title: Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche.
abstract: 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.
authors: Department of Biomedical Sciences and Cornell Stem Cell Program, Cornell University, Ithaca, New York 14853, USA.
authors: Andrea
authors: A
authors: Flesken-Nikitin
authors: Chang-Il
authors: CI
authors: Hwang
authors: Chieh-Yang
authors: CY
authors: Cheng
authors: Tatyana V
authors: TV
authors: Michurina
authors: Grigori
authors: G
authors: Enikolopov
authors: Alexander Yu
authors: AY
authors: Nikitin
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D000077216:Carcinoma, Ovarian Epithelial; D019070:Cell Lineage; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000378:metabolism / Q000473:pathology*; D005260:Female; D008297:Male; D051379:Mice; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D010053:Ovary / Q000378:metabolism / Q000473:pathology*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53