Expression of angiopoietins, Tie2 and vascular endothelial growth factor in angiogenesis and progression of hepatocellular carcinoma.
OBJECTIVE
To investigate the significance of angiopoietins, Tie2 and vascular endothelial growth factor (VEGF) expression in the angiogenesis and progress of hepatocellular carcinoma (HCC).


METHODS
Fresh surgically resected specimens of HCC and noncancerous liver (NCL) tissue from 38 patients with HCC were obtained, and expression of angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), Tie2, and VEGF messenger RNA (mRNA) was examined by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Expression pattern of each gene in HCC and NCL tissue specimens was compared and the potential role and interaction in angiogenesis of HCC were analyzed. Genes' expression level and its relationship with tumor's clinicopathological parameters were also investigated. Immunohistochemical staining of CD34 was performed to determine the microvessel density (MVD) and Ang-2/Ang-1 ratio was calculated. Relationships between Ang-2/Ang-1 ratio, VEGF and MVD and clinicopathological features were also tested so as to evaluate their significance in the progression of HCC.


RESULTS
Ang-2 and VEGF mRNAs in HCC were significantly higher than those in NCL tissue (P < 0.05), whereas the Ang-1 and Tie2 mRNAs showed no statistical significance (P > 0.05), though slightly lower level of Ang-1 mRNA in HCC was observed. Ang-2/Ang-1 ratio and VEGF were both positively correlated to MVD. The Ang-2/ Ang-1 ratio, Ang-2 and VEGF were all associated with tumor's clinicopathological parameters (P < 0.05) except for histological grades (P > 0.05). Ang-1 and Tie2 levels in different clinicopathological groups were not significantly different (P > 0.05).


CONCLUSIONS
Dominant Ang-2 expression against Ang-1 through Tie2 receptor in the presence of VEGF plays a critical role in initiating early neovascularization and transformation of noncancerous liver to hepatocellular carcinoma. Its consequently constant operation in formed HCC induces further angiogenesis and progression of HCC.
Zhang
Zhong-Lin
ZL
Department of General Surgery, Zhongnan Hospital, Wuhan University, No. 169, Donghu Road, Wuhan 430071, Hubei Province, China. zhangzhonglin221@sina.com
Liu
Zhi-Su
ZS
Sun
Quan
Q
D000328:Adult; D000368:Aged; D042683:Angiopoietin-1 / Q000235:genetics / Q000378:metabolism; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042682:Angiopoietins; D018952:Antigens, CD34; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042787:Receptor, TIE-2