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Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival

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Abstract

Purpose

To examine expression profile and prognostic significance of vascular endothelial growth factor (VEGF) and its receptors in hepatocellular carcinoma (HCC) and peritumoral tissue.

Methods

Expression of VEGF-A, VEGF-C, and VEGF receptor 1(VEGFR-1), VEGFR-2, and VEGFR-3 in tumor and peritumoral liver tissue was studied by immunohistochemistry in a tissue microarray from 107 patients with HCC. Unsupervised hierarchical cluster analyses were conducted to identify relevant clusters.

Results

Staining of VEGF-A, VEGF-C, VEGFR-2, and VEGFR-3 was mostly found on the tumor cells and peritumoral hepatocytes, but VEGFR-1 was mostly expressed in stromal cells. In most of the cases, the expression of VEGF-A, VEGFR-1, VEGFR-2, and VEGFR-3 in was higher in peritumoral liver tissue, while VEGF-C expression was higher in tumor. Unsupervised hierarchical clustering analysis identified four prognostically different clusters, of which cluster A was classified into the “poor prognosis group,” and the other three clusters were classified into the “good prognosis group” (P = 0.047). Further analysis with a set of seven markers reproduced the same four cluster groups with significantly different recurrence free probability (RFP) (P = 0.018), and the low RFP group was associated with more intrahepatic satellite lesions. Multivariate analysis showed that classification defined by seven biomarkers was of prognostic significance (P = 0.000).

Conclusions

Expression of VEGF and its receptors was higher in peritumoral tissue than in tumor in HCC. Seven biomarkers predicted patients’ RFP, which consisted of tumoral expression of VEGF-A, VEGFR-1, and VEGF-C as well as peritumoral expression of VEGF-A, VEGFR-1, VEGFR-2, and VEGFR-3.

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References

  • Alizadeh AA, Ross DT, Perou CM, van de Rijn M (2001) Towards a novel classification of human malignancies based on gene expression patterns. J Pathol 195:41–52. doi:10.1002/path.889

    Article  PubMed  CAS  Google Scholar 

  • Au NH, Cheang M, Huntsman DG et al (2004) Evaluation of immunohistochemical markers in non-small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers. J Pathol 204:101–109. doi:10.1002/path.1612

    Article  PubMed  CAS  Google Scholar 

  • Budhu A, Forgues M, Ye QH et al (2006) Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell 10:99–111. doi:10.1016/j.ccr.2006.06.016

    Article  PubMed  CAS  Google Scholar 

  • Calvisi DF, Ladu S, Gorden A et al (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130:1117–1128. doi:10.1053/j.gastro.2006.01.006

    Article  PubMed  CAS  Google Scholar 

  • El-Assal ON, Yamanoi A, Soda Y et al (1998) 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 27:1554–1562. doi:10.1002/hep.510270613

    Article  PubMed  CAS  Google Scholar 

  • Hicklin DJ, Ellis LM (2005) Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol 23:1011–1027. doi:10.1200/JCO.2005.06.081

    Article  PubMed  CAS  Google Scholar 

  • Hussain SP, Schwank J, Staib F et al (2007) TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene 26:2166–2176. doi:10.1038/sj.onc.1210279

    Article  PubMed  CAS  Google Scholar 

  • Jacquemier J, Ginestier C, Rougemont J et al (2005) Protein expression profiling identifies subclasses of breast cancer and predicts prognosis. Cancer Res 65:767–779

    PubMed  CAS  Google Scholar 

  • Kaipainen A, Korhonen J, Mustonen T et al (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92:3566–3570. doi:10.1073/pnas.92.8.3566

    Article  PubMed  CAS  Google Scholar 

  • Kajita T, Ohta Y, Kimura K et al (2001) The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer 85:255–260. doi:10.1054/bjoc.2001.1882

    Article  PubMed  CAS  Google Scholar 

  • Kaposi-Novak P, Lee JS, Gomez-Quiroz L et al (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582–1595. doi:10.1172/JCI27236

    Article  PubMed  CAS  Google Scholar 

  • Lee HS, Cho SB, Lee HE et al (2007) Protein expression profiling and molecular classification of gastric cancer by the tissue array method. Clin Cancer Res 13:4154–4163. doi:10.1158/1078-0432.CCR-07-0173

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Llovet JM, Burroughs A, Bruix J (2003) Hepatocellular carcinoma. Lancet 362:1907–1917. doi:10.1016/S0140-6736(03)14964-1

