Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma.
Human hepatocellular carcinoma (HCC) is a hypervascular tumor but the mechanisms underlying the process of angiogenesis are not fully understood. Angiopoietins (Ang) have been recently identified as ligands for Tie-2 receptor and are thought to be important factors in vascular maturation and stability during angiogenesis. In this study, we investigated the expression of Ang-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) in surgically resected specimens from 46 patients with HCC to determine their potential role in tumor angiogenesis and its progression. VEGF messenger RNA (mRNA) was significantly up-regulated in HCC compared to normal liver tissue from patients with hepatic metastases. No differences were found between HCC and adjacent liver tissue. Meanwhile, Ang-2 mRNA expression in HCC was significantly increased when compared to adjacent liver tissue. On the other hand, Ang-1 and Tie-2 mRNA expression in HCC was not different from that in adjacent liver tissue. Immunohistochemical staining also showed increased Ang-2 protein in HCC. Furthermore, a high Ang-2/1 mRNA ratio in HCC was closely associated with tumor portal vein invasion, tumor diameter, and the microvessel density level as assessed by CD34 immunostaining. With regard to prognosis, the survival time for patients in the high Ang-2/1 mRNA ratio group was significantly poorer when compared with the low Ang-2/1 mRNA ratio group. In conclusion, an increased expression of Ang-2/1 in the presence of VEGF may play a critical role in promoting tumor angiogenesis and progression in human HCC.
Mitsuhashi
Noboru
N
Department of General Surgery, Graduate School of Medicine, Chiba University, Japan.
Shimizu
Hiroaki
H
Ohtsuka
Masayuki
M
Wakabayashi
Yasuo
Y
Ito
Hiroshi
H
Kimura
Fumio
F
Yoshidome
Hiroyuki
H
Kato
Atsushi
A
Nukui
Yuji
Y
Miyazaki
Masaru
M
D043925:Angiogenesis Inducing Agents / Q000032:analysis / Q000235:genetics*; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D006528:Carcinoma, Hepatocellular / Q000737:chemistry / Q000401:mortality / Q000503:physiopathology*; D016228:Endothelial Growth Factors / Q000032:analysis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis / Q000235:genetics; D008103:Liver Cirrhosis / Q000503:physiopathology; D008113:Liver Neoplasms / Q000737:chemistry / Q000401:mortality / Q000503:physiopathology*; D008222:Lymphokines / Q000032:analysis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D012333:RNA, Messenger / Q000032:analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics*; D042787:Receptor, TIE-2; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
C467630:ANGPT1 protein, human; D043925:Angiogenesis Inducing Agents; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2