug resistance, and, like somatic stem cells, are thought to be capable of unlimited selfrenewal and, when stimulated, proliferation and differentiation. Here we select cells by expression of a panel of markers to enrich for a population with stem cell-like characteristics. A panel of eight was initially selected from 95 human cell surface antigens as each was shared among human ovarian primary cancers, ovarian cancer cell lines, and normal fimbria. A total of 150 combinations of markers were reduced to a panel of three-CD44, CD24, and Epcam-which selected, in three ovarian cancer cell lines, those cells which best formed colonies. Cells expressing CD44, CD24, and Epcam exhibited stem cell characteristics of shorter tumor-free intervals in vivo after limiting dilution, and enhanced migration in invasion assays in vitro. Also, doxorubicin, cisplatin, and paclitaxel increased this enriched population which, conversely, was significantly inhibited by Mülle-rian inhibiting substance (MIS) or the MIS mimetic SP600125. These findings demonstrate that flow cytometry can be used to detect a population which shows differential drug sensitivity, and imply that treatment of patients can be individualized to target both stem/progenitor cell enriched and nonenriched subpopulations. The findings also suggest that this population, amenable to isolation by flow cytometry, can be used to screen for novel treatment paradigms, including biologic agents such as MIS, which will improve outcomes for patients with ovarian cancer.anthrapyrazolone | chemotherapy resistance | stem/progenitor cell-enriched populations A s evidence is accumulating to indicate that cancer could be a stem cell disease (1-4), it is becoming increasingly important to be able to identify cancer stem/progenitor cells and to develop treatment modalities that specifically target the stem cell enriched population, coupled with treatments effective against the larger population not enriched for stem cells. The concept of cancer stem cells has opened new areas of research in carcinogenesis, but has the more immediate translational potential of uncovering new treatment targets.We previously identified somatic label-retaining cells with stem cell features in ovarian surface epithelium (5), and with others (6, 7), postulate that somatic stem cells or their immediate progenitors can revert to cancer stem cells (8). It is also possible that the stem cells may remain the same, but that signals which control the stem/progenitor cell activity may change. Several recent studies have demonstrated that cancer stem cells may confer chemotherapeutic resistant ovarian tumor growth and metastasis (2, 9).Ovarian cancer is diagnosed in approximately 25,000 new cases per year in the United States and is associated with a 50% mortality rate (10, 11); more than 90% of cases are epithelial in origin (12, 13). Epithelial ovarian cancers fall into four main subtypes: mucinous,...
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