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| 1.
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Hayashi, Tomoyuki ; Yamashita, Taro ; Terashima, Takeshi ; Suda, Tsuyoshi ; Okada, Hikari ; Asahina, Yoshiro ; Hayashi, Takehiro ; Hara, Yasumasa ; Nio, Kouki ; Sunagozaka, Hajime ; Takatori, Hajime ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi ; 林, 智之 ; 山下, 太郎 ; 寺島, 健志 ; 須田, 烈史 ; 岡田, 光 ; 朝日向, 良朗 ; 丹尾, 幸樹 ; 砂子阪, 肇 ; 鷹取, 元 ; 荒井, 邦明 ; 山下, 竜也 ; 水腰, 英四郎 ; 本多, 政夫 ; 金子, 周一
概要:
金沢大学先進予防医学研究科<br />Background: Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survi
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val in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles. Methods: Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-γ, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-β, TGF-α, TNF-α, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses. Results: The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-α. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL-8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL-5, IL-8, TGF-α, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC. Conclusions: Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment. © 2017 The Author(s).
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| 2.
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Nakamoto, Yasunari ; Mizukoshi, Eishiro ; Kitahara, Masaaki ; Arihara, Fumitaka ; Sakai, Yoshio ; Kakinoki, Kaheita ; Fujita, Yui ; Marukawa, Yohei ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mukaida, Naofumi ; Matsushima, Kouji ; Matsui, Osamu ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates
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remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0.1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 106 of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0.046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer. © 2010 The Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology.
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| 3.
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Kakinoki, Kaheita ; Nakamoto, Yasunari ; Kagaya, Takashi ; Tsuchiyama, Tomoya ; Sakai, Yoshio ; Nakahama, Tohru ; Mukaida, Naofumi ; Kaneko, Shuichi
概要:
金沢大学医薬保健研究域医学系<br />The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of i
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ntrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system.Methods: Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV-tk, CCL2/MCP-1 and LacZ at multiplicities of infection of Ad-tk/Ad-MCP1 = 3/0.03 (T/MLow), 3/3 (T/MHigh) and Ad-tk/Ad-LacZ = 3/3 (T/L) were injected into BALB/c mice.Results: Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor-specific cytolytic activities of splenocytes from T/MLow and T/MHigh mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac-1+ and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/MLow mice. In addition, interleukin-12 production was elevated in these tissues. Vascular endothelial growth factor-A expression and CD31+ microvessels were increased in T/MHigh mice.Conclusions: Collectively, these results demonstrate that an adequate amount of CCL2/MCP-1, together with the HSV-tk/GCV system, may induce T helper 1-polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. © 2010 John Wiley & Sons, Ltd.
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| 4.
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Hodo, Yuji ; Hashimoto, Shin-ichi ; Honda, Masao ; Yamashita, Taro ; Suzuki, Yutaka ; Sugano, Sumio ; Kaneko, Shuichi ; Matsushima, Kouji
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金沢大学医薬保健研究域医学系<br />To elucidate the molecular feature of human hepatocellular carcinoma (HCC), we performed 5'-end seri
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al analysis of gene expression (5'SAGE), which allows genome-wide identification of transcription start sites in addition to quantification of mRNA transcripts. Three 5'SAGE libraries were generated from normal human liver (NL), non-B, non-C HCC tumor (T), and background non-tumor tissues (NT). We obtained 226,834 tags from these libraries and mapped them to the genomic sequences of a total of 8,410 genes using RefSeq database. We identified several novel transcripts specifically expressed in HCC including those mapped to the intronic regions. Among them, we confirmed the transcripts initiated from the introns of a gene encoding acyl-coenzyme A oxidase 2 (. ACOX2). The expression of these transcript variants were up-regulated in HCC and showed a different pattern compared with that of ordinary ACOX2 mRNA. The present results indicate that the transcription initiation of a subset of genes may be distinctively altered in HCC, which may suggest the utility of intronic RNAs as surrogate tumor markers. © 2010 Elsevier Inc.
