Clinical Application of Anti-angiogenetic Therapy on Hepatocarcinogenesis and Hepatocellular carcinoma -With Special Reference to Matrix Metalloproteinases and Cytokines network-

本研究的目的是控制肝细胞癌（HCC）的肿瘤相关血管生成。本研究重点探讨了血管生成相关的基质金属蛋白酶（MMPs）、血管内皮生长因子（VEGF）和血管生成相关的细胞因子网络。在二乙基亚硝胺诱导的大鼠肝癌模型中，观察到MMP-2和MT 1-MMP的表达增强，这些位点的相容性和MMP-9在HCC浸润性病变中的表达增强，以及其纤维化和癌变。在临床病例中，在经导管动脉栓塞后的HCC活细胞中有趣地观察到MMP-7的表达增强，除了与上述结果相似的结果之外，其疑似参与MMP-3，7的增殖。MT 1-MMP可能是HCC发生的一个关键因素。在VEGF与MMP-9的相关性研究中，VEGF与MMP-9的相容性是比较常见的。在临床病例中，在癌变前后观察到特征性的IFN-γ降低和IL-8升高。体外研究也表明，I-ICV与血管生成特别密切相关。在基础研究中，MMP抑制剂和血管内皮细胞增殖抑制剂对肝癌具有肿瘤休眠、肿瘤缩小和化学预防作用。抗血管生成疗法的临床应用备受期待。

To purpose of this study is to control a tumor-related angiogenesis of hepatocellular carcinoma (HCC). In this particular study, angiogenesis-related matrix metallojroteinases (MMPs), vascular endothelial growth factor (VEGF) and angiogenesis-related cytokines network were forcused. In the examination using a diethylnitrosamine-induced rat HCC model, enhanced expression of MMP-2 and MT1-MMP, compatibility of these sites and enhanced expression of MMP-9 in HCC invasive lesion were observed together with its fibronation and carcinogenesis. In clinical cases, enhanced expression of MMP-7 was interestingly observed in HCC viable cells after transcatheter arterial embolization with its suspected involvement in the proliferation of MMP-3,7 in addition to similar results as those described above. Furthermore, MT1 -MMP seemed to be a key factor of HCC. It was noteworthy in the correlation of VEGF and MMPs that compatibility of VEGF and MMP-9 was often observed. In clinical cases, decreased IFN-γ and increased IL-8 were characteristically observed before and after carcinogenesis. it was also suggested from in vitro studies that I-ICV has a close relation to angiogenesis in particular. In the fundamental study, MMP inhibitor and vascular endothelial proliferation inhibitor showed tumor dormancy, tumor shrinkage and chemoprevention effects on HCC. The clinical application of antiangiogenetic therapy is greatly expected.