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Tokuhiro Matsubara,
Tatsuya Kanto,
Shoko Kuroda,
Sachiyo Yoshio,
Koyo Higashitani,
Naruyasu Kakita,
Masanori Miyazaki,
Mitsuru Sakakibara,
Naoki Hiramatsu,
Akinori Kasahara,
Yoshito Tomimaru, Akira Tomokuni,
Hiroaki Nagano,
Norio Hayashi,
Tetsuo Takehara
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ABSTRACT: Angiogenesis is deemed to be a critical step in the development and progression of vascular-rich hepatocellular carcinoma (HCC). In this process, myeloid lineage cells, such as macrophages and monocytes, have been reported to act as vascular progenitor cells. TIE-2, a receptor of angiopoietins, conveys pro-angiogenic signals. We thus aimed to clarify the roles of TIE2-expressing monocytes (TEMs) in the clinical management of HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC and examined the frequency of TEMs, as defined as CD14(+) CD16(+) TIE2(+) cells, in the periphery and in the liver. The localization of TEMs in the liver was determined by immunofluorescence. Micro-vessel formation in the liver was quantified by counting CD34(+) cells. In HCC patients, the frequency of TEMs in the periphery was significantly higher than those in non-HCC groups, and also was higher in the liver than in the periphery. In patients who underwent local ablation or resection of HCC, the frequency of TEMs dynamically changed in parallel with the recurrence of HCC. Most TEMs were identified in the perivascular area of cancer tissues. A significant positive correlation was observed between micro-vessel density in HCC tissues and the peripheral or intra-tumor frequencies of TEMs, suggesting that TEMs are involved in angiogenesis in the liver. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 levels as a diagnostic for HCC. CONCLUSION: TEMs are increased in patients with HCC and change in parallel with the therapeutic response or recurrence. The frequency of TEMs can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver. (HEPATOLOGY 2012.).
Hepatology 07/2012; · 11.66 Impact Factor
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Hiromitsu Hoshino,
Hiroaki Nagano,
Naotsugu Haraguchi,
Shimpei Nishikawa, Akira Tomokuni,
Yoshihiro Kano,
Takahito Fukusumi,
Toshiyuki Saito,
Miyuki Ozaki,
Daisuke Sakai,
Taroh Satoh,
Hidetoshi Eguchi,
Mitsugu Sekimoto,
Yuichiro Doki,
Masaki Mori,
Hideshi Ishii
[show abstract]
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ABSTRACT: Induced pluripotent stem (iPS)-like cancer cells (iPC) by the introduction of defined transcription factors reduce the prevalence of the malignant phenotype of digestive system cancer cells, but the induction efficiency is low. The role of hypoxia and TP53 deficiency in iPC cell generation remain unclear. Cellular reprogramming was performed by retroviral infection with OCT3/4, SOX2, KLF4 and c-MYC of wild-type HCT116 colorectal cancer cells and mutant TP53-deficient HCT116 cells. Cells were cultured in normoxia (21% O2) or hypoxia (5% O2) for 30 days after transduction, and the response to hypoxia and comparison of cellular proliferation, invasion and tumourigenesis before and after iPC cell generation were studied. iPC cell generation from wild-type HCT116 cells in hypoxia was approximately 4-times greater than in normoxia (p<0.05), and TP53 deficiency increased conversion efficiency significantly in normoxia (p<0.05). Significant involvement of hypoxia-inducible factors was observed in an immature carbohydrate epitope, Tra-1-60+, colony formation. Generated iPC cells exhibited multi-differentiation potential. Although the iPC cells in hypoxia exhibited reduced proliferation, invasiveness and tumourigenicity, TP53 deficiency in iPC cells resulted in higher tumourigenicity than in wild-type cells. Both hypoxia and TP53 deficiency increase iPC cell generation. TP53 deficiency can also result in deleterious mutations, whereas hypoxia may impact molecular targets of epigenome normalisation.