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Kaneko, Shuichi ; Furuse, Junji ; Kudo, Masatoshi ; Ikeda, Kenji ; Honda, Masao ; Nakamoto, Yasunari ; Onchi, Morikazu ; Shiota, Goshi ; Yokosuka, Osamu ; Sakaida, Isao ; Takehara, Tetsuo ; Ueno, Yoshiyuki ; Hiroishi, Kazumasa ; Nishiguchi, Shuhei ; Moriwaki, Hisataka ; Yamamoto, Kazuhide ; Sata, Michio ; Obi, Shuntaro ; Miyayama, Shiro ; Imai, Yukinori
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The "Guideline on the Use of New Anticancer Drugs for the Treatment of Hepatocellular Carcinoma" was prepared by the Stu
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dy Group on New Liver Cancer Therapies established by the "Research Project on Emergency Measures to Overcome Hepatitis" under the auspices of the Health and Labour Sciences Research Grant. The Guideline brings together data collected by the Study Group on the use and incidence of adverse events in 264 patients with advanced hepatocellular carcinoma (HCC) treated using sorafenib and in 535 patients with advanced HCC treated using miriplatin at 16 participating institutions up until 22 December 2010, as well as referring to the published studies, academic presentations, and reports from the private sector. The aim of this Guideline is to facilitate understanding and current thinking regarding the proper usage of new anticancer drugs towards actual use in therapy. In terms of the format, the Guideline presents "clinical questions" on issues pertaining to medical care, makes "recommendations" on diagnosis and treatment in response to each of these clinical questions, and provides a rationale for these recommendations in the form of "scientific statements". © 2012 The Japan Society of Hepatology.
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| 6.
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Terashima, Takeshi ; Yamashita, Tatsuya ; Arai, Kuniaki ; Sunagozaka, Hajime ; Kitahara, Masaaki ; Nakagawa, Hidetoshi ; Kagaya, Takashi ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
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Aim: Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC). However, although there is no prov
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en therapeutic procedure following the termination of sorafenib, hepatic arterial infusion chemotherapy (HAIC) may be a treatment option in advanced HCC. The aim of this study was to evaluate feasibility and efficacy of HAIC for patients with advanced HCC as subsequent therapy. Methods: We retrospectively evaluated 27 consecutive patients with advanced HCC who were treated with HAIC following sorafenib between June 2009 and December 2012 at our hospital. Cisplatin (20 mg/m2 per day) was administered via the hepatic artery for 10 min, prior to the continuous administration of 5-fluorouracil (330 mg/m2 per day) over 24 h from days 1-5 and 8-12 and the s.c. administration of pegylated interferon α-2b (1 μg/kg) on days 1, 8, 15, and 22. A treatment cycle consisted of 28 days of drug administration followed by 14 days of rest. Results: The toxicity profile showed that hematological toxicities were common, and grade 3/4 neutropenia and thrombocytopenia were observed (51.9% and 48.1%, respectively). Five patients (18.5%) experienced device-related complications. No unexpected adverse reactions and no treatmentrelated deaths were observed. Partial response was obtained in eight patients (29.6%), and stable disease was noted in nine patients (33.3%). Median progression-free survival and median survival time from initiation of HAIC were 4.0 and 7.6 months, respectively. Conclusions: Because HAIC was well tolerated and exhibited moderate antitumor activity, it is a potentially useful treatment procedure in patients with advanced HCC even after failure of sorafenib.
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| 7.
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Terashima, Takeshi ; Yamashita, Tatsuya ; Takata, Noboru ; Nakagawa, Hidetoshi ; Toyama, Tadashi ; Arai, Kuniaki ; Kitamura, Kazuya ; Yamashita, Taro ; Sakai, Yoshio ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi
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Aim: Although sorafenib is a standard drug for advanced hepatocellular carcinoma (HCC), little is known about a patient'
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s clinical course after treatment. We investigated the effect of post-progression survival (PPS) and progression-free survival (PFS) on overall survival (OS) in patients whose advanced HCC was treated by sorafenib. Methods: We searched in the PubMed database for reports with survival data of patients with HCC treated with sorafenib monotherapy, and selected reports with 20 or more patients each that provided data for both OS and PFS or time to progression (TTP). Median PPS (mPPS) was defined as the period obtained by subtracting median PFS or TTP (mPFS/TTP) from median OS (mOS). We identified 56 reports with 5803 patients. We investigated the correlation of mOS and either mPPS or mPFS/TTP using weighted linear regression. Results: Median PPS correlated with mOS (r=0.834) very strongly, whereas mPFS/TTP did not correlate with mOS as highly as PPS did (r=0.546). When we stratified survival data by Child-Pugh classification, a significantly greater average percentage of mPPS to mOS was seen in Child-Pugh class A (54.4±17.6%) than in Child-Pugh class B (32.0±11.6%) (P=0.015). Conclusion: PPS highly correlated with OS, and its importance should be more emphasized for advanced HCC patients treated after sorafenib therapy, whereas we need to take more care in interpreting the results of PFS to evaluate treatment efficacy in clinical trials of advanced HCC. © 2015 The Japan Society of Hepatology.<br />Embargo Period 12 months
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| 8.