    Article  PubMed  Google Scholar 

  • Makretsov NA, Huntsman DG, Nielsen TO et al (2004) Hierarchical clustering analysis of tissue microarray immunostaining data identifies prognostically significant groups of breast carcinoma. Clin Cancer Res 10:6143–6151. doi:10.1158/1078-0432.CCR-04-0429

    Article  PubMed  CAS  Google Scholar 

  • Otrock ZK, Makarem JA, Shamseddine AI (2007) Vascular endothelial growth factor family of ligands and receptors. Blood Cells Mol Dis 38:258–268. doi:10.1016/j.bcmd.2006.12.003 review

    Article  PubMed  CAS  Google Scholar 

  • Parkin DM (2001) Global cancer statistics in the year 2000. Lancet Oncol 2:533–543. doi:10.1016/S1470-2045(01)00486-7

    Article  PubMed  CAS  Google Scholar 

  • Poon RT, Ng IO, Lau C et al (2002) Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: a prospective study. J Clin Oncol 20:1775–1785. doi:10.1200/JCO.2002.07.089

    Article  PubMed  Google Scholar 

  • Price DJ, Miralem T, Jiang S et al (2001) Role of vascular endothelial growth factor in the stimulation of cellular invasion and signaling of breast cancer cells. Cell Growth Differ 12:129–135

    PubMed  CAS  Google Scholar 

  • Sun HC, Tang ZY, Li XM et al (1999) Microvessel density of hepatocellular carcinoma: its relationship with prognosis. J Cancer Res Clin Oncol 125:419–426. doi:10.1007/s004320050296

    Article  PubMed  CAS  Google Scholar 

  • Suzuki K, Hayashi N, Miyamoto Y et al (1996) Expression of vascular permeability factor/vascular endothelial growth factor in human hepatocellular carcinoma. Cancer Res 56:3004–3009

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Toi M, Bando H, Ogawa T et al (2002) Significance of vascular endothelial growth factor (VEGF)/soluble VEGF receptor-1 relationship in breast cancer. Int J Cancer 98:14–18. doi:10.1002/ijc.10121

    Article  PubMed  CAS  Google Scholar 

  • von Marschall Z, Cramer T, Hocker M et al (2001) Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 48:87–96. doi:10.1136/gut.48.1.87

    Article  Google Scholar 

  • Yamaguchi R, Yano H, Iemura A et al (1998) Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 28:68–77. doi:10.1002/hep.510280111

    Article  PubMed  CAS  Google Scholar 

  • Yamaguchi R, Yano H, Nakashima Y et al (2000) Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. Oncol Rep 7:725–729

    PubMed  CAS  Google Scholar 

  • Yu GR, Kim SH, Park SH et al (2007a) Identification of molecular markers for the oncogenic differentiation of hepatocellular carcinoma. Exp Mol Med 39:641–652

    PubMed  CAS  Google Scholar 

  • Yu D, Zhuang L, Sun X et al (2007b) Particular distribution and expression pattern of endoglin (CD105) in the liver of patients with hepatocellular carcinoma. BMC Cancer 7:122. doi:10.1186/1471-2407-7-122

    Article  PubMed  Google Scholar 

  • Zhu XD, Zhang JB, Zhuang PY et al (2008) High expression of macrophage colony-stimulating factor in peritumoral liver tissue associated with poor survival after curative resection of hepatocellular carcinoma. J Clin Oncol 26:2707–2716. doi:10.1200/JCO.2007.15.6521

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Liver Cancer Institute and Zhongshan Hospital, Fudan University, 200032, Shanghai, China

    Jin-Bin Jia, Peng-Yuan Zhuang, Hui-Chuan Sun, Ju-Bo Zhang, Wei Zhang, Xiao-Dong Zhu, Yu-Quan Xiong, Hua-Xiang Xu & Zhao-You Tang

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  1. Jin-Bin Jia
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  2. Peng-Yuan Zhuang
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  3. Hui-Chuan Sun
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  4. Ju-Bo Zhang
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  5. Wei Zhang
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  6. Xiao-Dong Zhu
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  7. Yu-Quan Xiong
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  8. Hua-Xiang Xu
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  9. Zhao-You Tang
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Corresponding author

Correspondence to Zhao-You Tang.

Additional information

J.-B. Jia and P.-Y. Zhuang contributed equally to this work.

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Jia, JB., Zhuang, PY., Sun, HC. et al. Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival. J Cancer Res Clin Oncol 135, 847–854 (2009). https://doi.org/10.1007/s00432-008-0521-0

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  • DOI: https://doi.org/10.1007/s00432-008-0521-0

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