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en: Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma

en: BMJ Publishing Group Ltd & Association of Clinical Pathologists

en: Aim: Angiopoietin 1 (Ang-1) and its antagonist, angiopoietin 2 (Ang-2), are novel ligands that regulate the Tie2 receptor. The Ang-2 gene is upregulated in the hypervascular type of human hepatocellular carcinoma (HCC). To gain a better understanding of the role of the Ang-Tie2 system in HCC the expression of these genes was investigated in a series of human HCCs. The expression of the angiopoietin and Tie2 proteins was investigated in nine normal liver tissues and 52 surgically resected HCCs. In addition, the effects of hypoxic stimuli on Ang-1, Ang-2, vascular endothelial growth factor (VEGF), and erythropoietin (EPO) expression was investigated in Hep3B cells. Ang-1, rather than Ang-2, was more frequently expressed in the normal liver. Ang-1 was expressed in 68% of HCCs, whereas Ang-2 was expressed in 81%, and was significantly higher in poorly differentiated HCCs characterised by high vascularity (p = 0.02), and in tumours with a peliotic change (p = 0.02). Strong expression of Tie2 was seen in tumour vessels in accordance with Ang-2 expression. In Hep3B cells, hypoxic stimuli upregulated VEGF and EPO, but not Ang-1 or Ang-2. These data support the evidence that the reversal of Ang-1 and Ang-2 expression plays an important role in the angiogenic and dedifferentiation processes in HCC. The hypoxic stimuli were not responsible for Ang-2 upregulation, unlike that of VEGF, in human HCC cells.


en: Hepatocyte growth factor and transforming growth factor beta1 contribute to regeneration of small-for-size liver graft immediately after transplantation

en: Springer-Verlag

ja: Springer-Verlag

en: Although the ability of the liver to regenerate to a predetermined size after resection made adult-to-adult living donor liver transplantation (LDLT) possible, there is little information regarding the growth regulatory mechanism for a small-for-size graft. Forty-one cases of LDLT were divided into two groups by graft volume to standard liver volume ratio (GV/SLV); small graft group (Group S, GV/SLV<40%, n=16) and non-small graft group (Group NS, GV/SLV>40%, n=25). The regeneration rate (GV at 1 week/harvested GV) and serum levels of hepatocyte growth factor (HGF), transforming growth factor-alpha (TGF-alpha) and transforming growth factor-beta1 (TGF-beta1) were compared between two groups. The regeneration rates in Group S were significantly higher than that of Group NS (217+/-12% and 178+/-10%, respectively, P<0.01). The serum HGF levels of Group S were significantly higher than those of Group NS on POD 1. The TGF-beta1 levels of Group S were significantly higher than those of Group NS on POD 3 and 5. The TGF-alpha levels were not different at any time points studied. These results indicate that a small-for-size graft retains the capacity to regenerate faster by modulation of expression pattern of HGF and TGF-beta1 immediately after LDLT. After the acceleration of the regenerative response by HGF, subsequent elevation of TGF-beta1 synergistically controls graft size, regulating uncontrolled proliferation of hepatocytes.


en: Tenascin expression at the invasive front is associated with poor prognosis in intrahepatic cholangiocarcinoma

en: United States and Canadian Academy of Pathology

en: Tenascin and decorin are components of the extracellular matrix (ECM) that are implicated in cell proliferation in tumors. Here, we propose that abnormal expression of stromal ECM may play an important role in the progression of intrahepatic cholangiocarcinoma, which is characterized by desmoplastic reaction. To explore this hypothesis, we performed immunohistochemical analysis in order to examine the expression and distribution of tenascin and decorin in 75 cases of intrahepatic cholangiocarcinoma. In the intratumoral stroma, positive staining for tenascin was observed in 51 (68%) cases, and positive staining for decorin was observed in 61 (81%) cases. However, at the invasive front, positive staining for tenascin was found in 23 (31%) cases, and positive staining for decorin was found in 6 (8%) cases. Decorin staining was not correlated with aggressive behavior of intrahepatic cholangiocarcinoma, whereas intratumoral tenascin staining was correlated with lymphatic permeation and proliferative activity measured by Ki67. Tenascin staining at the invasive front was associated with tumor size, lymphatic permeation, lymph node metastasis, and proliferative activity and appeared to be a useful prognostic factor by univariate analysis, although it was not an independent prognostic factor. These results indicate that tenascin plays a role in tumor progression in cases of intrahepatic cholangiocarcinoma and that tenascin expression, especially at the invasive front, may be a useful marker in evaluating an unfavorable prognosis in patients with intrahepatic cholangiocarcinoma.


