Ovarian surface epithelium at the junction area contains cancer-prone stem cell niche

Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, New York 14853, USA.
Nature (Impact Factor: 41.46). 03/2013; 495(7440). DOI: 10.1038/nature11979
Source: PubMed


Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood. Some epithelial cancers are known to occur in transitional zones between two types of epithelium, whereas others have been shown to originate in epithelial tissue stem cells. The stem cell niche of the ovarian surface epithelium (OSE), which is ruptured and regenerates during ovulation, has not yet been defined unequivocally. Here we identify the hilum region of the mouse ovary, the transitional (or junction) area between the OSE, mesothelium and tubal (oviductal) epithelium, as a previously unrecognized stem cell niche of the OSE. We find that cells of the hilum OSE are cycling slowly and express stem and/or progenitor cell markers ALDH1, LGR5, LEF1, CD133 and CK6B. These cells display long-term stem cell properties ex vivo and in vivo, as shown by our serial sphere generation and long-term lineage-tracing assays. Importantly, the hilum cells show increased transformation potential after inactivation of tumour suppressor genes Trp53 and Rb1, whose pathways are altered frequently in the most aggressive and common type of human EOC, high-grade serous adenocarcinoma. Our study supports experimentally the idea that susceptibility of transitional zones to malignant transformation may be explained by the presence of stem cell niches in those areas. Identification of a stem cell niche for the OSE may have important implications for understanding EOC pathogenesis.

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Available from: Grigori Enikolopov, May 10, 2014
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    • "G. Enikolopov et al. Gleiberman et al. 2005, 2008; Day et al. 2007; Mignone et al. 2007; Mendez-Ferrer et al. 2010; Flesken-Nikitin et al. 2013). This provides an ability to identify and analyze stem cells in these tissues in the same animal, thus facilitating the experimental design for multiplex monitoring changes in the stem-cell compartments of different tissues. "
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    ABSTRACT: Stem and progenitor cells of the developing and adult brain can be effectively identified and manipulated using reporter genes, introduced into transgenic reporter mouse lines or recombinant viruses. Such reporters rely on an ever-increasing variety of fluorescent proteins and a continuously expanding list of regulatory elements and of mouse lines engineered for cell- or time-specific recombination. An important extension of stem-cell-based genetic strategies is an opportunity to explore the properties of newly generated neurons and their contribution to synaptic plasticity. Here, we review available strategies for marking and quantifying various classes of stem and progenitor cells in the adult brain, genetically tracing their progeny, and studying the properties of stem cells and new neurons. We compare various experimental approaches to labeling and investigating stem cells and their progeny and discuss caveats and limitations inherent to each approach. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 08/2015; 7(8). DOI:10.1101/cshperspect.a018804 · 8.68 Impact Factor
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    • "Another possibility is that ovarian cancer may arise in the transitional zone between OSE and fimbrial epithelium. Flesken- Nikitin et al. [37] "
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    ABSTRACT: Histopathological examination of material from prophylactic salpingo-oophorectomies performed in patients at genetic risk of ovarian cancer can reveal abnormalities interpreted as possible pre-cancerous “ovarian dysplasia” and tubal precursors lesions. We sought to study the morphological features and immunohistochemical expression patterns of neoplasia-associated markers in prophylactically removed ovaries and fallopian tubes (pBSO) in comparison with a group of serous tubal intraepithelial carcinoma (STIC) and non-cancerous controls.Study designMorphological features and immunohistochemical expression patterns of Ki-67 (for proliferation biomarker), p53 (key pathway of mullerian serous tumorogenesis), Bcl2 (anti-apoptotic), γH2AX (a double-strand breaks marker) and ALDH1 (a stem cell marker significantly associated with early-stage ovarian cancer) were blindly evaluated by two pathologists in 111 pBSO, 12 STICs and 116 non-cancerous salpingo-oophorectomies (control group) (nBSO).ResultsMorphological ovarian and tubal dysplasia scores were significantly higher in the pBSO than in controls (respectively, 8.8 vs 3.12, p < 0.0001, for ovaries and 6.54 vs 1.58, p < 0.0001 for tubes). Increased γH2AX expression was observed in the pBSO and STICs compared with the controls whereas expression patterns of Ki67, p53 and bcl2 were low to moderate in the pBSO group. STICs overexpressed Ki67 and p53 while bcl2 expression was low; Interestingly, ALDH1 expression was low in non dysplastic epithelium, high in dysplasia and constantly low in STICs.Conclusion The morphological and immunohistochemical profile of tubo-ovarian dysplasia and STICs might be consistent with progression toward neoplastic transformation in the Serous Carcinogenesis Sequence. These changes may be pre-malignant and could represent an important phase in early neoplasia. ALDH1 activation in pBSO samples and its extinction in STICs should be considered as a target for prevention.
    European Journal of Obstetrics & Gynecology and Reproductive Biology 10/2014; 183. DOI:10.1016/j.ejogrb.2014.10.003 · 1.70 Impact Factor
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    • "Taking into consideration the hypothesis of GCS being harbored in the OSE, implicitly a niche must exist, but it has not yet been described. Very recently, Flesken-Nikitin et al. advanced the idea that hilum region of the mouse ovary harbors a putative niche for the OSE [42]. "
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    ABSTRACT: For many years, ovarian biology has been based on the dogma that oocytes reserve in female mammals included a finite number, established before or at birth and it is determined by the number and quality of primordial follicles developed during the neonatal period. The restricted supply of oocytes in adult female mammals has been disputed in recent years by supporters of postnatal neo-oogenesis. Recent experimental data showed that ovarian surface epithelium and cortical tissue from both mouse and human were proved to contain very low proportion of cells able to propagate themselves, but also to generate immature oocytes in vitro or in vivo, when transplanted into immunodeficient mice ovaries. By mentioning several landmarks of ovarian stem cell reserve and addressing the exciting perspective of translation into clinical practice as treatment for infertility pathologies, the purpose of this article is to review the knowledge about adult mammalian ovarian stem cells, a topic that, since the first approach quickly attracted the attention of both the scientific media and patients.
    Journal of Ovarian Research 07/2014; 7(1):71. DOI:10.1186/1757-2215-7-71 · 2.43 Impact Factor
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