Zhang ZY, Zhou M, Liu JJ, Zhang W. Folate receptor-positive circulating tumor cells might function as potential biomarkers for hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17(11): 113431 [DOI: 10.4251/wjgo.v17.i11.113431]
Corresponding Author of This Article
Wei Zhang, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan 430030, Hubei Province, China. weizhangtjh@hust.edu.cn
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Oncology
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Retrospective Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Nov 15, 2025 (publication date) through Nov 13, 2025
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World Journal of Gastrointestinal Oncology
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1948-5204
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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
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Zhang ZY, Zhou M, Liu JJ, Zhang W. Folate receptor-positive circulating tumor cells might function as potential biomarkers for hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17(11): 113431 [DOI: 10.4251/wjgo.v17.i11.113431]
World J Gastrointest Oncol. Nov 15, 2025; 17(11): 113431 Published online Nov 15, 2025. doi: 10.4251/wjgo.v17.i11.113431
Folate receptor-positive circulating tumor cells might function as potential biomarkers for hepatocellular carcinoma
Zun-Yi Zhang, Mi Zhou, Jun-Jie Liu, Wei Zhang
Zun-Yi Zhang, Jun-Jie Liu, Wei Zhang, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Mi Zhou, Department of Nursing, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
Co-first authors: Zun-Yi Zhang and Mi Zhou.
Author contributions: Zhang ZY performed the majority of the writing and prepared the table; Zhou M prepared the figure; Liu JJ and Zhang W designed the outline of this paper; Zhang ZY and Zhou M contributed equally to this manuscript and are co-first authors. All author approval the final manuscript.
Institutional review board statement: The studies involving human participants were reviewed and approved by the Ethics Committee of Tongji Hospital (Approval No. TJ-IRB202502081). All procedures were performed in accordance with the guidelines of the Declaration of Helsinki.
Informed consent statement: This was a retrospective study and was approved by the Ethics Committee of Tongji Hospital. Written informed consent was not obtained from the participants in this study.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: All the data generated or analyzed during this study are included in this published article.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei Zhang, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Road, Wuhan 430030, Hubei Province, China. weizhangtjh@hust.edu.cn
Received: August 26, 2025 Revised: September 14, 2025 Accepted: October 21, 2025 Published online: November 15, 2025 Processing time: 80 Days and 20.9 Hours
Abstract
BACKGROUND
Early metastasis and recurrence are risk factors that negatively affect the prognosis of advanced hepatocellular carcinoma (HCC). Alpha fetoprotein (AFP) is currently the most prevalent serum biomarker for detecting HCC and predicting tumor recurrence. However, its sensitivity and specificity are not sufficient, especially in patients who are AFP negative.
AIM
To detect folate receptor (FR)-positive circulating tumor cells (CTCs) and explore their role in the diagnosis and staging of HCC.
METHODS
This work is a retrospective study that included 128 consecutive patients with benign or malignant disease of the liver from 2020 to 2021. FR + CTCs were collected from 3 mL of peripheral blood via immunomagnetic depletion of leukocytes. After ligand-target polymerase chain reaction, the number of FR + CTCs was measured. Receiver operating characteristic curves were used to determine the threshold of sensitivity and specificity of FR + CTCs. The Youden index was used to identify the optimal cutoff point and diagnostic efficiency of FR + CTCs counts. Univariate and multivariate Cox proportional hazards regression analyses were performed to evaluate the associations of biomarkers or clinical parameters with disease-free survival (DFS).
RESULTS
The FR + CTCs counts showed excellent diagnostic efficacy in patients with HCC, with high sensitivity (0.905) and specificity (0.773) compared with patients with benign disease. Compared with that of the AFP level, the area under the receiver operating characteristic curve of the FR + CTC count is significantly greater (0.900 compared with 0.730, P < 0.05). FR + CTC levels were significantly correlated with macrovascular invasion, tumor size, tumor number, and extrahepatic tumor stage in HCC patients. FR + CTC counts were correlated with DFS in HCC patients after R0 resection. Univariate analysis of DFS revealed that the FR + CTC count, tumor number, Barcelona Clinic Liver Cancer stage and extrahepatic metastasis status were correlated with DFS. Multivariate analysis of DFS revealed that the FR + CTC count and tumor number were correlated with DFS.
CONCLUSION
Ligand-target polymerase chain reaction is a sensitive tool for quantifying the number of FR + CTCs in HCC patients. These findings could provide new insight for stratifying HCC patients and predicting the recurrence of HCC.
Core Tip: Ligand-target polymerase chain reaction is a sensitive tool for quantifying folate receptor (FR)-positive circulating tumor cells (CTCs) in hepatocellular carcinoma (HCC) patients. FR + CTCs counts were correlated with macrovascular invasion, tumor size, tumor number, extrahepatic tumor stage and disease-free survival time after surgery in HCC patients. These findings could provide new insights for stratifying HCC patients and predicting the recurrence of HCC by quantifying FR + CTCs.