en: Antioxidant and anti-inflammatory effects of a diet supplemented with sesamin on hepatic ischemia-reperfusion injury in rats

en: Thieme, Stuttgart, ALLEMAGNE

ja: Thieme, Stuttgart, ALLEMAGNE

en: The antioxidant and anti-inflammatory properties of sesamin (a non-fat constituent of sesame oil) have been attributed to an increased accumulation of dihomo-y-linolenic acid, a precursor of 1-series prostaglandins, and the decreasing production of proinflammatory 2-series prostaglandins and 4-series leukotrienes by inhibiting the delta-5 desaturase activity. We investigated the effects of a diet containing sesamin on hepatic ischemia-reperfusion injury in rats. After feeding rats either a basal diet (control group) or a diet supplemented with sesamin (sesamin group) for 14 days, the rats underwent 60 minutes of partial hepatic ischemia and 3 hours of reperfusion. The phospholipid fatty acid composition of both liver and lung tissue specimens were then analyzed. The plasma levels of leukotriene B4 and PCOOH (phosphatidylcholine hydroperoxide) were also determined. The consumption of the dietary sesamin resulted in a significant increase in the dihomo-y-linolenic acid content in the tissue phospholipids of the liver and lung specimens. The amounts of polyunsaturated fatty acids in the lungs subjected to the ischemia-reperfusion injury were well preserved in the animals from the sesamin group. Despite a lack of differences in the levels of arachidonic acid, the plasma levels of leukotriene B4 in the rats fed dietary sesamin (88 +/- 15 pg) tended to be lower (P = 0.07) than those fed the control diet (110 +/- 20 pg). Furthermore, the plasma concentrations of PCOOH in the sesamin group (130 +/- 62 pmol) were also significantly lower (P < 0.05) than those in the control group (223 +/- 33 pmol). These findings indicate that a diet containing sesamin may thus reduce hepatic ischemia-reperfusion injury by inducing both antioxidant and anti-inflammatory activities.


en: Analysis of the prognostic factors for liver metastasis of gastric cancer after hepatic resection: a multi-institutional study of the indications for resection

en: The number of reports of hepatic resection for metastatic gastric cancer is very small. The outcome and indications of hepatic resection for metastatic gastric cancer remains unknown. A multi-institutional study was made. Thirty-six patients who underwent a hepatic resection for liver metastasis of gastric cancer with no residual tumor were included in this study. The clinicopathological factors were examined as prognostic factors by multivariate analyses. Thirty patients had recurrence and the recurrence pattern and risk factors for extrahepatic recurrence was examined. The overall survival rate was 64% at 1 year, 43% at 2 years, 26% at 3 years 26% at 5 years, and 26% at 10 years after hepatectomy. Multivariate analysis showed that lymphatic invasion, venous invasion of cancer cells of primary gastric cancer and the number of the liver metastasis (> 3) were independent poor prognostic factors after hepatic resection. The most common recurrence pattern was intrahepatic recurrence in 22 patients (73%). The risk factors for extrahepatic recurrence was serosal invasion, lymph node metastasis of primary gastric cancer, stage, and curability of operation. Hepatic resection for liver metastasis should be attempted in case primary gastric cancer has neither lymphatic invasion nor venous invasion. The most common recurrent site was the liver. In patients with advanced gastric cancer, having neither serosal invasion nor lymph node metastasis, who underwent a less curative operation, the intra-hepatic recurrence would be expected. Thus, aggressive adjuvant chemotherapy through the hepatic artery may improve the survival after hepatectomy in these patients.


en: Antisense RNAs transcribed from the upstream region of the precore/core promoter of hepatitis B virus

en: Society for General Microbiology

ja: Society for General Microbiology

en: The bidirectional activity of the precore/core promoter of hepatitis B virus (HBV) has been demonstrated in cultured cell lines. However, HBV antisense transcripts (asRNAs) have not been demonstrated in vivo. In the present study using liver tissue from patients with chronic hepatitis, an anchored 5'RACE mapping the 5' ends at position 1680/1681, 1655 or 1609/1602 was carried out. In limited cases, RLM-3'RACE detected asRNAs to terminate at four or five consecutive dT residues in the 0.7 kb downstream region. PCR of oligo(dT)-primed cDNA did not amplify a typical polyadenylated asRNA. RT-PCR using various primers did not detect any spliced forms. Competitive RT-PCR estimated the copy numbers of the asRNAs to be 0.05-0.4 % of total sense RNAs. All sequenced asRNAs had ORF6 but, in one patient, the asRNA initiating at position 1680/1681 had additional initiation and termination codons in front of ORF6. Therefore, asRNAs are transcribed by RNA polymerase III at a low level, encompass a dispensable ORF6 gene and might be retained in the nucleus. The endogenous asRNAs complementary to the common ends of all sense RNAs suggest antisense-mediated self-regulation of hepadnavirus.


