Clinical and Molecular Hepatology

"Vascular endothelial growth factor"

Special topic: Alcoholic liver diseases
The 14th International Symposium on Alcoholic Liver and Pancreatic Diseases and Cirrhosis (ISALPDC)

Alcohol-related liver disease

The lymphatic system in alcohol-associated liver disease: Reiichiro Kondo, Yasuko Iwakiri; Clin Mol Hepatol 2020;26(4):633-638.
Published online September 21, 2020; DOI: https://doi.org/10.3350/cmh.2020.0179

Abstract
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The lymphatic system plays vital roles in interstitial fluid balance and immune cell surveillance. The effect of alcohol on the lymphatic system is poorly understood. This review article explores the role of the lymphatic system in the pathogenesis of alcohol-related disease including alcoholic liver disease (ALD) and the therapeutic potential of targeting hepatic lymphatics for the treatment of ALD.

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Journal of Personalized Medicine.2022; 12(7): 1086. CrossRef

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Original Articles

Cyclooxygenase-2 and vascular endothelial growth factor in chronic hepatitis, cirrhosis and hepatocellular carcinoma: Soon Ha Kwon, Soung Won Jeong, Jae Young Jang, Ji Eun Lee, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Young Deok Cho, Hong Soo Kim, Boo Sung Kim, So-Young Jin; Korean J Hepatol 2012;18(3):287-294.
Published online September 25, 2012; DOI: https://doi.org/10.3350/cmh.2012.18.3.287

Abstract
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Background/Aims

Cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) are up-regulated in hepatocellular carcinoma (HCC). To investigate the levels of COX-2 and VEGF expression in chronic hepatitis (CH), cirrhosis, and HCC.

Methods

The immunohistochemical expressions of COX-2 and VEGF were evaluated in tissues from patients with CH (n=95), cirrhosis (n=38), low-grade HCC (LG-HCC; n=6), and high-grade HCC (HG-HCC; n=29).

Results

The COX-2 expression scores in CH, cirrhosis, LG-HCC, and HG-HCC were 3.3±1.9 (mean±SD), 4.2±1.7, 5.5±1.0, and 3.4±2.4, respectively (CH vs. cirrhosis, P=0.016; CH vs. LG-HCC, P=0.008; LG-HCC vs. HG-HCC, P=0.004), and the corresponding VEGF expression scores were 0.9±0.8, 1.5±0.7, 1.8±0.9, and 1.6±1.1 (CH vs. cirrhosis, P<0.001; CH vs. LG-HCC, P=0.011; LG-HCC vs. HG-HCC, P=0.075). Both factors were correlated with the fibrosis stage in CH and cirrhosis (COX-2: r=0.427, P<0.001; VEGF: r=0.491, P<0.001). There was a significant correlation between COX-2 and VEGF in all of the tissue samples (r=0.648, P<0.001), and between high COX-2 and VEGF expression scores and survival (COX-2: P=0.001; VEGF: P<0.001).

Conclusions

The expressions of both COX-2 and VEGF are significantly higher in cirrhosis and LG-HCC than in CH. High COX-2 and high VEGF expressions are associated with a high survival rate.

Citations

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Intercellular crosstalk of liver sinusoidal endothelial cells in liver fibrosis, cirrhosis and hepatocellular carcinoma
Hui Li
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Altered expression of COX-2 and TNF-a in patients with hepatocellular carcinoma
Andressa de-Freitas-Alves, Vanessa Dido-Baldissera, Eduardo Cremonese-Filippi-Chiela, Carlos Thadeu Schmidt-Cerski, Paulo Roberto Ott-Fontes, Marilda da-Cruz-Fernandes, Marilene Porawski, Márcia Giovenardi
Revista Española de Enfermedades Digestivas.2019;[Epub] CrossRef
HBx combined with AFB1 triggers hepatic steatosis via COX‐2‐mediated necrosome formation and mitochondrial dynamics disorder
Yuan‐Yuan Chen, Yi Lin, Pei‐Yu Han, Shan Jiang, Lin Che, Cheng‐Yong He, Yu‐Chun Lin, Zhong‐Ning Lin
Journal of Cellular and Molecular Medicine.2019; 23(9): 5920. CrossRef
Fluorescence imaging of hepatocellular carcinoma with a specific probe of COX-2
Haibo Wang, Chengyong Dong, Keqiu Jiang, Shuangzhe Zhang, Fei Long, Rixin Zhang, Deguang Sun, Rui Liang, Zhenming Gao, Shujuan Shao, Liming Wang
RSC Advances.2018; 8(2): 994. CrossRef
Hepatic sinusoids in liver injury, inflammation, and fibrosis: new pathophysiological insights
Thomas Greuter, Vijay H. Shah
Journal of Gastroenterology.2016; 51(6): 511. CrossRef
Immunohistochemical angiogenic biomarkers in hepatocellular carcinoma and cirrhosis: correlation with pathological features
Osmar Damasceno Ribeiro, Nathalie Henriques Silva Canedo, Vera Lucia Pannain
Clinics.2016; 71(11): 639. CrossRef
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Laurie D. DeLeve
Hepatology.2015; 61(5): 1740. CrossRef
Constitutive activation of AMPK α1 in vascular endothelium promotes high‐fat diet‐induced fatty liver injury: role of COX‐2 induction
Yan Liang, Bosheng Huang, Erfei Song, Bo Bai, Yu Wang
British Journal of Pharmacology.2014; 171(2): 498. CrossRef
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Hong-Jhang Chen, Shih-Pei Kang, I-Jung Lee, Yun-Lian Lin
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Meloxicam Executes Its Antitumor Effects against Hepatocellular Carcinoma in COX-2- Dependent and -Independent Pathways
Xiaofeng Dong, Rui Li, Peng Xiu, Xuesong Dong, Zongzhen Xu, Bo Zhai, Feng Liu, Hongchi Jiang, Xueying Sun, Jie Li, Haiquan Qiao, Diego Calvisi
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Epithelial VEGF signaling is required in the mouse liver for proper sinusoid endothelial cell identity and hepatocyte zonation in vivo
Teagan J. Walter, Ashley E. Cast, Kari A. Huppert, Stacey S. Huppert
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Expression of vascular endothelial growth factor (VEGF) family members and prognosis after hepatic resection in HBV-related hepatocellular carcinoma: Ju Ik Moon, M.D., Jong Man Kim, M.D., Gum Oh Jung, M.D., Jae Min Chun, M.D., Gyu-Seong Choi, M.D., Jae Berm Park, M.D., Choon Hyuck David Kwon, M.D., Sung Joo Kim, M.D., Jae Won Jo, M.D.,; Korean J Hepatol 2008;14(2):185-196.
Published online June 20, 2008; DOI: https://doi.org/10.3350/kjhep.2008.14.2.185

