Korean J Hepatol.  2004 Mar;10(1):62-72.

The Role of Angiostatin, Vascular Endothelial Growth Factor, Matrix Metalloproteinase 9 and 12 in the Angiogenesis of Hepatocellular Carcinoma

  • 1Department of Pathology, Institute for Medical Sciences, Medical School, Chonbuk National University, Korea. mws@moak.chonbuk.ac.kr
  • 2Department of Pathology, Soon Chun Hyang Gumi Hospital, Korea.


BACKGROUND/AIMS: Tumor angiogenesis, a major requirement for tumor growth and metastasis, is regulated by pro- and anti-angiogenic factors. Hepatocellular carcinoma (HCC) has become a common malignant tumor worldwide. It is characterized by a high vascularity. METHODS: We studied the immunohistochemical expression of angiostatin, vascular endothelial cell growth factor (VEGF), matrix metalloproteinase (MMP)-9 and MMP-12, and the relationship between these results and the microvessel density (MVD) in 48 HCC specimens. To determine whether HCC cells express angiostatin per se, we examined the expression of angiostatin, MMP-9 and MMP-12 by Western blotting in four HCC cell lines. RESULTS: Expression of angiostatin and MMP-12 (but not MMP-9) were strongly correlated with decreased MVD in HCCs (P=0.006, P=0.038, respectively). VEGF positive tumors showed a significantly higher MVD than VEGF negative tumors (P=0.01). We divided the 48 cases into the following four groups: group A, angiostatin (+), MMP-9 or -12 (+), and VEGF (-); group B, angiostatin (-) and VEGF (-); group C, angiostatin (+), MMP-9 or -12 (+), and VEGF (+); group D, angiostatin (-) and VEGF (+). There was a significant correlation with MVD among these groups (P<0.001). Angiostatin was detected by Western blotting in 2 out of 4 HCC cell lines and was associated with plasminogen and MMP expression. CONCLUSIONS: These results indicate that angiogenesis in HCC is a complex process involving multiple factors including angiostatin, VEGF, and MMP. Our results suggest that angiostatin is generated by MMP-mediated proteolysis of plasminogen in HCC cells.


Angiogenesis; Angiostatins; Hepatocellular carcinoma; Matrix metalloproteinase; Vascular endothelial growth factor

MeSH Terms

Angiogenesis Inhibitors/analysis/physiology
Carcinoma, Hepatocellular/*blood supply/chemistry
English Abstract
Gelatinase B/analysis/physiology
Liver Neoplasms/*blood supply/chemistry
Middle Aged
Neovascularization, Pathologic/metabolism/*physiopathology
Vascular Endothelial Growth Factor A/analysis/physiology
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