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 hepatocellula r carcinoma (HCC). Summary Background Data Tumor angiogenesis is believed to derive from the balance between angiogeni c stimulators and inhibitors. it has been suggested that the switch to the angiogenic phenotype requires both upregulation of the first and downregula tion of the second. However, its molecular basis in vivo remains obscure. I n this study the authors analyze the participation of two factors in angiog enesis of HCC- human macrophage metalloelastase (HME), a matrix metalloprot einase 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 u nderwent curative partial hepatectomy were subjected to Northern blot analy sis to detect HME and VEGF messenger RNA (mRNA) expression. Western blot an alysis was used to detected angiostatin. Tumor vascularity was evaluated us ing 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. T he median of HME mRNA expression (tumorous/nontumorous ratio) was 6.5 (rang e 0-264.5) in the hypovascular group and 0 (range 0-3.2) in the hypervascul ar group. A stepwise logistic analysis revealed that HME and VEGF mRNA expr ession were two independent variables significantly affecting the vasculari ty of HCC tumors. Conclusion HME gene expression is significantly associated with hypovascular tumors; m oreover, angiogenesis in HCC is not determined by a single factor, but depe nds on the net balance between HME and VEGF gene expressions.