To understand the genetic mechanisms underlying the progression of hepatocellular carcinoma(HCC) metastasis, differences of genomic alter-ations between 10 pairs of primary HCC tumors and their matched metastatic lesions were analyzed by comparative genomic hybridization. Several chromosomal alterations including loss of 8p, 4q, 17p, and 19p, gain of 5p and high-level amplification of lq12-q22 were detected in two or more cases. The most significant finding is the loss of 8p which was detected in 8 metastatic tumors but only in 3 corresponding primary tumors(P=0.03). This result suggests that the deletion of chromosome 8p might contribute to the development of HCC metastasis. Another inter-esting result is the detection of a minimum high-lever amplification region at lq12-q22 in HCC. This result provides a candidate amplification region at lq12-q22 in HCC. This result provies a candidate amplification region in HCC for further study to identify amplified oncogenes related to the development or progression of HCC. Finally, this study provides a prac-ticable model to detect specific genetic alterations related to the tumormetastasis through comparing the primary tumor and its corresponding metastatic lesion using comparative genomic hybridization technique.

Hepatocellular carcinoma(HCC) is one of the most common and aggressive human malignan-cies. Its high mortality rate is mainly a result of intra-hepatic metastases. We analyzed the ex-pression profiles of HCC samples without or with intra-hepatic metastases. Using a supervised machine-learning algorithm, we generated for the first time a molecular signature that can clas-sify metastatic HCC patients and identified genes that were relevant to metastasis and patient survival. We found that the gene expression signature of primary HCCS with accompanying metastasis was very similar to that of their corresponding metastases, implying that genes fa-voring metastasis progression were initiated in the primary tumors. Osteopontin, which was identified as a lead gene in the signature, was over-expressed in metastatic HCC; an osteopon-tin-specific antibody effectively blocked HCC cell invasion in vitro and inhibited pulmonary metastasis of HCC cells in nude mice. Thus, osteopontin acts as both a diagnostic marker and a potential therapeutic target for metastatic HCC.

Postoperative recurrence of human hepatocellular carcinoma (HCC) is the major issue that must be addressed to further improve prognosis. This study was undertaken to investigate the effects of interferon-alfa-1b (IFN-a-1b) on recurrent tumor and metastasis after curative resection in nude mice bearing an HCC xenograft with high metastatic potential. Tumor tissues from LCI-D20, a metastatic model of HCC in nude mice, were orthotopically implanted in 105 nude mice. Eleven days later, 64 mice underwent curative resection of liver tumors. IFN-a at different doses was administered subcutaneously to mice with or without resection. In mice without resection, when comparison was made among control, IFN 7.5 3 106 U/kg/day, 1.5 3 107 U/kg/day for treated groups, and 3 3 107 U/kg/day; tumor volume was 8,475 mm3 6 2,636 mm3, 7,963 mm3 6 3,214 mm3, 769 mm3 6 287 mm3, and 13 mm3 6 9 mm3; incidence of lung metastasis being 100%, 80%, 40%, and 0%; life span was 45 6 4 days, 53 6 8 days, 81 6 6 days, and 105 6 24 days, respectively. In mice with curative resection, when comparison was made among control, IFN 5 3 105 U/kg/day, 1 3 106 U/kg/day, 4 3 106 U/kg/day, 7.5 3 106 U/kg/day, 1.5 3 107 U/kg/day, and 3 3 107 U/kg/day for treated groups; incidence of recurrent tumor was 100%, 100%, 87.5%, 100%, 87.5%, 62.5%, and 12.5%; lung metastasis being 100%, 75%, 87.5%, 50%, 62.5%, 0%, and 0%, respectively. IFN-a inhibited neovascularization induced by LCI-D20 tumor specimens implanted into the micropocket of nude mice corneas. In conclusion, high-dose and longterm therapy with IFN-a dose-dependently inhibits tumor growth and recurrence after resection of HCC. The effect of IFN-a may be attributed to antiangiogenesis in this experiment. These results provide potential clinical implication, particularly for the prevention of recurrence after curative resection of HCC.