Implications of human macrophage metalloelastase and vascular endothelial growth factor gene expression in angiogenesis of hepatocellular carcinoma.
OBJECTIVE
To determine molecular mechanisms involved in angiogenesis of hepatocellular carcinoma (HCC).


BACKGROUND
Tumor angiogenesis is believed to derive from the balance between angiogenic stimulators and inhibitors. It has been suggested that the switch to the angiogenic phenotype requires both upregulation of the first and downregulation of the second. However, its molecular basis in vivo remains obscure. In this study the authors analyze the participation of two factors in angiogenesis of HCC- human macrophage metalloelastase (HME), a matrix metalloproteinase responsible for the generation of angiostatin, a potent angiogenesis inhibitor, and vascular endothelial growth factor (VEGF), the most potent endogenous angiogenic factor.


METHODS
Tumorous and contiguous nontumorous tissues from 25 patients with HCC who underwent curative partial hepatectomy were subjected to Northern blot analysis to detect HME and VEGF messenger RNA (mRNA) expression. Western blot analysis was used to detected angiostatin. Tumor vascularity was evaluated using hepatic angiography.


RESULTS
Eleven of the 15 cases expressing the HME gene showed hypovascular tumors, whereas hypervascular tumors were seen in 9 of the 10 HME-negative cases. The median of HME mRNA expression (tumorous/nontumorous ratio) was 6.5 (range 0-264.5) in the hypovascular group and 0 (range 0-3.2) in the hypervascular group. A stepwise logistic analysis revealed that HME and VEGF mRNA expression were two independent variables significantly affecting the vascularity of HCC tumors.


CONCLUSIONS
HME gene expression is significantly associated with hypovascular tumors; moreover, angiogenesis in HCC is not determined by a single factor, but depends on the net balance between HME and VEGF gene expressions.
Gorrin-Rivas
M J
MJ
Department of Surgery & Surgical Basic Science, Graduate School of Medicine, Kyoto University, Japan.
Arii
S
S
Mori
A
A
Takeda
Y
Y
Mizumoto
M
M
Furutani
M
M
Imamura
M
M
D000328:Adult; D000368:Aged; D043168:Angiostatins; D015152:Blotting, Northern; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics*; D004730:Endothelium, Vascular / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006498:Hepatectomy; D006801:Humans; D008099:Liver / Q000098:blood supply; D008113:Liver Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D008222:Lymphokines / Q000235:genetics*; D008297:Male; D053508:Matrix Metalloproteinase 12; D008666:Metalloendopeptidases / Q000235:genetics*; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments / Q000235:genetics; D010958:Plasminogen / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D043168:Angiostatins; D010958:Plasminogen; D008666:Metalloendopeptidases; C507122:MMP12 protein, human; D053508:Matrix Metalloproteinase 12