Circulating stem cell–like epithelial cell adhesion molecule–positive tumor cells indicate poor prognosis of hepatocellular carcinoma after curative resection

Authors

  • Yun-Fan Sun,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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    • These authors contributed equally to this work.

  • Yang Xu,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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    • These authors contributed equally to this work.

  • Xin-Rong Yang,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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    • These authors contributed equally to this work.

  • Wei Guo,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
    2. Department of Laboratory Medicine, Zhongshan Hospital, Fudan University
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  • Xin Zhang,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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  • Shuang-Jian Qiu,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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  • Ruo-Yu Shi,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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  • Bo Hu,

    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
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  • Jian Zhou,

    Corresponding author
    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
    2. Institute of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
    • Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, People's Republic of China===

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    • fax: (86)-21-64037181

  • Jia Fan

    Corresponding author
    1. Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P. R. China
    2. Institute of Biomedical Sciences, Fudan University, Shanghai 200032, P. R. China
    • Liver Cancer Institute, Zhongshan Hospital, Fudan University, 136 Yi Xue Yuan Road, Shanghai 200032, People's Republic of China===

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    • fax: (86)-21-64037181


  • Potential conflict of interest: Nothing to report.

Abstract

Epithelial cell adhesion molecule–positive (EpCAM+) hepatocellular carcinoma (HCC) cells may constitute a tumor-initiating subpopulation in tumorigenic cell lines and HCC specimens. In the present study, EpCAM+ circulating tumor cells (CTCs) were identified prospectively in HCC patients undergoing curative resection, and the prognostic significance and their stem cell–like characteristics were investigated further. Blood samples from 123 HCC patients were tested prior to resection and 1 month thereafter. CTCs were present in 66.67% of patients, and the cell count measured in 7.5 mL of blood (CTC7.5) ranged between 1 and 34. Fifty-one patients had CTC7.5 of ≥2 preoperatively, and these patients developed tumor recurrence earlier than those with CTC7.5 of <2 CTCs (P < 0.001). A preoperative CTC7.5 of ≥2 was an independent prognostic factor for tumor recurrence (P < 0.001). Its prognostic significance also applied to patients with alpha-fetoprotein (AFP) levels of ≤400 ng/mL or subgroups with low recurrence risk (all P < 0.05). A significant decrease of CTC-positive rates (66.67% to 28.15%, P < 0.05) and CTC7.5 values (2.60 ± 0.43 to 1.00 ± 0.36, P < 0.05) was observed 1 month after resection. Patients with consistent CTC7.5 <2 had lower recurrence rates than those with values consistently ≥2 (15.5% versus 87.50%, P < 0.001). EpCAM+ CTCs displayed cancer stem cell biomarkers (CD133 and ABCG2), epithelial-mesenchymal transition, Wnt pathway activation, high tumorigenic potential, and low apoptotic propensity. Conclusion: Stem cell–like phenotypes are observed in EpCAM+ CTCs, and a preoperative CTC7.5 of ≥2 is a novel predictor for tumor recurrence in HCC patients after surgery, especially in patient subgroups with AFP levels of ≤400 ng/mL or low tumor recurrence risk. EpCAM+ CTCs may serve as a real-time parameter for monitoring treatment response and a therapeutic target in HCC recurrence. (HEPATOLOGY 2013)

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