Abstract
Purpose
To evaluate the prognosis value of vascular endothelial growth factor (VEGF) and platelet-derived endothelial cell growth factor (PD-ECGF) in alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) patients after curative resection.
Methods
Tumor tissue microarrays (TMAs) were used to detect the expressions of VEGF and PD-ECGF in consecutive 162 AFP-negative HCC patients undergoing curative resection between 1997 and 2000 in our institute. Clinicopathologic data for these patients were evaluated. The prognostic significance was assessed using Kaplan–Meier survival estimates and log-rank tests. Multivariate study with Cox’s proportional hazard model was used to evaluate the prognosis-related aspects.
Results
The positive rates of VEGF and PD-ECGF in tumor tissues were 59.9% (97/162) and 62.3% (101/162), respectively. Univariate analysis showed that VEGF and PD-ECGF were prognostic factors for relapse-free survival (P = 0.034 and P = 0.033, respectively). Multivariate analyses demonstrated that the co-index (VEGF/PD-ECGF) was an independent prognostic factor for overall survival and relapse-free survival (P = 0.002 and P = 0.000, respectively).
Conclusion
The co-index of VEGF and PD-ECGF is a promising independent predictor for recurrence and survival of AFP-negative HCC patients after curative resection.
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Abbreviations
- HCC:
-
Hepatocellular carcinoma
- AFP:
-
Alpha-fetoprotein
- HBV:
-
Hepatitis B virus
- HCV-Ab:
-
Hepatitis C virus antibody
- VEGF:
-
Vascular endothelial growth factor
- PD-ECGF:
-
Platelet-derived endothelial cell growth factor
- TMAs:
-
Tissue microarrays
- TNM:
-
Tumor-node metastasis
- TACE:
-
Transcatheter arterial chemoembolization
- OS:
-
Overall survival
- RFS:
-
Relapse-free survival
References
Abou-Alfa GK, Schwartz L, Ricci S et al (2006) Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol 24:4293–4300. doi:10.1200/JCO.2005.01.3441
Baron RL, Brancatelli G (2004) Computed tomographic imaging of hepatocellular carcinoma. Gastroenterology 127:S133–S143. doi:10.1053/j.gastro.2004.09.027
Berse B, Brown LF, Van de Water L et al (1992) Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell 3:211–220
Bosch FX, Ribes J, Cleries R et al (2005) Epidemiology of hepatocellular carcinoma. Clin Liver Dis 9:191–211. doi:10.1016/j.cld.2004.12.009
Chao Y, Li CP, Chau GY et al (2003) Prognostic significance of vascular endothelial growth factor, basic fibroblast growth factor, and angiogenin in patients with resectable hepatocellular carcinoma after surgery. Ann Surg Oncol 10:355–362. doi:10.1245/ASO.2003.10.002
Chen G, Lin W, Shen F et al (2006) Past HBV viral load as predictor of mortality and morbidity from HCC and chronic liver disease in a prospective study. Am J Gastroenterol 101:1797–1803. doi:10.1111/j.1572-0241.2006.00647.x
Daniele B, Bencivenga A, Megna AS et al (2004) Alpha-fetoprotein and ultrasonography screening for hepatocellular carcinoma. Gastroenterology 127:S108–S112. doi:10.1053/j.gastro.2004.09.023
Deli G, Jin CH, Mu R et al (2005) Immunohistochemical assessment of angiogenesis in hepatocellular carcinoma and surrounding cirrhotic liver tissues. World J Gastroenterol 11:960–963
Edmondson HA, Steiner PE (1954) Primary carcinoma of the liver: a study of 100 cases among 48, 900 necropsies. Cancer 7:462–503. doi:10.1002/1097-0142(195405)7:3<462::AID-CNCR2820070308>3.0.CO;2-E
Ferrara N (2001) Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol 280:C1358–C1366
Folkman J (2002) Role of angiogenesis in tumor growth and metastasis. Semin Oncol 29:15–18
Folkman J, Shing Y (1992) Angiogenesis. J Biol Chem 267:10931–10934
Guo L, Kuroda N, Toi M et al (2001) Increased expression of platelet-derived endothelial cell growth factor in human hepatocellular carcinomas correlated with high Edmondson grades and portal vein tumor thrombosis. Oncol Rep 8:871–876
Haraguchi M, Miyadera K, Uemura K et al (1994) Angiogenic activity of enzymes. Nature 368:198. doi:10.1038/368198a0
Hu L, Lau SH, Tzang CH et al (2004) Association of vimentin overexpression and hepatocellular carcinoma metastasis. Oncogene 23:298–302. doi:10.1038/sj.onc.1207150
Johnson PJ (2001) The role of serum alpha-fetoprotein estimation in the diagnosis and management of hepatocellular carcinoma. Clin Liver Dis 5:145–159. doi:10.1016/S1089-3261(05)70158-6
Li XM, Tang ZY, Qin LX et al (1999) Serum vascular endothelial growth factor is a predictor of invasion and metastasis in hepatocellular carcinoma. J Exp Clin Cancer Res 18:511–517
Li D, Mallory T, Satomura S (2001) AFP-L3: a new generation of tumor marker for hepatocellular carcinoma. Clin Chim Acta 313:15–19. doi:10.1016/S0009-8981(01)00644-1
Liu WC, Lim JH, Park CK et al (2003) Poor sensitivity of sonography in detection of hepatocellular carcinoma in advanced liver cirrhosis: accuracy of pretransplantation sonography in 118 patients. Eur Radiol 13:1693–1698. doi:10.1007/s00330-002-1814-3
Llovet JM, Ricci S, Mazzaferro V et al (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390. doi:10.1056/NEJMoa0708857