International Journal of Oncology 01/2012; 40(5):1423-30. · 2.40 Impact Factor
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Akira Tomokuni,
Hidetoshi Eguchi,
Yoshito Tomimaru,
Hiroshi Wada,
Koichi Kawamoto,
Shogo Kobayashi,
Shigeru Marubashi,
Masahiro Tanemura,
Hiroaki Nagano,
Masaki Mori,
Yuichiro Doki
[show abstract]
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ABSTRACT: Interferon-based (IFN-based) therapy is effective in the treatment of advanced hepatocellular carcinoma (HCC). However, the issue of resistance to this therapy remains to be solved. The aim of this study was to identify microRNAs (miRNAs) that govern the sensitivity to IFN-α in HCC cells.
miRNA microarray analysis using IFN-α-resistant clones of PLC/PRF/5 (PLC-Rs) and their parental cells (PLC-P) was conducted. Changes in the anti-cancer effects of IFN-α were studied after gain-of-function and loss-of-function of the candidate miRNA.
miR-146a expression was significantly higher in PLC-Rs than in PLC-P. miR-146a decreased the sensitivity to IFN-α through the suppression of apoptosis. Further experiments showed that miR-146a-related resistance to IFN-α was mediated through SMAD4.
The results indicated that miR-146a regulated the sensitivity of HCC cells to the cytotoxic effects of IFN-α through SMAD4, suggesting that this miRNA could be suitable for prediction of the clinical response and potential therapeutic target in HCC patients on IFN-based therapy.
Biochemical and Biophysical Research Communications 11/2011; 414(4):675-80. · 2.48 Impact Factor
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Takahiro Kodama,
Tetsuo Takehara,
Hayato Hikita,
Satoshi Shimizu,
Minoru Shigekawa,
Hinako Tsunematsu,
Wei Li,
Takuya Miyagi,
Atsushi Hosui,
Tomohide Tatsumi, [......],
Tatsuya Kanto,
Naoki Hiramatsu,
Satoshi Kubota,
Masaharu Takigawa,
Yoshito Tomimaru, Akira Tomokuni,
Hiroaki Nagano,
Yuichiro Doki,
Masaki Mori,
Norio Hayashi
[show abstract]
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ABSTRACT: The tumor suppressor p53 has been implicated in the pathogenesis of non-cancer-related conditions such as insulin resistance, cardiac failure, and early aging. In addition, accumulation of p53 has been observed in the hepatocytes of individuals with fibrotic liver diseases, but the significance of this is not known. Herein, we have mechanistically linked p53 activation in hepatocytes to liver fibrosis. Hepatocyte-specific deletion in mice of the gene encoding Mdm2, a protein that promotes p53 degradation, led to hepatocyte synthesis of connective tissue growth factor (CTGF; the hepatic fibrogenic master switch), increased hepatocyte apoptosis, and spontaneous liver fibrosis; concurrent removal of p53 completely abolished this phenotype. Compared with wild-type controls, mice with hepatocyte-specific p53 deletion exhibited similar levels of hepatocyte apoptosis but decreased liver fibrosis and hepatic CTGF expression in two models of liver fibrosis. The clinical significance of these data was highlighted by two observations. First, p53 upregulated CTGF in a human hepatocellular carcinoma cell line by repressing miR-17-92. Second, human liver samples showed a correlation between CTGF and p53-regulated gene expression, which were both increased in fibrotic livers. This study reveals that p53 induces CTGF expression and promotes liver fibrosis, suggesting that the p53/CTGF pathway may be a therapeutic target in the treatment of liver fibrosis.
The Journal of clinical investigation 08/2011; 121(8):3343-56. · 15.39 Impact Factor
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Yoshito Tomimaru,
Hidetoshi Eguchi,
Hiroaki Nagano,
Hiroshi Wada,
Shogo Kobayashi,
Shigeru Marubashi,
Masahiro Tanemura, Akira Tomokuni,
Ichiro Takemasa,
Koji Umeshita,
Tatsuya Kanto,
Yuichiro Doki,
Masaki Mori
[show abstract]
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ABSTRACT: Several groups have reported the significance of circulating microRNA as a biochemical marker of cancer. To our knowledge, however, there are no reports on the significance of circulating microRNA in hepatocellular carcinoma. The aim of this study was to evaluate the significance of plasma microRNA-21 level as a biochemical marker for hepatocellular carcinoma.
Plasma microRNA-21 level was measured by qRT-PCR in 10 patients before and after curative resection of hepatocellular carcinoma. Plasma microRNA-21 was also compared in other groups of: 126 patients with hepatocellular carcinoma, 30 patients with chronic hepatitis, and 50 healthy volunteers. The power of microRNA-21 in differentiating hepatocellular carcinoma from chronic hepatitis or from healthy volunteers was compared to that of α-fetoprotein.