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Okada, Hikari ; Honda, Masao ; Campbell, Jean S. ; Takegoshi, Kai ; Sakai, Yoshio ; Yamashita, Taro ; Shirasaki, Takayoshi ; Takabatake, Riuta ; Nakamura, Mikiko ; Tanaka, Takuji ; Kaneko, Shuichi
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医薬保健研究域保健学系<br />Differentially regulated microRNA (miRNA) are associated with hepatic fibrosis; however, their potentia
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l usefulness for blocking hepatic fibrosis has not been exploited fully. We examined the expression of miRNA in the liver of a transgenic mouse model in which platelet-derived growth factor C (PDGF-C) is overexpressed (Pdgf-c Tg), resulting in hepatic fibrosis and steatosis and the eventual development of hepatocellular carcinoma (HCC). Robust induction of miR-214 correlated with fibrogenesis in the liver of Pdgf-c Tg mice, atherogenic high-fat diet-induced NASH mice, and patients with chronic hepatitis B or C. Pdgf-c Tg mice were injected with locked nucleic acid (LNA)-antimiR-214 via the tail vein using Invivofectamine 2.0 and the degree of hepatic fibrosis and tumor incidence were evaluated. Pdgf-c Tg mice treated with LNA-antimiR-214 showed a marked reduction in fibrosis and tumor incidence compared with saline or LNA-miR-control-injected control mice. In vitro, LNA-antimiR-214 significantly ameliorated TGF-β1-induced pro-fibrotic gene expression in Lx-2 cells. MiR-214 targets a negative regulator of EGFR signaling, Mig-6. Mimic-miR-214 decreased the expression of Mig-6 and increased the levels of EGF-mediated p-EGFR (Y1173 and Y845) and p-Met (Tyr1234/1235) in Huh-7 cells. Conversely, LNA-antimiR-214 repressed the expression of these genes. In conclusion, miR-214 appears to participate in the development of hepatic fibrosis by modulating the EGFR and TGF-β signaling pathways. LNA-antimiR-214 is a potential therapy for the prevention of hepatic fibrosis. MiR-214 appears to participate in the development of hepatic fibrosis by modulating EGFR and TGF-β signaling pathways. LNA-anti-miR-214 may be a potentially therapy in the prevention of hepatic fibrosis. © 2015 Japanese Cancer Association.
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Yamashita, Taro ; Honda, Masao ; Kaneko, Shuichi
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金沢大学医薬保健研究域医学系<br />Hepatitis C virus (HCV) infection is a major cause of hepatocellular carcinoma (HCC) and chronic liv
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er disease worldwide. Recent developments and advances in HCV replication systems in vitro and in vivo, transgenic animal models, and gene expression profiling approaches have provided novel insights into the mechanisms of HCV replication. They have also helped elucidate host cellular responses, including activated/inactivated signaling pathways, and the relationship between innate immune responses by HCV infection and host genetic traits. However, the mechanisms of hepatocyte malignant transformation induced by HCV infection are still largely unclear, most likely due to the heterogeneity of molecular paths leading to HCC development in each individual. In this review, we summarize recent advances in knowledge about the mechanisms of hepatocarcinogenesis induced by HCV infection. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.
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| 10.
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Takata, Yoshiko ; Nakamoto, Yasunari ; Nakada, Akiko ; Terashima, Takeshi ; Arihara, Fumitaka ; Kitahara, Masaaki ; Kakinoki, Kaheita ; Arai, Kuniaki ; Yamashita, Taro ; Sakai, Yoshio ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Kaneko, Shuichi
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金沢大学医薬保健研究域医学系<br />The purpose of this study was to assess the properties of CD4+CD25high/low/negative T cell subsets a
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nd analyze their relation with dendritic cells (DCs) in patients with hepatocellular carcinoma (HCC). In HCC patients, the prevalence of CD45RO+ cells in CD4+CD25high T cells was increased and associated with higher frequencies of plasmacytoid DCs. Larger proportions of this T cell subset were detected in the patients with larger tumor burdens. These results suggest that increased frequencies of the CD45RO+ subset in CD4+CD25high Tregs in HCC patients may establish the immunosuppressive environment cooperatively with tolerogenic plasmacytoid DCs to promote disease progression of liver cancer. © 2011.
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| 11.
