Vascular Endothelial Growth Factor Level as A Predictor of Hepatocellular Carcinoma in Liver Cirrhosis Patients

Benyamin Lukito, Ivet Suriapranata, Pendrianto Pendrianto, Ali Sulaiman, Irawan Yusuf, FX Budhianto Suhadi, George Mathew, Ferry Sandra

Abstract


BACKGROUND: Alpha-fetoprotein (AFP) has been used for hepatocellular carcinoma (HCC) diagnosis and screening, however, AFP has poor specificity. The extensive hypervascularity associated with HCC could be driven in part by the pro-angiogenic factor known as vascular endothelial growth factor (VEGF). Furthermore, invasiveness of certain HCC lesions has recently been linked to high levels of VEGF. Therefore, circulating VEGF levels of patients with liver cirrhosis (LC) and HCC were investigated and analysed.

METHODS: An analytical cross sectional study was designed. Diagnosis of HCC and LC was performed using clinical criteria and findings obtained from B-mode ultrasonography (USG), computed tomography (CT) angiography, or magnetic resonance imaging (MRI). Blood were collected intravenously from all subjects. Obtained serum and plasma were stored in -80°C for following analyses: hepatitis B surface antigen (HBSAg), hepatitis C virus (HCV), alanine aminotransferase (ALT), total bilirubin, albumin, VEGF and AFP.

RESULTS: Levels of VEGF and AFP were significantly higher in HCC group compared with LC group with p = 3.05 x 10-6 and p = 8.74 x 10-5, respectively. There was a significant positive correlation (p=0.029, r=0.309) between VEGF level and tumor size in HCC group. The area under curve (AUC) for VEGF level in HCC and LC groups was 0.771. In the level of median 435.6 pg/mL VEGF, the sensitivity was 50% and specificity was 86%. In the level of 199.99 pg/mL VEGF the sensitivity was 74% and specificity was 76%.

CONCLUSION: The present findings suggested that VEGF level could be a useful marker for the presence of HCC in patients with LC.

KEYWORDS: hepatocellular carcinoma, HCC, liver cirrhosis, LC, vascular endothelial growth factor, VEGF, alpha-fetoprotein, AFP

 


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References


Sun HC, Tang ZY. Angiogenesis in hepatocellular carcinoma: The retrospectives and perspectives. J Cancer Res Clin Oncol. 2004; 130: 307-19, CrossRef.

Abelev GI. Production of embryonal serum alpha-globulin by hepatomas: review of experimental and clinical data. Cancer Res.1968; 28: 1344-50, PMID.

O’Conor GT, Tatarinov YS, Abelev GI, Uriel J. A collaborative study for the evaluation of a serologic test for primary liver cancer. Cancer. 1970; 25: 1091-8, CrossRef.

Di Bisceglie AM, Sterling RK, Chung RT, Everhart JE, Dienstag JL, Bonkovsky HL, et al. Serum alpha-fetoprotein levels in patients with advanced hepatitis C: results from the HALT-C Trial. J Hepatol. 2005; 43: 434-41, CrossRef.

Ezaki T, Yukaya H, Ogawa Y, Chang YC, Nagasue N. Elevation of alpha-fetoprotein level without evidence of recurrence after hepatectomy for hepatocellular carcinoma. Cancer. 1988; 61: 1880-3, CrossRef.

Pang R, Poon RT. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett. 2006; 242: 151-67, CrossRef.

Li XM, Tang ZY, Zhou G, Lui YK, Ye SL. Significance of vascular endothelial growth factor mRNA expression in invasion and metastasis of hepatocellular carcinoma. J Exp Clin Cancer Res. 1998; 17: 13-7, PMID.

Kanda M, Nomoto S, Nishikawa Y, Sugimoto H, Kanazumi N, Takeda S, et al. Correlations of the expression of vascular endothelial growth factor B and its isoforms in hepatocellular carcinoma with clinico-pathological parameters. J Surg Oncol. 2008; 98: 190-6, CrossRef.

