Postoperative Recurrence of Hepatocellular Carcinoma

Nagao, Toshiyasu; Inoue, Sumio; Yoshimi, Fuyo; Sodeyama, Motohide; Omori, Yoshimichi; Mizuta, T.; Kawano, Nobuhiro; Morioka, Yasuhiko

doi:10.1097/00000658-199001000-00005

Cited by 196 publications

(94 citation statements)

References 8 publications

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“…28,29 IM is thought to develop through tumor cell dissemination through the portal vein. 30 Previous studies using the mouse IM model indicate activation of RhoA 21 and AKT, 31 and overexpression of cortactin 32 Reduced TGFBR2 expression correlated with portal vain invasion in HCC cases, and poorly differentiated HCC cells showed lower TGFBR2 expression compared with well-differentiated cells.…”

Section: Tgfbr2 Expression In Hccsmentioning

confidence: 99%

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Mamiya

Yamazaki

Masugi

et al. 2010

Laboratory Investigation

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Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-b (TGF-b) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-b signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-b signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-b receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-b. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (Po0.001), poor differentiation (Po0.001), portal vein invasion (P ¼ 0.002), intrahepatic metastasis (IM) (Po0.001), and shorter recurrence-free survival (P ¼ 0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC. Hepatocellular carcinoma (HCC) is a common cause of death from cancer worldwide. 1 Prolonged infection with hepatitis virus often causes chronic hepatitis, followed by liver cirrhosis. 2 During the development of these liver diseases, transforming growth factor-b (TGF-b) has an important role in fibrosis of the lesions. 3 HCCs mainly occur in those injured livers with activated TGF-b signaling, although TGF-b inhibits hepatocyte cell growth in the normal liver. 4,5 TGF-b signaling is activated when a TGF-b ligand binds to its receptor on the cell membrane. The downstream effectors, SMAD2 and SMAD3, together with SMAD4, translocate to the nucleus and regulate the expression of various genes, including cyclin-dependent kinase inhibitor 1A (CDKN1A), which is involved in cell growth arrest. 6,7 TGF-b signaling is also suggested to be involved in the malignant progression of tumors. TGF-b can induce epithelial-mesenchymal transition and promote tumor cell invasion, and may also have angiogenic and immunosuppressive effects on the tumor microenvironment, all of which promote metastasis. 8 Mutations in the TGF-b superfamily genes have been found in various cancers. The TGF-b receptor II (TGFBR2) gene is frequently mutated in colon cancers, 9,10 gastric cancers, 10,11 and in gliomas 12 with microsatellite instability. SMAD4 mutations occur mainly in pancreatic cancers, in which the SMAD4 gene was first identified as a tumorsuppressor gene. 13 In HCCs, however, mutations in TGF-b superfamily genes are rare, 14,15 and alteration of TGF-b signaling is still unclear and controversial. To investigate alterations of TGF-b signaling in HCC progression, we compared the expression profiles of TGF-b signalingrelated genes in HCC cells exhibiting different metastatic potential. We...

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Section: Tgfbr2 Expression In Hccsmentioning

confidence: 99%

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Mamiya

Yamazaki

Masugi

et al. 2010

Laboratory Investigation

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“…Prognosis of HCC is extremely poor with a 5-year survival rate of less than 5% for late primary HCC (Block et al, 2003). The poor prognosis of HCC patients is mainly attributed to the high rate of intrahepatic metastasis after treatment (Nagao et al, 1990). Despite the advances in molecular technologies, which allow the identification of novel targets involved in HCC metastasis, the precise mechanisms involved remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Clusterin plays an important role in hepatocellular carcinoma metastasis

et al. 2005

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To identify genes associated with tumor metastasis in hepatocellular carcinoma (HCC), gene expression profiles between a pair of primary HCC (H2-P) and their matched metastatic HCC (H2-M) were compared. Overexpression of clusterin (CLU) was found in H2-M cells. To determine the roles CLU played in HCC metastasis, CLU was transfected into H2-P cells. Overexpression of CLU in H2-P cells increased cell migration by twofold in vitro and formation of metastatic tumor nodules in liver by eightfold in vivo. To evaluate the correlation of CLU expression with HCC metastasis, the expression levels of CLU in HCCs were investigated using a tissue microarray (TMA) containing 104 pairs of primary HCCs and their matched metastases. The frequency of CLU overexpression increased significantly in metastatic HCCs (59.1%) compared with that in primary tumors (32.6%, Po0.001). To gain additional insight into the function of CLU, the expression profile of H2P-CLU was compared with vector-transfected H2-P cells by cDNA microarray. A total of 35 upregulated and 14 downregulated genes were detected in H2P-CLU. One of the upregulated genes known as YKL-40, which is implicated in matrix-remodeling and metastasis, was further studied using TMA. A significant correlation (Po0.001) between the expression levels of YKL-40 and CLU was observed, implying that the CLU-YKL-40 pathway may play an important role in HCC metastasis.

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“…However, prognosis after hepatectomy is still unsatisfactory because of a high incidence of disease recurrence. 1,2 Pathologic and genetic studies have identified two types of recurrence of HCC, i.e., intrahepatic metastasis of the primary HCC and multicentric development of new tumors, although the two types cannot always be distinguished. It is generally believed that disease recurrence due to intrahepatic metastasis is likely to appear soon after surgical resection and that its risk decreases with prolongation of the postoperative period.…”

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confidence: 99%

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma

Nakanishi¹,

Sakamoto

Yamasaki

et al. 2005

Cancer

213

173

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BACKGROUND Patients with hepatocellular carcinoma (HCC) who showed early massive disease recurrence due to hematogenous intrahepatic metastasis after curative resection had a poor prognosis. The authors previously reported that Akt phosphorylation was correlated with hematogenous intrahepatic metastasis, using HCC cell lines. METHODS The authors analyzed clinicopathologic features and the status of selected biologic markers, including phosphorylated Akt, to identify risk factors for early disease recurrence and poor prognosis in HCC. In the current series, 49 postoperative patients developed intrahepatic disease recurrence within 6 months (Group 1) and 86 patients remained disease recurrence free > 3 years after resection (Group 2). Group 1 was further divided into 2 subgroups: 19 patients who died of disease recurrence within a year after resection (Group 1A) and 27 patients who survived > 1 year (Group 1B). RESULTS Using univariate analysis, the risk factors for early disease recurrence were tumor size, macroscopic classification, tumor differentiation, microscopic capsule infiltration, microscopic portal vein (MPV) invasion, microscopic intrahepatic metastasis (MIM), and positive immunostaining for phosphorylated Akt, Ki‐67, and p53 (P < 0.05). The risk factors for poor prognosis were the number of intrahepatic metastases, tumor differentiation, and positive immunostaining for phosphorylated Akt and Ki‐67 (P < 0.05). Multivariate analysis revealed that the risk factors for early disease recurrence were MPV invasion, MIM, and positive immunostaining for phosphorylated Akt, and that the risk factors for poor prognosis were positive immunostaining for phosphorylated Akt and Ki‐67 (P < 0.05). CONCLUSIONS The current clinical study showed the critical involvement of Akt phosphorylation in the aggressiveness of HCC. The potential benefits of surgery should be assessed carefully in patients with any of these risk factors. Cancer 2005. © 2004 American Cancer Society.

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Postoperative Recurrence of Hepatocellular Carcinoma

Cited by 196 publications

References 8 publications

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Clusterin plays an important role in hepatocellular carcinoma metastasis

Akt phosphorylation is a risk factor for early disease recurrence and poor prognosis in hepatocellular carcinoma

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