en: The role of MTA1 gene expression in human hepatocellular carcinoma

en: The MTA1 gene has been identified as metastasis-associated gene and has been seen to correlate with the degree of invasion and lymphatic metastasis in gastric, colorectal, and esophageal carcinomas. We investigated the possible role of MTA1 gene expression in hepatocellular carcinoma (HCC). The mRNA expression level of the MTA1 gene was examined using reverse transcription polymerase chain reaction (RT-PCR) in HCC and paired non-tumor liver tissues which were obtained from 33 patients who underwent curative hepatectomy. The expression level of each case was calculated as tumor/non-tumor (T/N) ratios. To clarify the clinical significance of MTA1 gene expression in HCC, patient disease-free survival rate after hepatectomy were univariately analyzed using 25 clinicopathological variables, including MTA1 expression level. High expression (T/N > or =1) of the MTA1 gene in HCC as compared to the paired non-tumor tissues was recognized in 14 of 33 (42%) samples. With regard to the differentiation of HCC, the high expression of MTA1 gene in well or moderately differentiated HCC and poorly differentiated HCC were observed in 9 of 27 (33%) and 5 of 6 (83%) samples, respectively. There was no relation between expression levels of the MTA1 gene and cancer invasion to the portal vein or intrahepatic metastasis. However, the disease-free survival rate of the MTA1-high expression group (T/N > or =1) was significantly lower than that of the MTA1-low expression group (T/N <1) (p<0.05). High expression of the MTA1 gene is suggested to be a new prognostic indicator after curative hepatectomy for HCC.


en: Histone deacetylase inhibitor trichostatin A induces cell-cycle arrest/apoptosis and hepatocyte differentiation in human hepatoma cells

en: Wiley-Liss, Inc.

ja: Wiley-Liss, Inc.

en: Remodeling of the chromatin template by inhibition of HDAC activities represents a potential transcriptional therapy for neoplastic disease. A number of HDAC inhibitors that modulate in vitro cell growth and differentiation have been developed. We analyzed the effects of TSA, a specific and potent HDAC inhibitor, on the human hepatoma cell lines HepG2 and Huh-7. TSA increased levels of acetylated histones H3 and H4 in both HepG2 and Huh-7. It inhibited cell proliferation in vitro and induced G(0)/G(1) arrest in HepG2 and apoptosis in Huh-7. Gene expression of liver-specific functions and liver-enriched transcription factors was upregulated by TSA. TSA upregulated the ammonia removal rate and the albumin synthesis rate of HepG2 and Huh-7. Our results indicate that TSA can induce cell-cycle arrest/apoptosis and hepatocyte differentiation in human liver cancer cell lines.


en: Low-dose cisplatin plus oral tegafur and uracil for the treatment of lung metastases of hepatocellular carcinoma

en: An effective treatment for unresectable multiple lung metastases of hepatocellular carcinoma have never been established. Six patients received the chemotherapy described herein as an initial treatment for lung metastases of hepatocellular carcinoma. Low-dose cisplatin infusion plus oral tegafur and uracil administration combination therapy essentially consisted of cisplatin (10 mg/day over 1 hour) infused on days 1-5 every week and oral tegafur and uracil (300 mg/day) administrated every day. This treatment was repeated weekly for essentially 4 consecutive weeks. Complete response was observed in no cases and partial response in 3 cases, while no change was observed in 4 cases and progressive disease in one case. An overall response rate was 50%. The serum alpha-fetoprotein and des-Y-carboxyprothrombin were reduced in most of the patients. Leukopenia of grade 2 was observed in only 1 (17%) patient. Thrombocytopenia of grade 2 was observed in 2 (33%) patients. Nausea (up to Grade 2) was occurring in 4 (67%) patients. Three patients with no other distant metastasis survive more than two years after lung metastasis, and the quality of life of these patients are well preserved. Low-dose cisplatin infusion combined with oral tegafur and uracil administration for the treatment of lung metastases of hepatocellular carcinoma may be an effective regimen with a high response rate and acceptable toxicities, although a larger study will be necessary to confirm the efficacy.


