骨髄系血管・免疫前駆細胞を標的とした新規肝癌治療法の開発

• 研究課題/領域番号: 22590729
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器内科学
• 研究機関: 大阪大学
• 研究代表者: 考藤 達哉 大阪大学, 医学系研究科, 寄附講座准教授 (80372613)
• 研究分担者: 竹原 徹郎 大阪大学, 大学院・医学系研究科, 教授 (70335355) ; 平松 直樹 大阪大学, 大学院・医学系研究科, 講師 (30362700)
• 研究期間 (年度): 2010 – 2012
• 研究課題ステータス: 完了 (2012年度)
• 配分額: 4,420千円 (直接経費: 3,400千円、間接経費: 1,020千円); 2012年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2011年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2010年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
• キーワード: 肝癌 / 血管新生 / TIE2 / 骨髄系前駆細胞

研究概要

肝癌の発癌、治療後の再発や転移には、腫瘍血管新生が関与している。TIE2 陽性単球(TEM)は、血管新生因子 Angiopoietin の受容体(TIE2)を発現し、癌における血管新生への関与が報告されている。本研究では肝癌における TEM の臨床的意義と、肝癌による TEM への分化誘導機序を明らかにすることを目的とした。肝癌患者では末梢血、肝癌組織で TEM が増加しており、TEM 頻度は血管新生の指標と有意に正相関した。TEM は肝硬変と肝癌の判別能に優れており、 肝癌治療後の再発に伴って増加し、 診断・予後マーカーとして有用である。 TEM への分化には肝癌由来の M-CSF、TNF-α、IL-1βが関与していた。TEM は肝癌における血管新生の制御を目指す治療標的となりうる。