Abstract
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Background/Aims
Human hepatocellular carcinoma (HCC) is a hypervascular tumor, and vascular endothelial growth factor (VEGF) plays a key role in the regulation of tumor-associated angiogenesis. In this study, we analyzed the significance of the expression of VEGF family members on the prognosis and clinicopathologic progress of HCC. Methods: Surgically resected specimens of HCC and noncancerous liver tissue were obtained from 323 patients with HCC, and VEGF mRNA was examined by quantitative reverse transcriptase-polymerase chain reactions (RT-PCRs). Patients who were seropositive for hepatitis B surface antigen were selected for the analysis (n=208). The VEGF_tumor/GAPDH (glyceraldehyde-3-phosphate dehydrogenase) _tumor/VEGF_nontumor/GAPDH_nontumor ratio was calculated using a quantitative RT-PCR assay, and the relationships between the expressions of VEGF family members and clinicopathologic parameters were analyzed to evaluate their significance in the prognosis of HCC. Results: The disease-free survival was significantly worse in the high-VEGF-A group than in the low-VEGF-A group (P=0.035), whereas VEGF-A expression was not significantly related to overall survival (P=0.172). The factors significantly related to poor prognosis in univariate analysis were tumor size, portal vein invasion, microvascular thrombi, intrahepatic metastasis, tumor capsule invasion, liver capsule invasion, preoperative serum albumin level, and VEGF-A ratio. Multivariate analysis showed that a poor prognosis in HCC patients was significantly related to portal vein invasion (hazard ratio=3.381, P<0.001), intrahepatic metastasis (hazard ratio=2.379, P<0.001), tumor size (hazard ratio=1.834, P=0.003), and preoperative serum albumin level (hazard ratio=2.050, P=0.006). Conclusions: Our study showed that the expression of VEGF-A is positively correlated with the recurrence rate of HCC after curative resection. Therefore, a high expression of VEGF-A might be predictive of HCC recurrence after curative resection. (Korean J Hepatol 2008;14:185-196)

Citations

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The tumor microenvironment in the postsurgical liver: Mechanisms and potential targets of postoperative recurrence in human hepatocellular carcinoma
Junyu Wu, Yau‐Tuen Chan, Yuanjun Lu, Ning Wang, Yibin Feng
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Woodchuck VEGF (wVEGF) characteristics: Model for angiogenesis and human hepatocellular carcinoma directed therapies
Huayi Huang, Oreste Salavaggione, Lee Rivera, Sarbajit Mukherjee, Rolf Brekken, Bud Tennant, Renuka Iyer, Araba Adjei
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Pengyuan Yang, Geoffrey J. Markowitz, Xiao-Fan Wang
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Andrew X. Zhu, Dan G. Duda, Dushyant V. Sahani, Rakesh K. Jain
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The Role of Angiostatin, Vascular Endothelial Growth Factor, Matrix Metalloproteinase 9 and 12 in the Angiogenesis of Hepatocellular Carcinoma: Sook Kim, M.D.1, Ho Sung Park, M.D., Hyun Jin Son, M.D. and Woo Sung Moon, M.D.; Korean J Hepatol 2004;10(1):62-72.

Abstract
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Background/Aims
Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. Hepatocellular carcinoma (HCC) has become a common malignant tumor worldwide. It is characterized by a high vascularity. Methods: We studied the immunohistochemical expression of angiostatin, vascular endothelial cell growth factor (VEGF), matrix metalloproteinase (MMP)-9 and MMP-12, and the relationship between these results and the microvessel density (MVD) in 48 HCC specimens. To determine whether HCC cells express angiostatin per se, we examined the expression of angiostatin, MMP-9 and MMP-12 by Western blotting in four HCC cell lines.
Results
Expression of angiostatin and MMP-12 (but not MMP-9) were strongly correlated with decreased MVD in HCCs (P=0.006, P=0.038, respectively). VEGF positive tumors showed a significantly higher MVD than VEGF negative tumors (P=0.01). We divided the 48 cases into the following four groups: group A, angiostatin (+), MMP-9 or -12 (+), and VEGF (-); group B, angiostatin (-) and VEGF (-); group C, angiostatin (+), MMP-9 or -12 (+), and VEGF (+); group D, angiostatin (-) and VEGF (+). There was a significant correlation with MVD among these groups (P<0.001). Angiostatin was detected by Western blotting in 2 out of 4 HCC cell lines and was associated with plasminogen and MMP expression.
Conclusions
These results indicate that angiogenesis in HCC is a complex process involving multiple factors including angiostatin, VEGF, and MMP. Our results suggest that angiostatin is generated by MMP-mediated proteolysis of plasminogen in HCC cells.(Korean J Hepatol 2004;10:62-72)