Identification of Gastric Cancer Stem Cells Using the Cell Surface Marker CD44

Authors

  • Shigeo Takaishi,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
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  • Tomoyuki Okumura,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
    2. Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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  • Shuiping Tu,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
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  • Sophie S.W. Wang,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
    2. Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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  • Wataru Shibata,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
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  • Ramanathan Vigneshwaran,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
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  • Shanisha A.K. Gordon,

    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
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  • Yutaka Shimada,

    1. Department of Surgery and Science, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
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  • Timothy C. Wang

    Corresponding author
    1. Division of Digestive and Liver Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York, USA
    • Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA
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    • Telephone: 212-851-4581; Fax: 212-851-4590


  • Author contributions: S. Takaishi: conception and design, execution and collection of data, data analysis, manuscript writing; T.O.: experimental design, execution and collection of data; S. Tu and S.S.W.W.: execution and collection of data; W.S., R.V., S.A.K.G., and Y.S.: provision of study materials; T.C.W.: principal investigator, conception and design, laboratory facility and financial support, experimental design, manuscript writing, final approval of manuscript.

  • First published online in Stem CellsExpress February 12, 2009

Abstract

Cancer stem cells (CSCs) have been defined as a unique subpopulation in tumors that possess the ability to initiate tumor growth and sustain tumor self-renewal. Although the evidence has been provided to support the existence of CSCs in various solid tumors, the identity of gastric CSCs has not been reported. In this study, we have identified gastric cancer-initiating cells from a panel of human gastric cancer cell lines using cell surface marker CD44. Among six gastric cancer cell lines, three lines MKN-45, MKN-74, and NCI-N87 had a sizeable subpopulation of CD44(+) cells, and these cells showed spheroid colony formation in serum-free media in vitro as well as tumorigenic ability when injected into stomach and skin of severe combined immunodeficient (SCID) mice in vivo. The CD44(+) gastric cancer cells showed the stem cell properties of self-renewal and the ability to form differentiated progeny and gave rise to CD44(−) cells. CD44 knockdown by short hairpin RNA resulted in much reduced spheroid colony formation and smaller tumor production in SCID mice, and the CD44(−) populations had significantly reduced tumorigenic ability in vitro and in vivo. Other potential CSC markers, such as CD24, CD133, CD166, stage-specific embryonic antigen-1 (SSEA-1), and SSEA-4, or sorting for side population did not show any correlation with tumorigenicity in vitro or in vivo. The CD44(+) gastric cancer cells showed increased resistance for chemotherapy- or radiation-induced cell death. These results support the existence of gastric CSCs and may provide novel approaches to the diagnosis and treatment of gastric cancer. Stem Cells 2009;27:1006–1020

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