Circulating stem cell–like epithelial cell adhesion... : Hepatology (original) (raw)

Hepatobiliary Malignancies

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

Sun, Yun-Fan1; Xu, Yang1; Yang, Xin-Rong1; Guo, Wei1,2; Zhang, Xin1; Qiu, Shuang-Jian1; Shi, Ruo-Yu1; Hu, Bo1; Zhou, Jian1,3,*; Fan, Jia1,3,*

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_

3_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

Email:[email protected]

Received 12 March 2012; Accepted 27 October 2012

View this article online atwileyonlinelibrary.com.

Grant sponsor: Major Program of National Natural Science Foundation of China; Grant Number: 81030038; Grant sponsor: National Key Sci-Tech Project; Grant Numbers: 2012ZX10002011-002 2013ZX10002011-004 2012ZX0930100-007 2012ZX10002-016; Grant sponsor: National Natural Science Foundation of China; Grant Numbers: 81000927 81071661 81172277 30972949; Grant sponsor: Research Fund for the Doctoral Program of Higher Education of China; Grant Number: 20100071120064; Grant sponsor: Shanghai New Project for Excellent Youth; Grant Number: XYQ2011020; Grant sponsor: National Science Foundation for Distinguished Young Scholars of China; Grant Number: 81225019; Grant sponsor: Shanghai Rising-Star Follow-up Program Fundings; Grant Number: 10QH1400500.

Potential conflict of interest: Nothing to report.

These authors contributed equally to this work.

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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.