Zhao J, Hu J, Cai J, Yang X, Yang Z. Vascular endothelial growth factor expression in serum of patients with hepatocellular carcinoma. Chin Med J. 2003; 1 16: 772-6, PMID.

Ferroni P, Spila A, D’Alessandro R, Martini F, Iacovone F, Ettorre GM, et al. Platelet activation and vascular endothelial growth factor 165 release in hepatocellular cancer. Clin Chim Acta. 2011; 412: 450-4, CrossRef.

Poon RT, Lau CPY, Cheung ST, Yu WC, Fan ST. Quantitative correlation of serum levels and tumor expression of vascular endothelial growth factor in patients with hepatocellular carcinoma. Cancer Res. 2003; 63: 3121-6, PMID.

Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist. 2004; 9 (Suppl 1): 2-10, CrossRef.

Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J. 1999; 18: 3964-72, CrossRef.

Assy N, Paizi M, Gaitini D, Boruch Y, Spira G. Clinical implication of VEGF serum levels in cirrhotic patients with or without portal hypertension. World J Gastroenterol. 1999; 5: 296-300, PMID.

Desideri G, Ferri C. Circulating vascular endothelial growth factor levels are decreased in patients with chronic hepatitis and liver cirrhosis depending on the degree of hepatic damage. Clin Sci. 2000; 99: 159-160, CrossRef.

Ishikawa K, Mochida S, Mashiba S, Inao M, Matsui A, Ikeda H, et al. Expression of vascular endothelial growth factor in non parenchymal as parenchymal cells in rat liver after necrosis. Biochem Biophys Res Commun. 1999; 254: 587-93, CrossRef.

Coulon S, Heindryckx F, Geerts A, Van Steenkiste C, Colle I, Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int. 2011; 31: 146-62, CrossRef.

Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, et al. Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic ibrogenesis. Gut. 2003; 52: 1347-54, CrossRef.

Chen JA, Shi M, Li JQ, Qian CN. Angiogenesis: multiple masks in hepatocellular carcinoma and liver regeneration. Hepatol Int. 2010; 29; 4: 537-47, CrossRef.

Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, et al. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: signiicance for VEGF measurements and cancer biology. Br J Cancer. 1998; 77: 956-64, CrossRef.

Webb NJ, Bottomley MJ, Watson CJ, Brenchley PE. Vascular endothelial growth factor (VEGF) is released from platelets during blood clotting: implications for measurement of circulating VEGF levels in clinical disease. Clin Sci. 1998; 94: 395-404, CrossRef.

Alkozai EM, Porte RJ, Adelmeijer J, Zanetto A, Simioni P, Senzolo M, et al. Levels of angiogenic proteins in plasma and platelets are not different between patients with hepatitis B/C related cirrhosis and patients with cirrhosis and hepatocellular carcinoma. Platelet. 2015; 26: 577-82, CrossRef.

Jinno K, Tanimizu M, Hyodo I, Nishikawa Y, Hosokawa Y, Doi T, et al. Circulating vascular endothelial growth factor (VEGF) is a possible tumor marker for metastasis in human hepatocellular carcinoma. J Gastroenterol. 1998; 33: 376-82, CrossRef.

Li XM, Tang ZY, Qin LX, Zhou J, Sun HC. Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res. 1999; 18: 511-7, PMID.

Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM, et al. Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg. 2001; 233: 227-35, CrossRef.

Chao Y, Li CP, Chau GY, Chen CP, King KL, Lui WY, et al. Prognostic signiicance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol. 2003; 10: 355-62, CrossRef.

Schoenleber SJ, Kurtz DM, Talwalkar JA, Roberts LR, Gores GJ.Prognostic role of vascular endothelial growth factor in hepatocellular carcinoma: systematic review and meta-analysis. Br J Cancer. 2009; 100, 1385-92, CrossRef.

El-Assal ON, Yamanoi A, Soda Y, Yamaguchi M, Igarashi M, Yamamoto A, et al. Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology.1998; 27: 1554-62, CrossRef.

Plate KH, Breier G, Weich HA, Risau W. Vascular endotherial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 1992; 359: 845-8, CrossRef.