In the 10-patient group, plasma microRNA-21 levels significantly diminished after surgery compared with the pre-operative values (p=0.0125). Plasma microRNA-21 level in the 126 patients with hepatocellular carcinoma was significantly higher than in patients with chronic hepatitis and healthy volunteers (p<0.0001, p<0.0001, respectively). ROC analysis of plasma microRNA-21 yielded an AUC of 0.773 with 61.1% sensitivity and 83.3% specificity when differentiating hepatocellular carcinoma from chronic hepatitis, and an AUC of 0.953 with 87.3% sensitivity and 92.0% specificity when differentiating hepatocellular carcinoma from healthy volunteers. Both sets of values were superior to α-fetoprotein and improved for the combination of microRNA-21 and α-fetoprotein.
Plasma microRNA-21 level is a promising biochemical marker for hepatocellular carcinoma.
Journal of Hepatology 07/2011; 56(1):167-75. · 9.26 Impact Factor
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Yoshito Tomimaru,
Hidetoshi Eguchi,
Hiroshi Wada, Akira Tomokuni,
Shogo Kobayashi,
Shigeru Marubashi,
Yutaka Takeda,
Masahiro Tanemura,
Koji Umeshita,
Masaki Mori,
Yuichiro Doki,
Hiroaki Nagano
[show abstract]
[hide abstract]
ABSTRACT: Interferon (IFN)-ß is reported to have more potent antitumor effects than IFN-α. The aim of this study was to compare the synergistic antitumor activity of both IFNs when combined with gemcitabine on cultured pancreatic cancer cells expressing various levels of IFN receptor. The growth-inhibitory effects of IFN-α and IFN-ß in combination with gemcitabine on three human pancreatic cancer cell lines (BxPC-3, MIAPaCa-2, Panc-1) were evaluated by MTT assay and isobolographic analysis. We also correlated their growth-inhibitory effects with the expression status of type I IFN receptor type 2 (IFNAR2). Western blot analysis indicated strong expression of IFNAR2 in BxPC-3 and MIAPaCa-2, but weak expression in Panc-1. The growth-inhibitory effect of gemcitabine was enhanced synergistically by IFN-α in BxPC-3 and MIAPaCa-2, but not in Panc-1. IFN-ß exhibited more potent synergistic growth-inhibitory effects with gemcitabine in BxPC-3 and MIAPaCa-2 compared to IFN-α, and also synergistic enhancement in Panc-1. In conclusion, our results indicated that the growth-inhibitory effect of IFN-ß with gemcitabine was synergistic not only in pancreatic cancer cells with strong expression of IFNAR2, but also in those with weak expression of IFNAR2.
International Journal of Oncology 02/2011; 38(5):1237-43. · 2.40 Impact Factor
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Hisanori Hatano,
Shogo Kobayashi,
Hiroaki Nagano, Akira Tomokuni,
Yoshito Tomimaru,
Masahiro Murakami,
Shigeru Marubashi,
Hidetoshi Eguchi,
Yutaka Takeda,
Masahiro Tanemura,
Kenichi Wakasa,
Yuichiro Doki,
Masaki Mori
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ABSTRACT: We report a case of successful multimodal treatment for combined hepatocellular and cholangiocarcinoma with portal venous tumor thrombus. A 66-year-old man was diagnosed with hepatocellular carcinoma with Vp3 by abdominal enhanced CT. He underwent a complete tumor resection and following interferon and 5-FU combined intra-arterial chemotherapy as an adjuvant setting. The histological findings were consistent with combined hepatocellular and cholangiocarcinoma. At 9 months after the surgery, lymph node metastases were detected. Then we started an oral fluoropyrimidine anticancer agent S-1, because the recurrence was suspected to be originated from the cholangiocarcinoma component. Thereafter, sustained partial remission was achieved. In case of combined hepatocellular and cholangiocarcinoma, we need to create a treatment strategy against characteristics of both components.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2009; 36(12):2374-6.
