[The role of angiostatin, vascular endothelial growth factor, matrix metalloproteinase 9 and 12 in the angiogenesis of hepatocellular carcinoma].
OBJECTIVE
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.
Kim
Sook
S
Department of Pathology, Institute for Medical Sciences, Medical School, Chonbuk National University.
Park
Ho Sung
HS
Son
Hyun Jin
HJ
Moon
Woo Sung
WS
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000032:analysis / Q000502:physiology; D043168:Angiostatins / Q000032:analysis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000737:chemistry; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000737:chemistry; D008297:Male; D053508:Matrix Metalloproteinase 12; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000502:physiology; D008666:Metalloendopeptidases / Q000032:analysis / Q000502:physiology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000503:physiopathology*; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000502:physiology
D020533:Angiogenesis Inhibitors; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D008666:Metalloendopeptidases; D020780:Matrix Metalloproteinase 9; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12