Implications of Human Macrophage Metalloelastase and Vascular Endothelial Growth Factor Gene Expression in Angiogenesis of Hepatocellular Carcinoma
2000
The growth of solid tumors requires new blood vessel formation to facilitate the delivery of nutrients and oxygen and the removal of catabolites, as has been experimentally demonstrated. 1,2 Thus, long-term suppression of angiogenesis may become a therapeutic option for malignancies. 3,4 However, the mechanisms that control it are not completely understood. Recently, it has been proposed that a balance between endogenous angiogenic stimulators, including members of the vascular endothelial growth factor (VEGF), fibroblast growth factor, and platelet derived-endothelial cell growth factor families, among many others, and endogenous angiogenic inhibitors, such as angiostatin, endostatin, and thrombospondin, is a critical condition for the promotion of the neovascularization of tumors. Indeed, several reports have stated that the switch to the angiogenic phenotype requires both upregulation of the first and downregulation of the second. 5,6 These molecular bases, in association with the lack of detailed studies on this aspect in human tumors, encouraged us to explore possible molecules regulating tumor angiogenesis in hepatocellular carcinoma (HCC), which is generally considered to be a hypervascular tumor with an unsatisfactory long-term survival rate after surgical resection and conventional adjuvant chemotherapy.
The matrix metalloproteinase (MMP) family includes an increasing list of enzymes characterized by their ability to degrade extracellular matrix as well as nonmatrix substrates. Although MMPs have long been associated with tumor invasion and metastasis, 7 their association with angiogenesis remains controversial. In our recent report, 8 we demonstrated, for the first time to our knowledge, that human macrophage metalloelastase (HME), identified as MMP-12, and formerly isolated from alveolar macrophages of cigarette smokers, 9,10 can be directly expressed by some human HCCs (62.5%), and that its expression is strongly associated with the generation in situ of human angiostatin, 11 a potent inhibitor of angiogenesis. Previously, only one basic experimental approach had been reported, in which a mouse counterpart of HME produced by tumor-infiltrating macrophages was responsible for the generation of angiostatin from plasminogen, inhibiting the growth and metastasis of Lewis lung carcinoma in mice. 12
Among angiogenic factors, VEGF is the most potent endogenous mediator of angiogenesis known. 13,14 VEGF is a diffusible endothelial cell-specific mitogen and angiogenic factor that also increases vascular permeability. These actions are mediated through two endothelial cell tyrosine kinase receptors, the fms-like tyrosine kinase and the kinase domain receptor. 15,16 Both VEGF and its receptors have been found to be expressed in a variety of tumors, 17–19 where overexpression of VEGF results in dramatically increased angiogenesis and subsequent tumor expansion, whereas the blockade of the VEGF receptors inhibits angiogenesis, leading to a reduction of new vessels, a higher degree of necrosis, and a reduction in size of certain tumors. In HCC, it has been demonstrated that 60% of these tumors exhibit high expression of VEGF, which significantly correlates with the hypervascularity of the tumors. 20
We designed the present study to clarify the in vivo molecular role of HME gene expression in angiogenesis of HCC, and to examine whether VEGF expression can modify the angiogenic response of HME gene expression. The results presented here indicate that HME messenger RNA (mRNA) expression is significantly associated with hypovascular tumors and, moreover, that the final angiogenic phenotype of HCC tumors does not depend on a single factor, but on the net balance between HME and VEGF.
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