In vivo analysis of the effect of antiangiogenic drug on hepatocarcinogenesis

肝细胞癌（HCC）通常表现为从发育不良结节（DN）到明显的高血管性HCC的多步骤肝癌发生。因此，人们认为在肝癌发生的早期给予抗血管生成因子可能预防或延缓HCC的发展。为此，开展了基础研究和临床研究。采用荧光生命显微镜和免疫组织化学方法观察大鼠实验性肝转移隐匿性瘤内微血管在给予抗血管生成药物沙利度胺后的形态学变化。沙利度胺对隐匿性肝转移瘤有抗血管生成作用，但肿瘤血管中不同的血管组分对抗血管生成治疗的反应不同。研究了dn和hcc中血管内皮生长因子（VEGF）及其受体（Flt-1和Flk-1）、缺氧诱导因子-1 （HIF-1）和CD34在肝癌发生过程中的变化。毛细血管区未配对动脉数量增加被认为是早期恶性转化的表现。与VEGF相关的Flk-1和HIF-1表达的增加与窦状动脉毛细血管化和这些区域未配对动脉数量的增加有关。为了评价明胶水凝胶作为抗血管生成因子载体在经导管动脉栓塞治疗中的有效性，bFGF(强。将含血管生成因子的明胶水凝胶直接注入大鼠肝脏。然而，没有确切的效果得到证实，为此目的需要进一步的技术改进。在低血管性DNs中，通过影像学早期发现高血管灶对于了解抗血管生成治疗的时间非常重要，动态CT和/或MRI在临床实践中被认为是有效的。

Heptocellular carcinoma (HCC) often shows multi-step hepatocarcinogenesis from dysplastic nodule (DN) to overt hypervascular HCC. Therefore, it has been considered that administration of antiangiogenic factors during early stage of hepatocarcinogenesis might prevent or delay the development of HCC. For this purpose, basic and clinical studies were carried out. To investigate the morphological change of intratumoral microvessels after administration of thalidomide (antiangiogenic agent) in occult hepatic metastases experimentally induced in rats were analyzed by fluorescent vital microscopy and immunohistochemistry. Thalidomide exerted antiangiogenic effect on the occult hepatic metastases, however, the different vascular components in the tumor vasculature demonstrated various responses to antiangiogenic therapy. The vascular changes during hepatocarcinogenesis were examined with respect to vascular endothelial growth factor (VEGF) and its receptors (Flt-1 and Flk-1), hypoxia inducible factor-1 (HIF-1), and CD34 in DNs and HCCs. The capillarized areas with increased numbers of unpaired arteries in DNs were considered to represent an early malignant transformation. Increased expression of Flk-1 and HIF-1 associated with VEGF was involved in sinusoidal capillarization and the increased numbers of unpaired arteries in these areas. To evaluate the effectiveness of gelatine hydrogel as a carrier of antiangiogenic factor for transcatheter arterial embolization therapy, bFGF (strong. angiogenic factor) contained gelatine hydrogel was directly injected into the rat liver. However, no definite effect was confirmed, and further technical improvement is necessary for this purpose. The early detection of hypervascular foci in hypovascular DNs by imaging is important to know the time of antiangiogenic therapy, and dynamic CT and/or MRI were considered to be effective in clinical practice.