MANABU FUKUMOTO, 2 JUN FUJITA, 3 AND MASAYUKI IMAMURA 1 liver tumors, whereas basic FGF may be involved in the Hepatocellular carcinoma (HCC) is a typical hypervasinvasion of HCC into the surrounding tissues. (HEPATOLcular tumor. However, the relationship between the vas-OGY 1996;23:455-464.) cularity of HCC and the expression of angiogenic factors has not been investigated. In addition, no detailed studies have examined the possible involvement of angio-It is well known that the development of a tumor genic factors in the grade of malignancy of HCC. The requires oxygen and nutrients, which are supplied aim of this study was to determine which angiogenic through neovascularization. Angiogenic potential is factors regulate tumor angiogenesis and contribute to therefore, a prerequisite for tumor growth. Furtherthe invasive ability of liver tumors, especially of HCC. more angiogenesis likely contributes to the grade of Northern blot analysis was used to examine the tranmalignancy, because this process may be accompanied scriptional expression of vascular endothelial growth by the degradation of the extracellular matrix. 1
factor (VEGF), basic fibroblast growth factor (FGF), and
Several factors participating in the development of acidic FGF in resected surgical specimens (20 HCC and microvasculature have been identified. These include 9 metastatic liver tumors). Correlations between messenger RNA (mRNA) expression and arteriographic find-epidermal growth factor, 2 transforming growth factor a ings, as well as histopathological findings, were evaluand b, 2,3 tumor necrosis factor a (TNFa), 4 angiogenin, 5 ated. Immunohistochemistry was performed to identify acidic and basic fibroblast growth factor (FGF), and the localization of cells expressing VEGF in HCC. Higher platelet-derived endothelial cell growth factor (PDlevels of VEGF mRNA were observed in 12 of 20 HCC and ECGF). 11 Recently, a novel angiogenic factor vascular in 2 of 9 metastatic liver tumors than in corresponding endothelial growth factor (VEGF) was purified from nontumorous tissues. The degree of VEGF mRNA exthe conditioned medium of bovine pituitary folliculo pression was significantly correlated with the intensity stellate cells 12 and was found to be identical to vascular of tumor staining in angiograms (P Γ΅ .01). On immunopermeability factor (VPF). histochemical observation, VEGF protein was intensely Hepatocellular carcinoma (HCC) is generally considdetected in HCC cells. Furthermore, basic FGF mRNA was detected in 9 of 20 HCC and was related to the capsu-ered to be a hypervascular tumor, but the type of vascular infiltration of cancer cells (P Γ΅ .05). In contrast, no lature is not uniform. For instance, small-sized and significant difference was observed in the very low levwell-differentiated HCC usually exhibit no remarkable els of acidic FGF mRNA found in the tumorous and nondevelopment of tumor vessels, whereas in advanced tumorous portions of the liver. In conclusion, these restage HCC is richly supplied with blood vessels. Howsults suggest that VEGF contributes to angiogenesis of ever, there is a considerable difference in the abundance of vasculature between individual tumors, and the key factors promoting the production of tumor ves-Abbreviations: FGF, fibroblast growth factor; PD-ECGF, platelet-derived sels in HCC have not been clearly defined. Furtherendothelial cell growth factor; VEGF, vascular endothelial growth factor; VPF, more, it is not known if the expression of angiogenic vascular permeability factor; HCC, hepatocellular carcinoma; PCR, polymerase chain reaction; cDNA, complementary DNA; mRNA, messenger RNA; S26r, factors is correlated with the clinicopathological fea-S26 ribosomal protein; fc-inf, microscopic infiltration of cancer cells into the tures of the tumor that are used to determine the grade tumor capsule; PA, plasminogen activator. of malignancy. 15,