Journal Article

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

Cheng, Chieh-Yang, Michurina, Tatyana V., Enikolopov, Grigori, Flesken-Nikitin, Andrea, Nikitin, Alexander Yu, Hwang, Chang-Il

2013

Overview

The hilum (a transitional region) of the mouse ovary is identified as a stem cell niche of the ovarian surface epithelium, and its cells are prone to malignant transformation after inactivation of common tumour suppressor genes, suggesting that they may be the origin of ovarian carcinoma. Stem cell niche linked to ovarian cancer The recent publication of integrated genomic analyses of ovarian carcinoma has provided an extensive catalogue of molecular aberrations of this deadly disease, but uncertainty about which epithelial cells the cancer originates in has complicated the application of such results. This study identifies a stem cell population in the hilum region of the mouse ovary as the origin of ovarian cancers induced by the loss of the RB1 and TRP53 tumour suppressors, whose pathways are altered frequently in the most aggressive and common types of human epithelial ovarian cancers. Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood 1 , 2 , 3 . 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 4 , 5 , 6 . 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 7 , 8 . 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/532/2118 / 631/532/2139 / 631/67/1517/1709 / 631/67/70 / Animals / Biomarkers - analysis / Biomarkers - metabolism / Cancer / Carcinoma, Ovarian Epithelial / Cell Lineage / Cell Separation / Cell Transformation, Neoplastic - metabolism / Cell Transformation, Neoplastic - pathology / Disease susceptibility / Epithelium / Epithelium - metabolism / Epithelium - pathology / Experiments / Female / Health aspects / Humanities and Social Sciences / Inactivation / letter / Male / Medical research / Medicine, Experimental / Mice / multidisciplinary / Neoplasms, Glandular and Epithelial - metabolism / Neoplasms, Glandular and Epithelial - pathology / Neoplastic Stem Cells - metabolism / Neoplastic Stem Cells - pathology / Ovarian cancer / Ovarian Neoplasms - metabolism / Ovarian Neoplasms - pathology / Ovary - metabolism / Ovary - pathology / Physiological aspects / Receptors, G-Protein-Coupled - metabolism / Retinoblastoma Protein - deficiency / Retinoblastoma Protein - genetics / Retinoblastoma Protein - metabolism / Risk factors / Science / Spheres / Stem Cell Niche / Stem cells / Tumor Suppressor Protein p53 - deficiency / Tumor Suppressor Protein p53 - genetics / Tumor Suppressor Protein p53 - metabolism