Brown LF, Berse B, Tognazzi K, Manseau EJ, Van de Water L, Senger DR, et al. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int. 1992; 42: 1457-61, CrossRef.

Mise M, Arii S, Higashituji H, Furutani M, Niwano M, Harada T, et al. Clinical significance of vascular endothelial growth factor and basic ibroblast growth factor gene expression in liver tumor. Hepatology. 1996; 23: 455-64, CrossRef.

von Marschall Z, Cramer T, Höcker M, Finkenzeller G, Wiedenmann B, Rosewicz S. Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut. 2001; 48: 87-96, CrossRef.

Harris AL. Hypoxia - A key regulatory factor in tumor growth. Nat Rev Cancer. 2002; 2: 38-47, CrossRef.

Zhao J, Hu J, Cai J, Yang X, Yang Z. Vascular endothelial growth factor expression in serum of patients with hepatocellular carcinoma. Chin Med J. 2003; 1 16: 772-6, PMID.

Kamel L, Nessim I, Abd-el-Hady A, Ghali A, Ismail A. Assessment of the clinical significance of serum vascular endothelial growth factor and matrix metalloproteinase-9 in patients with hepatocellular carcinoma. J Egypt Soc Parasitol. 2005; 35: 875-90, PMID.

Rosmorduc O, Housset C. Hypoxia: A link between fibrogenesis, angiogenesis, and carcinogenesis in liver disease. Semin Liver Dis. 2010; 30: 258-70, CrossRef.

Li Q, Xu B, Fu L, Hao XS. Correlation of four vascular specific growth factors with carcinogenesis and portal vein tumor thrombus formation in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2006; 25: 403-9, PMID.

Coulon S, Heindryckx F, Geerts A, Van Steenkiste C, Colle I, Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int. 2011; 31: 146-162, CrossRef.

Jeng KS, Sheen IS, Wang YC, Gu SL, Chu CM, Shih SC, et al. Prognostic significance of preoperative circulating vascular endothelial growth factor mRNA expression in resectable hepatocellular carcinoma: A prospective study. World J Gastroenterol. 2004; 10: 643-8, CrossRef.

Yeh SH, Chen PJ, Lai MY, Chen DS. Allelic loss on chromosomes 4q and 16q in hepatocellular carcinoma: association with elevated alpha-fetoprotein production. Gastroenterology. 1996; 110: 184-92, CrossRef.

Noda K, Miyoshi E, Gu J, Gao CX, Nakahara S, Kitada T, et al. Relationship between elevated FX expression and increased production of GDP-L-fucose, a common donor substrate for fucosylation in human hepatocellular carcinoma and hepatoma cell lines. Cancer Res. 2003; 63: 6282-9, PMID.

Murata K, Sakamoto A. Impairment of clathrin-mediated endocytosis via cytoskeletal change by epithelial to fibroblastoid conversion in HepG2 cells: A possible mechanism of des-γ-carboxy prothrombin production in hepatocellular carcinoma. Int J Oncol. 2008; 33: 1149-55, CrossRef.

Murata K, Suzuki H, Okano H, Oyamada T, Yasuda Y, Sakamoto A. Cytoskeletal changes during epithelial-toibroblastoid conversion as a crucial mechanism of des-γ- carboxy prothrombin production in hepatocellular carcinoma. Int J Oncol. 2009; 35: 1005-14, CrossRef.

Mizuta T, Ozaki I, Eguchi Y, Yasutake T, Kawazoe S, Fujimoto K, et al. The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study. Cancer. 2006; 106: 867-72, CrossRef.

Kim KA, Lee JS, Jung ES, Kim JY, Bae WK, Kim NH, et al. Usefulness of serum alpha-fetoprotein (AFP) as a marker for hepatocellular carcinoma (HCC) in hepatitis C virus related cirrhosis: analysis of the factors inluencing AFP elevation without HCC development. Korean J Gastroenterol. 2006; 48: 321-6, PMID.




DOI: https://doi.org/10.18585/inabj.v6i3.30

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