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Akira Tomokuni,
Shigeru Marubashi,
Hiroaki Nagano,
Shogo Kobayashi,
Hidetoshi Eguchi,
Yutaka Takeda,
Masahiro Tanemura,
Toru Kitagawa,
Keizo Dono,
Morito Monden,
Yuichiro Doki,
Masaki Mori
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ABSTRACT: A 68-year-old man lost in unconscious and was diagnosed as ruptured hepatocellular carcinoma (HCC) in a local emergency hospital. He was treated by transcatheter arterial embolization, and further investigation revealed simultaneous cancer in rectum. He was referred to our institute, and admitted in June 2005. He underwent lateral segment and S8 partial resection of the liver, cholecystectomy, anterior resection of rectum, and D3 lymphadenectomy in August 2005. Multiple HCC recurrences in the remnant liver appeared in December 2005. He was subsequently treated with transcatheter chemoembolization four times. In May 2006, CT scan revealed multiple metastatic nodules in bilateral lungs with remarkably elevated serum AFP and PIVKA-II. The nodules were diagnosed as lung metastasis of the HCC. Because the lesions grew larger, S-1 was started in February 2007. Diagnostic imaging and tumor markers showed a marked improvement 2 months after S-1 administration, and no recurrence has been found since then. This case illustrates that S-1 may be an effective treatment for HCC with extrahepatic metastasis.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2009; 36(12):2383-5.
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Daisuke Takiuchi,
Masahiro Tanemura,
Hiroaki Nagano,
Yoshiaki Ohmura, Akira Tomokuni,
Hironori Hatano,
Shogo Kobayashi,
Shigeru Marubashi,
Hidetoshi Eguchi,
Yutaka Takeda,
Toru Kitagawa,
Morito Monden,
Masaki Mori,
Yuichiro Doki
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ABSTRACT: A 50-year-old woman with epigastric uncomfortable feeling was referred to our hospital. We have diagnosed her as an advanced gallbladder cancer with direct liver invasion and lymph node metastasis of hepatoduodenal ligament by the image analysis, including enhanced abdominal CT, MRI and FDG-PET. Subsequently, we performed operation with cholecystectomy, hepatic segmentectomy of S4a/5, bile duct resection and D2 lymph node dissection, resulted in the curative operation. We additionally performed adjuvant chemotherapy with 6 courses of 800 mg/m2 of gemcitabine (GEM) on days 1, 8 and 15 for every 35 days. No recurrent signs were observed for 33 months after curative operation.
Gan to kagaku ryoho. Cancer & chemotherapy 11/2009; 36(12):2395-7.
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Tsunekazu Mizushima,
Hitoshi Mizuno,
Takashi Sugiura,
Toshikazu Ito,
Yuko Udatsu,
Mika Okazawa,
Keijiro Sugimura, Akira Tomokuni,
Hidenori Kusumoto,
Tomo Nakagawa,
Tomoya Kishimoto,
Kazuhiro Iwase,
Masaaki Izukura
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ABSTRACT: We investigated the efficacy of 5-FU hepatic artery infusion (HAI)for patients with unresectable colorectal liver metastasis. Fifteen patients who received HAI between June 2004 and December 2006 were studied. HAI was attempted as first-line chemotherapy in seven patients(Group A)and as second-line or more in eight(Group B). The response rate, time to progression, survival and toxicity were compared with those of 39 patients treated with systemic chemotherapy(18 as first-line: Group C, 21 as second-line or more: Group D). Response rate was 85.7%, 35.7%, 50.0%, and 4.8% in Groups A, B, C, and D, respectively. Time to progression was 12.5 months, 4.7 months, 5.8 months, and 2.3 months, in Groups A, B, C, and D, respectively, and significantly longer in Group A compared with Group C, as well as in Group B compared with Group D. Median survival was 15.4 months, 9.1 months, 11.3 months, and 8.0 months in Groups A, B, C, and D, respectively, and significantly longer in Group B compared with Group D. Grade 3 or 4 non-hematological toxicity was not observed in Group A and B. HAI was effective for the control of unresectable colorectal liver metastasis and improved survival as second-line chemotherapy or more.
Gan to kagaku ryoho. Cancer & chemotherapy 07/2008; 35(7):1139-42.
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ABSTRACT: We treated a patient with solitary fibrous tumor of the pleura (SFT) whose angiograms demonstrated its feeders and strongly contrasted tumor stain. Although no one has clearly identified the specific features of SFT on angiograms, SFT can be suspected in the clinical setting if a localized chest wall tumor presents with the feeders and strongly contrasted tumor stain shown by angiography.
The Japanese Journal of Thoracic and Cardiovascular Surgery 09/2004; 52(8):398-400.