Mattern J, Koommagi R, Volm M (1999) Biological characterization of subgroups of squamous cell lung carcinomas. Clin Cancer Res 5:1459–1463
Ng IO, Poon RT, Lee JM et al (2001) Microvessel density, vascular endothelial growth factor and its receptors Flt-1and Flk-1/KDR in hepatocellular carcinoma. Am J Clin Pathol 116:838–845. doi:10.1309/FXNL-QTN1-94FH-AB3A
Nolte W, Hartmann H, Ramadori G et al (1995) Glucose metabolism and liver cirrhosis. Exp Clin Endocrinol Diabetes 103:63–74
Park JH, Koh KC, Choi MS et al (2006) Analysis of risk factors associated with early multinodular recurrences after hepatic resection for hepatocellular carcinoma. Am J Surg 192:29–33. doi:10.1016/j.amjsurg.2005.11.010
Peng SY, Chen WJ, Lai PL et al (2004) High alpha-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and beta-catenin mutations. Int J Cancer 112:44–50. doi:10.1002/ijc.20279
Poon RT, Ng IO, Lau C et al (2001) Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg 233:227–235. doi:10.1097/00000658-200102000-00012
Poon RT, Ho JW, Tong CS et al (2004) Prognostic significance of serum vascular endothelial growth factor and endostatin in patients with hepatocellular carcinoma. Br J Surg 91:1354–1360. doi:10.1002/bjs.4594
Schmitt M, Horbach A, Kubitz R et al (2004) Disruption of hepatocellular tight junctions by vascular endothelial growth factor (VEGF): a novel mechanism for tumor invasion. J Hepatol 41:274–283. doi:10.1016/j.jhep.2004.04.035
Shah SA, Cleary SP, Wei AC et al (2007) Recurrence after liver resection for hepatocellular carcinoma: risk factors, treatment, and outcomes. Surgery 141:330–339. doi:10.1016/j.surg.2006.06.028
Shiraki K, Takase K, Tameda Y et al (1995) A clinical study of lectin-reactive alpha-fetoprotein as an early indicator of hepatocellular carcinoma in the follow-up of cirrhotic patients. Hepatology 22:802–807
Taketa K, Endo Y, Sekiya C et al (1993) A collaborative study for the evaluation of lectinreactive alpha-fetoproteins in early detection of hepatocellular carcinoma. Cancer Res 53:5419–5423
Tang ZY, Ye SL, Liu YK et al (2004) A decade’s studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 130:187–196. doi:10.1007/s00432-003-0511-1
Toi M, Matsumoto T, Bando H et al (2001) Vascular endothelial growth factor: its prognostic, predictive, and therapeutic implications. Lancet Oncol 2:667–673. doi:10.1016/S1470-2045(01)00556-3
Tralhao JG, Dagher I, Lino T et al (2004) Treatment of tumour recurrence after resection of hepatocellular carcinoma. Analysis of 97 consecutive patients. Eur J Surg Oncol 33:746–751. doi:10.1016/j.ejso.2006.11.015
Uematsu S, Higashi T, Nouso K et al (2005) Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 20:583–588. doi:10.1111/j.1440-1746.2005.03726.x
Valls C, Cos M, Figueras J et al (2004) Pretransplantation diagnosis and staging of hepatocellular carcinoma in patients with cirrhosis: value of dual-phase helical CT. AJR Am J Roentgenol 182:1011–1017
Yang Y, Nagano H, Ota H et al (2007) Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery 141:196–202. doi:10.1016/j.surg.2006.06.033
Yang GH, Fan J, Xu Y et al (2008) Osteopontin combined with CD44, a novel prognostic biomarker for patients with hepatocellular carcinoma undergoing curative resection. Oncologist 13:1155–1165. doi:10.1634/theoncologist.2008-0081
Yoshiji H, Kuriyama S, Hicklin DJ et al (1999) KDR/Flk-1 is a major regulator of vascular endothelial growth factor-induced tumor development and angiogenesis in murine hepatocellular carcinoma cells. Hepatology 30:1179–1186. doi:10.1002/hep.510300509
Zhou J, Tang ZY, Fa J et al (2000) Expression of platelet-derived endothelial cell growth factor and vascular endothelial growth factor in hepatocellular carcinoma and portal vein tumor thrombus. J Cancer Res Clin Oncol 126:57–61. doi:10.1007/s004320050009
Zhu AX (2008) Development of sorafenib and other molecularly targeted agents in hepatocellular carcinoma. Cancer 112:250–259
Acknowledgments
This study was supported by grants from the National Natural Science Foundation of China (No. 30873039), Shanghai Science and Technology Development Funds (No. 07JC14010, 06QA14012, 07SP07003) and National Hi-Tech Research and Development Program of China (No.2007AA02Z479).
Conflict of interest statement
This is an original work by all the authors and no previous presentations, reports or publications contain any material that appears in the article. We certify that no actual or potential conflict of interest in relation to this article exists.
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J. Hu, Y. Xu and Z.-Z. Shen have contributed equally to this work.
An erratum to this article can be found at http://dx.doi.org/10.1007/s00432-009-0663-8
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Hu, J., Xu, Y., Shen, ZZ. et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein-negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol 135, 1359–1367 (2009). https://doi.org/10.1007/s00432-009-0577-5
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DOI: https://doi.org/10.1007/s00432-009-0577-5