Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 21, 2021; 27(27): 4453-4467
Published online Jul 21, 2021. doi: 10.3748/wjg.v27.i27.4453
Prognostic role of plasma level of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor in hepatocellular carcinoma
Gwang Hyeon Choi, Eun Sun Jang, Jin-Wook Kim, Sook-Hyang Jeong
Gwang Hyeon Choi, Eun Sun Jang, Jin-Wook Kim, Sook-Hyang Jeong, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, South Korea
Author contributions: Choi GH, and Jeong SH were responsible for the study concept and design, data acquisition, analysis, and interpretation, statistical analysis, and manuscript drafting; Jang ES and Kim JW assisted in data acquisition, analysis, and interpretation.
Supported by Seoul National University Bundang Hospital Research Fund, No. 02-2019-037.
Institutional review board statement: This study approval by the Institutional Review Board (IRB) of the SNUBH, No. B-1201/143-002.
Informed consent statement: Written informed consent was obtained from each HCC patient after approval by the Institutional Review Board (IRB) of the SNUBH, No. B-1201/143-002.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Data sharing statement: We regret, but we are not willing to share data.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Sook-Hyang Jeong, PhD, Professor, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173 beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, Seongnam 13620, South Korea. jsh@snubh.org
Received: February 21, 2021
Peer-review started: February 21, 2021
First decision: May 13, 2021
Revised: May 16, 2021
Accepted: July 7, 2021
Article in press: July 7, 2021
Published online: July 21, 2021
Processing time: 148 Days and 12.1 Hours
Abstract
BACKGROUND

Most hepatocellular carcinomas (HCCs) are hypervascular, with characteristic features of hepatic arterial supply to the tumor. The factors involved in tumor angiogenesis include angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), and vascular endothelial growth factor (VEGF).

AIM

To investigate the profiles of plasma levels of angiogenesis markers in patients with HCC and evaluate their roles in predicting overall survival (OS) and progression-free survival (PFS).

METHODS

Plasma samples from 240 prospectively enrolled HCC patients in the very early to advanced stages were used to measure the levels of Ang-1, Ang-2, and VEGF. Their associations with clinical characteristics, OS, and PFS were analyzed.

RESULTS

The median plasma levels of Ang-1, Ang-2, and VEGF were 3216 pg/mL, 1684 pg/mL, and 26.5 pg/mL, respectively. The plasma level of Ang-2 showed a significant increase from early stage [Barcelona clinic liver cancer (BCLC) A] to intermediate (BCLC B) and advanced stage HCC (BCLC C/D), whereas Ang-1, VEGF, and alpha-fetoprotein (AFP) levels in the plasma did not show any such changes. Multivariable analysis, propensity score-matched analysis, and time-dependent receiver operating curve analysis revealed that Ang-2 levels had the highest predictive power for OS and PFS. Neither Ang-1 nor VEGF was significantly associated with OS or PFS. The neutrophil-to-lymphocyte ratio was an independent factor for OS and PFS.

CONCLUSION

The plasma levels of Ang-2 correlated with liver function, tumor stage, and tumor invasiveness, showing better performance in predicting OS and PFS than AFP, Ang-1, or VEGF.

Keywords: Hepatocellular carcinoma; Angiogenesis; Biomarker; Prognosis; Survival

Core Tip: Most hepatocellular carcinomas (HCCs) are hypervascular tumor, thus angiogenesis markers can be a potential biomarker. This study explored the potential of each plasma level of angiopoietin (Ang)-1, Ang-2, and vascular endothelial growth factor as a prognostic biomarker for very early to advanced stages of HCC via detailed analysis in comparison with alpha-fetoprotein. The plasma level of Ang-2 correlated with liver function, tumor stage, and tumor invasiveness. Multivariable and propensity score-matched analyses revealed Ang-2 levels with the highest predictive power for overall survival in patients with HCC.