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

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Abstract

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer deaths among women in the United States, but its pathogenesis is poorly understood1,2,3. 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 cells4,5,6. 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 adenocarcinoma7,8. 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.

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Figure 1: Identification and location of putative OSE stem cells.
Figure 2: Functional characterization of the hilum OSE cells.
Figure 3: Tracing the fate of LGR5 + hilum cells.
Figure 4: Hilum cells show preferential transformation after conditional inactivation of Trp53 and Rb1.

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Gene Expression Omnibus

Data deposits

Microarray data discussed in this publication have been deposited in the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus and are accessible through GEO Series accession number GSE43897.

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Acknowledgements

We would like to thank T. Tumbar for critical reading of this manuscript, J. Choi for help with immunostainings, L. Sayam (NYSTEM supported FACS Core) for help with FACS experiments and F. M. Vermeylen (Cornell Statistical Consulting Unit) for help with statistical analysis. This work was supported by grants from the US National Institutes of Health (NIH) and National Cancer Institute (NCI) (CA096823 and CA112354), NYSTEM (C023050 and N11G-160) and the Marsha Rivkin Center for Ovarian Cancer Research to A.Yu.N.; the NIH National Institute of Mental Health (MH092928), NIH National Institute on Aging (AG040209), NYSTEM (C024323) and Russian Ministry of Education and Science to G.E.; and postdoctoral fellowships to A.F.-N. (NIH NICHD T32HD052471) and C-.I.H. (Cornell Comparative Cancer Biology Training Program).

Author information

Author Contributions A.F.-N. and A.Yu.N. designed the study, interpreted data and wrote the manuscript. A.F.-N., C.-I.H., C.-Y.C., T.V.M. and G.E. performed experiments and analysed data. All authors discussed the results and commented on the manuscript.

Correspondence to Alexander Yu. Nikitin.

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Flesken-Nikitin, A., Hwang, C., Cheng, C. et al. Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature 495, 241–245 (2013) doi:10.1038/nature11979

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