In vivo analysis of the effect of antiangiogenic drug on hepatocarcinogenesis

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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.