Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma.
OBJECTIVE
Angiopoietin 1 (Ang-1) and its antagonist, angiopoietin 2 (Ang-2), are novel ligands that regulate the Tie2 receptor. The Ang-2 gene is upregulated in the hypervascular type of human hepatocellular carcinoma (HCC). To gain a better understanding of the role of the Ang-Tie2 system in HCC the expression of these genes was investigated in a series of human HCCs.


METHODS
The expression of the angiopoietin and Tie2 proteins was investigated in nine normal liver tissues and 52 surgically resected HCCs. In addition, the effects of hypoxic stimuli on Ang-1, Ang-2, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) expression was investigated in Hep3B cells.


RESULTS
Ang-1, rather than Ang-2, was more frequently expressed in the normal liver. Ang-1 was expressed in 68% of HCCs, whereas Ang-2 was expressed in 81%, and was significantly higher in poorly differentiated HCCs characterised by high vascularity (p = 0.02), and in tumours with a peliotic change (p = 0.02). Strong expression of Tie2 was seen in tumour vessels in accordance with Ang-2 expression. In Hep3B cells, hypoxic stimuli upregulated VEGF and EPO, but not Ang-1 or Ang-2.


CONCLUSIONS
These data support the evidence that the reversal of Ang-1 and Ang-2 expression plays an important role in the angiogenic and dedifferentiation processes in HCC. The hypoxic stimuli were not responsible for Ang-2 upregulation, unlike that of VEGF, in human HCC cells.
Sugimachi
K
K
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Tanaka
S
S
Taguchi
K
K
Aishima
S
S
Shimada
M
M
Tsuneyoshi
M
M
D000368:Aged; D000369:Aged, 80 and over; D042683:Angiopoietin-1 / Q000235:genetics / Q000502:physiology; D042702:Angiopoietin-2 / Q000235:genetics / Q000502:physiology; D042682:Angiopoietins / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D018450:Disease Progression; D004921:Erythropoietin / Q000235:genetics; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000098:blood supply* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D042787:Receptor, TIE-2 / Q000502:physiology; D012189:Retrospective Studies; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D042682:Angiopoietins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D042787:Receptor, TIE-2