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Sunagozaka, Hajime ; Honda, Masao ; Yamashita, Taro ; Nishino, Ryuhei ; Takatori, Hajime ; Arai, Kuniaki ; Yamashita, Tatsuya ; Sakai, Yoshio ; Kaneko, Shuichi
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金沢大学医薬保健研究域医学系<br />The identification of genes involved in tumor growth is crucial for the development of inventive ant
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icancer treatments. Here, we have cloned a 17-kDa secretory protein encoded by c19orf10 from hepatocellular carcinoma (HCC) serial analysis of gene expression libraries. Gene expression analysis indicated that c19orf10 was overexpressed in approximately two-thirds of HCC tissues compared to the adjacent noncancerous liver tissues, and its expression was significantly positively correlated with that of alpha-fetoprotein (AFP). Overexpression of c19orf10 enhanced cell proliferation of AFP-negative HLE cells, whereas knockdown of c19orf10 inhibited cell proliferation of AFP-positive Hep3B and HuH7 cells along with G1 cell cycle arrest. Supplementation of recombinant c19orf10 protein in culture media enhanced cell proliferation in HLE cells, and this effect was abolished by the addition of antibodies developed against c19orf10. Intriguingly, c19orf10 could regulate cell proliferation through the activation of Akt/mitogen-activated protein kinase pathways. Taken together, these data suggest that c19orf10 might be one of the growth factors and potential molecular targets activated in HCC. © 2010 UICC.
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Zeng, Sha Sha ; Yamashita, Taro ; Kondo, Mitsumasa ; Nio, Kouki ; Hayashi, Takehiro ; Hara, Yasumasa ; Nomura, Yoshimoto ; Yoshida, Mariko ; Hayashi, Tomoyuki ; Oishi, Naoki ; Ikeda, Hiroko ; Honda, Masao ; Kaneko, Shuichi
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Background & Aims: Recent evidence suggests that hepatocellular carcinoma can be classified into certain molecular subty
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pes with distinct prognoses based on the stem/maturational status of the tumor. We investigated the transcription program deregulated in hepatocellular carcinomas with stem cell features. Methods: Gene and protein expression profiles were obtained from 238 (analyzed by microarray), 144 (analyzed by immunohistochemistry), and 61 (analyzed by qRT-PCR) hepatocellular carcinoma cases. Activation/suppression of an identified transcription factor was used to evaluate its role in cell lines. The relationship of the transcription factor and prognosis was statistically examined. Results: The transcription factor SALL4, known to regulate stemness in embryonic and hematopoietic stem cells, was found to be activated in a hepatocellular carcinoma subtype with stem cell features. SALL4-positive hepatocellular carcinoma patients were associated with high values of serum alpha fetoprotein, high frequency of hepatitis B virus infection, and poor prognosis after surgery compared with SALL4-negative patients. Activation of SALL4 enhanced spheroid formation and invasion capacities, key characteristics of cancer stem cells, and up-regulated the hepatic stem cell markers KRT19, EPCAM, and CD44 in cell lines. Knockdown of SALL4 resulted in the down-regulation of these stem cell markers, together with attenuation of the invasion capacity. The SALL4 expression status was associated with histone deacetylase activity in cell lines, and the histone deacetylase inhibitor successfully suppressed proliferation of SALL4-positive hepatocellular carcinoma cells. Conclusions: SALL4 is a valuable biomarker and therapeutic target for the diagnosis and treatment of hepatocellular carcinoma with stem cell features. © 2013 European Association for the Study of the Liver.
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Fujii, Chifumi ; Nakamoto, Yasunari ; Lu, Peirong ; Tsuneyama, Koichi ; Popivanova, Boryana K. ; Kaneko, Shuichi ; Mukaida, Naofumi
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金沢大学がん研究所がん病態制御<br />Most cases of human hepatocellular carcinoma develop after persistent chronic infection with human
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hepatitis B virus or hepatitis C virus, and host responses are presumed to have major roles in this process. To recapitulate this process, we have developed the mouse model of hepatocellular carcinoma using hepatitis B virus surface antigen transgenic mice. To identify the genes associated with hepatocarcinogenesis in this model, we compared the gene expression patterns between pre-malignant lesions surrounded by hepatocellular carcinoma tissues and control liver tissues by using a fluorescent differential display analysis. Among the genes that were expressed differentially in the pre-malignant lesions, we focused on Pim-3, a member of a proto-oncogene Pim family, because its contribution to hepatocarcinogenesis remains unknown. Moreover, the unavailability of the nucleotide sequence of full-length human Pim-3 cDNA prompted us to clone it from the cDNA library constructed from a human hepatoma cell line, HepG2. The obtained 2,392 bp human Pim-3 cDNA encodes a predicted open reading frame consisting of 326 amino acids. Pim-3 mRNA was selectively expressed in human hepatoma cell lines, but not in normal liver tissues. Moreover, Pim-3 protein was detected in human hepatocellular carcinoma tissues and cell lines but not in normal hepatocytes. Furthermore, cell proliferation was attenuated and apoptosis was enhanced in human hepatoma cell lines by the ablation of Pim-3 gene with RNA interference. These observations suggest that aberrantly expressed Pim-3 can cause autonomous cell proliferation or prevent apoptosis in hepatoma cell lines. © 2004 Wiley-Liss, Inc.
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