Article

Müllerian inhibiting substance preferentially inhibits stem/progenitors in human ovarian cancer cell lines compared with chemotherapeutics

Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 10/2010; 107(44):18874-9. DOI: 10.1073/pnas.1012667107
Source: PubMed

ABSTRACT 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 self-renewal 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 Müllerian 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.

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Available from: Katia Meirelles, Apr 03, 2014
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    • "In addition, CD24+ cancer cell colonies isolated from ovarian tumors of a human patient showed heterogeneity in proliferation rate, cell cycle distribution, and expression profile of genes and proteins, and demonstrated stem cell properties [49]. Furthermore, CD24+ stem-like cells detected in ovarian cancer also exhibited enhanced chemoresistance [50]. Notably, in breast cancer, the absence of CD24 combined with the presence of CD44 and EpCAM (CD24−CD44+EpCAM+) appears to be critical for the identification of breast CSCs [15]. "
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    ABSTRACT: Cancer stem cells (CSCs) represent a unique sub-population of tumor cells with the ability to initiate tumor growth and sustain self-renewal. Although CSC biomarkers have been described for various tumors, only a few markers have been identified for nasopharyngeal carcinoma (NPC). In this study, we show that CD24+ cells isolated from human NPC cell lines express stem cell genes (Sox2, Oct4, Nanog, Bmi-1, and Rex-1), and show activation of the Wnt/β-catenin signaling pathway. CD24+ cells possess typical CSC characteristics that include enhanced cell proliferation, increased colony and sphere formation, maintenance of cell differentiation potential in prolonged culture, and enhanced resistance to chemotherapeutic drugs. Notably, CD24+ cells produce tumors following inoculation of as few as 500 cells in immunodeficient NOD/SCID mice. CD24+ cells further show increased invasion ability in vitro, which correlates with enhanced expression of matrix metalloproteinase 2 and 9. In summary, our results suggest that CD24 represents a novel CSC biomarker in NPC.
    PLoS ONE 06/2014; 9(6):e99412. DOI:10.1371/journal.pone.0099412 · 3.23 Impact Factor
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    • "In fact, Wei at al., investigating about Müllerian Inhibiting Factor with the aim to inhibit stem progenitors in EOC, identified eight marker panels on three human ovarian cancer cell lines and found that the combination of Epcam+, CD24+, and CD44+ formed more colonies than other marker combinations. It was necessary to use these 3+ panels in combination, as each marker alone was not sufficiently selective 66. Two studies have independently defined ovarian cancer SC by evaluating CD44+ CD117+ and CD133+ phenotypes. "
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    ABSTRACT: Currently we are more and more improving our knowledge about the characteristics and the role of cancer stem cells in human cancer. Particularly we have realized that self-renewing ovarian cancer stem cells (CSCs) or ovarian cancer-initiating cells, and mesenchymal stem cells (SCs) too, are probably implicated in the etiopathogenesis of epithelial ovarian cancer (EOC). There is clear evidence that these cells are also involved in its intra- and extra-peritoneal diffusion and in the occurrence of chemo-resistance. In assessing the molecular characteristics of ovarian CSCs, we have to take note that these cellular populations are rare and the absence of specific cell surface markers represents a challenge to isolate and identify pure SC populations. In our review, we focused our attention on the molecular characteristics of epithelial ovarian CSCs and on the methods to detect them starting from their biological features. The study of ovarian CSCs is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future.
    Journal of Cancer 03/2014; 5(5):301-310. DOI:10.7150/jca.8610 · 2.64 Impact Factor
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    • "In fact,Wei at al., investigating about Müllerian Inhibiting Substance with the aim of inhibit stem/progenitors in EOC, identified eight marker panel on three human ovarian cancer cell lines and found that the combination of Epcam+, CD24+, and CD44+ formed more colonies than other marker combinations. It was necessary to use this 3+ panel in combination, as each marker alone was not sufficiently selective [82]. "
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    ABSTRACT: In 2013 there will be an estimated 22,240 new diagnoses and 14,030 deaths from ovarian cancer in the United States. Despite the improved surgical approach and the novel active drugs that are available today in clinical practice, about 80% of women presenting with late-stage disease have a 5-year survival rate of only 30%. In the last years a growing scientific knowledge about the molecular pathways involved in ovarian carcinogenesis has led to the discovery and evaluation of several novel molecular targeted agents, with the aim to test alternative models of treatment in order to overcome the clinical problem of resistance. Cancer stem cells tend to be more resistant to chemotherapeutic agents and radiation than more differentiated cellular subtypes from the same tissue. In this context the study of ovarian cancer stem cells is taking on an increasingly important strategic role, mostly for the potential therapeutic application in the next future. In our review, we focused our attention on the molecular characteristics of epithelial ovarian cancer stem cells, in particular on possible targets to hit with targeted therapies.
    Journal of Experimental & Clinical Cancer Research 08/2013; 32(1):48. DOI:10.1186/1756-9966-32-48 · 4.23 Impact Factor
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