en: Efficacy of a polyurethane foam/spheroid artificial liver by using human hepatoblastoma cell line (Hep G2)

en: Cognizant Communication Corporation

ja: Cognizant Communication Corporation

en: We invesigated the availability of human hepatoblastoma cell line (Hep G2), compared with human primary hepatocytes (HH) and porcine primary hepatocytes (PH), as a cell source for the hybrid artificial liver support system (HALSS) by using polyurethane foam (PUF). All three kinds of hepatocytes spontaneously formed spherical multicellular aggregates (spheroids) of 100-200 microm diameter in the pores of PUF within 3 days of culture. In a PUF stationary culture, Hep G2 spheroids recovered the ammonia removal activity that was lost in monolayer culture, although the removal for each unit cell number was about one tenth that of HH spheroids and about one eighth of PH spheroids. The synthesis activities of albumin and fibrinogen of each unit cell number of Hep G2 were also upregulated by PUF spheroid culture, and were about twice as high as in monolayer culture. The albumin secretion activity of Hep G2 spheroids was almost the same as that of PH spheroids. HH scarcely secreted these proteins in this experiment, probably because they were cultured in a serum-free medium. In the PUF module in a circulation culture, HH had high ammonia removal and low synthesis activities similar to stationary culture. Hep G2 proliferated to a high cell density, such as about 4.8 x 10(7) cells/cm3-module at 10 days of culture. Although Hep G2 spheroids had low ammonia removal activity in each cell, the removal rate in the PUF module was almost the same as for PH at 7 days of culture because of the high cell density culture by cell proliferation. The albumin secretion rate by Hep G2 in the PUF module also increased with cell proliferation and was about 10 times higher than the initial for the rate for PH at 7 days of culture. These results suggest that Hep G2 is a potential cell source PUF-HALSS.


en: Potent cytotoxic effect of the trans10, cis12 isomer of conjugated linoleic acid on rat hepatoma dRLh-84 cells

en: Elsevier Science

ja: Elsevier Science


en: Dose-dependent effect of dietary conjugated linoleic acid on the growth of rat hepatoma dRLh-84 cells in vivo

en: The Japanese Society of Food & Nutrition and the Vitamin Society of Japan

en: In this study, the effect of varying doses of conjugated linoleic acid (CLA) on the growth of transplanted hepatoma dRLh-84 cells and the relationship between tumor growth and prostaglandin (PG) E2 production or cyclooxygenase (COX)-2 expression were examined. Donryu rats were fed an experimental diet containing 0, 0.1, 0.5, or 2 wt.% CLA for 3 wk, and then dRLh-84 cells were transplanted into the liver. Results show that dietary CLA (0.5 and 2 wt.%) significantly enhanced the growth of the transplanted hepatoma cells compared to the non-CLA diet group at 20 d after cell transplantation. Tumor weight at 10 d after transplantation was also significantly higher in the 2 wt.% CLA group than in non-CLA fed rats. Ten days after transplantation, the PGE2 level in the tumor tissue was shown to be depressed in a CLA dose-dependent manner. Cyclooxygenase-2 (COX-2) mRNA expression in the tumor also tended to be lower in the CLA group than in the non-CLA diet group 10 d after transplantation. Dietary CLA did not affect the tumor phospholipid arachidonic acid level, which is a substrate for PG synthesis. These results indicate that dietary CLA of at least 0.5 wt.% enhances the growth of transplanted dRLh-84 cells in vivo. It is believed that growth promotion of dRLh-84 cells in vivo by CLA cannot be clarified by the PG synthesis dependent mechanism.


en: The utility of keratin 903 as a new prognostic marker in mass-forming-type intrahepatic cholangiocarcinoma

en: the United States and Canadian Academy of Pathology,Inc

en: The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development. We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80% of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10%), 6 (20%), and 1 (3%) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74%), 66 (90%), and 61 (84%) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P <.0001), in those with medullary-type stromal reaction (P =.0327), in those without perineural invasion (P =.0001), and in those without lymph node metastasis (P =.0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P =.0153 and P <.0001, respectively). Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor. In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.


en: ロボット手術システム(da Vinci)のための術中ナビゲーターの開発

ja: ロボット手術システム(da Vinci)のための術中ナビゲーターの開発