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Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells

Oncogene volume 28, pages 209–218 (2009)Cite this article

Abstract

The cancer stem cell hypothesis posits that malignant growth arises from a rare population of progenitor cells within a tumor that provide it with unlimited regenerative capacity. Such cells also possess increased resistance to chemotherapeutic agents. Resurgence of chemoresistant disease after primary therapy typifies epithelial ovarian cancer and may be attributable to residual cancer stem cells, or cancer-initiating cells, that survive initial treatment. As the cell surface marker CD133 identifies cancer-initiating cells in a number of other malignancies, we sought to determine the potential role of CD133+ cells in epithelial ovarian cancer. We detected CD133 on ovarian cancer cell lines, in primary cancers and on purified epithelial cells from ascitic fluid of ovarian cancer patients. We found CD133+ ovarian cancer cells generate both CD133+ and CD133− daughter cells, whereas CD133− cells divide symmetrically. CD133+ cells exhibit enhanced resistance to platinum-based therapy, drugs commonly used as first-line agents for the treatment of ovarian cancer. Sorted CD133+ ovarian cancer cells also form more aggressive tumor xenografts at a lower inoculum than their CD133− progeny. Epigenetic changes may be integral to the behavior of cancer progenitor cells and their progeny. In this regard, we found that CD133 transcription is controlled by both histone modifications and promoter methylation. Sorted CD133− ovarian cancer cells treated with DNA methyltransferase and histone deacetylase inhibitors show a synergistic increase in cell surface CD133 expression. Moreover, DNA methylation at the ovarian tissue active P2 promoter is inversely correlated with CD133 transcription. We also found that promoter methylation increases in CD133− progeny of CD133+ cells, with CD133+ cells retaining a less methylated or unmethylated state. Taken together, our results show that CD133 expression in ovarian cancer is directly regulated by epigenetic modifications and support the idea that CD133 demarcates an ovarian cancer-initiating cell population. The activity of these cells may be epigenetically detected and such cells might serve as pertinent chemotherapeutic targets for reducing disease recurrence.

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Acknowledgements

We thank Drs John Lancaster, Jeffrey Boyd, Thomas Hamilton, Gordon Mills and Jean Hurteau for providing many of the cell lines used in these studies; Dr William E Grizzle for preparing tissue microarrays; Mike Cook for help with flow cytometry and Nancy Glover and Julie Fuller for the preparation of slides used for immunohistochemistry. This study was supported by the Kislak-Fields Family Fund, the Duke Comprehensive Cancer Center, and the Gail Parkins Memorial Ovarian Awareness Fund.

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Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA

    T Baba, P A Convery, N Matsumura, R S Whitaker, E Kondoh, T Perry, Z Huang, A Berchuck & S K Murphy

  2. Department of Gynecology and Obstetrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    T Baba, N Matsumura, E Kondoh & S Fujii

  3. Department of Pathology, Duke University, Durham, NC, USA

    R C Bentley & S K Murphy

  4. Duke Institute for Genome Sciences and Policy, Durham, NC, USA

    S Mori, J R Marks, A Berchuck & S K Murphy

  5. Department of Surgery, Duke University, Durham, NC, USA

    J R Marks

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Correspondence to S K Murphy.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Baba, T., Convery, P., Matsumura, N. et al. Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells. Oncogene 28, 209–218 (2009). https://doi.org/10.1038/onc.2008.374

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