Protein expression profiling of vascular endothelial growth factor and its receptors identifies subclasses of hepatocellular carcinoma and predicts survival.
OBJECTIVE
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.
Jia
Jin-Bin
JB
Liver Cancer Institute and Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Zhuang
Peng-Yuan
PY
Sun
Hui-Chuan
HC
Zhang
Ju-Bo
JB
Zhang
Wei
W
Zhu
Xiao-Dong
XD
Xiong
Yu-Quan
YQ
Xu
Hua-Xiang
HX
Tang
Zhao-You
ZY
D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011379:Prognosis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000096:biosynthesis; D055815:Young Adult
D014408:Biomarkers, Tumor; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D040321:Vascular Endothelial Growth Factor Receptor-3