World J Gastroenterol. 2021;27(27):4453-4467.

Prognostic role of plasma level of angiopoietin-1, angiopoietin-2, and vascular endothelial growth factor in hepatocellular carcinoma.

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제1저자 최광현 · 교신저자 정숙향

PMID 34366616 PMC8316901 DOI 10.3748/wjg.v27.i27.4453 IF 7.7 소화기내과

소속 (2)

Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, South Korea.
Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, South Korea. jsh@snubh.org.

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

AngiogenesisBiomarkerHepatocellular carcinomaPrognosisSurvival

Figures

**Figure 1** **Plasma levels of angiopoietin-1, angiopoietin-2, vascular endothelial growth factor, and alpha fetoprotein in the hepatocellular carcinoma patients according to tumor stage.**A: Angiopoietin-1; B: Angiopoietin-2; C: Vascular endothelial growth factor; D: Alpha-fetoprotein. AFP: Alpha-fetoprotein; Ang-1: Angiopoietin-1; Ang-2: Angiopoietin-2; BCLC: Barcelona clinic liver cancer; VEGF: Vascular endothelial growth factor.

**Figure 2** **Factors correlated with plasma level of angiopoietin-1, angiopoietin-2 and vascular endothelial growth factor in hepatocellular carcinomas patients with their interrelationship.**The heat map showing a red background indicates a positive correlation, the blue background indicates negative correlation, and the numbers in the box indicate rho (ρ). AFP: Alpha-fetoprotein; Ang-1: Angiopoietin-1; Ang-2: Angiopoietin-2; BCLC: Barcelona clinic liver cancer; BMI: Body mass index; MELD: Model for end stage liver disease; NLR: Neutrophil-lymphocyte ratio; PLR: Platelet-lymphocyte ratio; VEGF: Vascular endothelial growth factor.

**Figure 3** **Overall survival according to plasma angiogenesis marker level.**A: Angiopoietin-1; B: Angiopoietin-2; C: Vascular endothelial growth factor; D: Alpha-fetoprotein. AFP: Alpha-fetoprotein; Ang-1: Angiopoietin-1; Ang-2: Angiopoietin-2; VEGF: Vascular endothelial growth factor; HR: Hazard ratio; CI: Confidence interval.

**Figure 4** **Time-dependent receiver operating characteristic for survival at each time point.**AFP: Alpha-fetoprotein; Ang-1: Angiopoietin-1; Ang-2: Angiopoietin-2; VEGF: Vascular endothelial growth factor; ROC: Receiver operating characteristic; AUC: Area under the ROC curve.

**Figure 5** **Progression-free survival according to plasma angiogenesis marker level.**A: Angiopoietin-1; B: Angiopoietin-2; C: Vascular endothelial growth factor; D: Alpha-fetoprotein. AFP: Alpha-fetoprotein; Ang-1: Angiopoietin-1; Ang-2: Angiopoietin-2; VEGF: Vascular endothelial growth factor; HR: Hazard ratio; CI: Confidence interval.

그림 출처: PubMed Central 공개 논문 (PMC8316901)

Conflict of interest statement

Conflict-of-interest statement: The authors have no conflicts of interest to declare.

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