ORIGINAL ARTICLE

Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma

K Sugimachi^1,2, S Tanaka², K Taguchi¹, S Aishima¹, M Shimada² and M Tsuneyoshi¹

¹ Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
² Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

Correspondence to:
Correspondence to:
Dr S Tanaka
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University. 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan; shinjit{at}surg2.med.kyushu-u.ac.jp

Aim: 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.

Keywords: angiopoietin; Tie2; hypoxia; angiogenesis; hepatocellular carcinoma

Abbreviations: Ang, angiopoietin; EC, vascular endothelial cell; EPO, erythropoietin; HCC, hepatocellular carcinoma; HIF, hypoxia inducible factor; PC, vascular pericyte/smooth muscle cell; PCR, polymerase chain reaction; RT, reverse transcriptase; Tie2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 2; VEGF, vascular endothelial growth factor

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