研究成果

• [雑誌論文] TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlated with angiogenesis (2013)
  • 著者名/発表者名: Matsubara, T., Kanto, T., Kuroda, S., Yoshio, S., Higashitani, K., Kakita, N., Miyazaki, M., Sakakibara, M., Hiramatsu, N., Kasahara, A., Tomimaru, Y., Tomokuni, A., Nagano, H., Hayashi, N. and Takehara, T.
  • 雑誌名: Hepatology 巻: 57 ページ: 1416-1425
• [雑誌論文] Incidence of hepatocellular carcinoma in HCV -infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines (2013)
  • 著者名/発表者名: Harada, N., Hiramatsu, N., Oze, T., Yamada, R., Kurokawa, M., Miyazaki, M., Yakushijin, T., Miyagi, T., Tatsumi, T., Kiso, S., Kanto, T., Kasahara, A., Oshita, M., Mita, E., Hagiwara, H., Inui, Y., Katayama, K., Tamura, S., Yoshihara, H., Imai, Y., Inoue
  • 雑誌名: J Gastroenterol
  • NAID: 10031169228
• [雑誌論文] TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlated with angiogenesis. (2013)
  • 著者名/発表者名: Matsubara T
  • 雑誌名: Hepatology 巻: 印刷中 号: 4 ページ: 1416-1425
  • DOI: 10.1002/hep.25965
  • 査読あり
• [雑誌論文] Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines. (2013)
  • 著者名/発表者名: Harada N
  • 雑誌名: Journal of Gastroenterology 巻: 印刷中
  • 査読あり
• [雑誌論文] Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients. (2012)
  • 著者名/発表者名: Kanto, T., Inoue, M., Oze, T., Miyazaki, M., Sakakibara, M., Kakita, N., Matsubara, T., Higashitani, K., Hagiwara, H., Iio, S., Katayama, K., Mita, E., Kasahara, A., Hiramatsu, N., Takehara, T. and Hayashi, N
  • 雑誌名: J Gastroenterol 巻: 47 ページ: 169-178
• [雑誌論文] Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. (2012)
  • 著者名/発表者名: Tsunematsu, H., Tatsumi, T., Kohga, K., Yamamoto, M., Aketa, H., Miyagi, T., Hosui, A., Hiramatsu, N., Kanto, T., Hayashi, N. and Takehara, T
  • 雑誌名: Int J Cancer 巻: 130 ページ: 356-364
• [雑誌論文] Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma: a crucial role of CD25(-) FOXP3(-) T cells (2012)
  • 著者名/発表者名: Kakita, N., Kanto, T., Itose, I., Kuroda, S., Inoue, M., Matsubara, T., Higashitani, K., Miyazaki, M., Sakakibara, M., Hiramatsu, N., Takehara, T., Kasahara, A. and Hayashi, N
  • 雑誌名: Int J Cancer 巻: 31 ページ: 2573-2583
• [雑誌論文] Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. (2012)
  • 著者名/発表者名: Tsunematsu H
  • 雑誌名: International Journal of Cancer 巻: 130 ページ: 356-364
  • 査読あり
• [雑誌論文] Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma : A crucial role of CD25-FOXP3-T cells (2012)
  • 著者名/発表者名: Kakita N., Kanto T., et al
  • 雑誌名: International Journal of Cancer 巻: (印刷中)
  • 査読あり
• [雑誌論文] Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients (2012)
  • 著者名/発表者名: Kanto T., Inoue M., et al
  • 雑誌名: Journal of Gastroenterology 巻: 47 ページ: 169-178
  • 査読あり
• [雑誌論文] Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide (2011)
  • 著者名/発表者名: Sakakibara, M., Kanto, T., Hayakawa, M., Kuroda, S., Miyatake, H., Itose, I., Miyazaki, M., Kakita, N., Higashitani, K., Matsubara, T., Hiramatsu, N., Kasahara, A., Takehara, T.and Hayashi, N
  • 雑誌名: Cancer Immunol Immunother 巻: 60 ページ: 1565-1575
• [雑誌論文] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. (2011)
  • 著者名/発表者名: Shimizu, S., Takehara, T., Hikita, H., Kodama, T., Tsunematsu, H., Miyagi, T., Hosui, A., Ishida, H., Tatsumi, T., Kanto, T., Hiramatsu, N., Fujita, N., Yoshimori, T. and Hayashi, N
  • 雑誌名: Int J Cancer 巻: 131 ページ: 548-557
• [雑誌論文] nvolvement of STAT3-regulated hepatic soluble factors in attenuation of stellate cell activity and liver fibrogenesis in mice (2011)
  • 著者名/発表者名: Shigekawa, M., Takehara, T., Kodama, T., Hikita, H., Shimizu, S., Li, W., Miyagi, T., Hosui, A., Tatsumi, T., Ishida, H., Kanto, T., Hiramatsu, N. and Hayashi, N
  • 雑誌名: Biochem Biophys Res Commun 巻: 406 ページ: 614-620
• [雑誌論文] Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., Yakushijin, T., Mochizuki, K., Oshita, M., Hagiwara, H., Mita, E., Ito, T., Inui, Y., Fukui, H., Hijioka, T., Katayama, K., T amura, S., Yoshihara, H., Inoue, A., Imai, Y., Hayashi, E., Kato, M., Hosui, A., Miyagi, T., Ishida, H.
  • 雑誌名: J Gastroenterol 巻: 46 ページ: 1031-1037
  • NAID: 10029563329
• [雑誌論文] alpha-Galactosylceramide activates antitumor immunity against liver tumor. (2011)
  • 著者名/発表者名: Tatsumi, T., Takehara, T., Miyagi, T., Sugiyama, T., Aketa, H., Sasakawa, A., Kanto, T., Hiramatsu, N. and Hayashi, N
  • 雑誌名: Hepatol Res 巻: 41 ページ: 160-169
• [雑誌論文] and Hayashi, N., Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin (2011)
  • 著者名/発表者名: Inoue, Y., Hiramatsu, N., Oze, T., Yakushijin, T., Mochizuki, K., Fukuda, K., Mita, E., Haruna, Y., Inoue, A., Imai, Y., Hosui, A., Miyagi, T., Yoshida, Y., Tatsumi, T., Kiso, S., Kanto, T., Kasahara, A., Takehara, T
  • 雑誌名: J Med Virol 巻: 83 ページ: 419-427
• [雑誌論文] Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide (2011)
  • 著者名/発表者名: Sakakibara M., Kanto T., et al
  • 雑誌名: Cancer Immunology Immunotherapy 巻: 60 号: 11 ページ: 1565-1575
  • DOI: 10.1007/s00262-011-1051-1
  • 査読あり
• [雑誌論文] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma (2011)
  • 著者名/発表者名: Shimizu S, Takehara T, Hikita H, Kodama T, Tsunematsu H, Miyagi T, Hosui A, Ishida H, Tatsumi T, Kanto T, Hiramatsu N, Fujita N, Yoshimori T, Hayashi N
  • 雑誌名: Int.J.Cancer 巻: 131 号: 3 ページ: 548-57
  • DOI: 10.1002/ijc.26374
  • 査読あり
• [雑誌論文] Involvement of STAT3-regulated hepatic soluble factors in attenuation of stellate cell activity and liver fibrogenesis in mice (2011)
  • 著者名/発表者名: Shigekawa, M., Takehara, T., et al
  • 雑誌名: Biochem Biophys Res Commun 巻: 406 ページ: 614-620
  • 査読あり
• [雑誌論文] Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., et al
  • 雑誌名: Journal of Gastroenterology 巻: 46 ページ: 1031-1037
  • NAID: 10029563329
  • 査読あり
• [雑誌論文] Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin. (2011)
  • 著者名/発表者名: Inoue, Y., Hiramatsu, N., et al.
  • 雑誌名: J Med Virol 巻: 83 ページ: 419-427
  • 査読あり
• [雑誌論文] Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet. (2010)
  • 著者名/発表者名: Miyagi, T., Takehara, T., Uemura, A., Nishio, K., Shimizu, S., Kodama, T., Hikita, H., Li, W., Sasakawa, A., Tatsumi, T., Ohkawa, K., Kanto, T., Hiramatsu, N. and Hayashi, N
  • 雑誌名: J Gastroenterol 巻: 45 ページ: 1247-1254
  • NAID: 10027700169
• [雑誌論文] EphA2-derived peptide vaccine with amphiphilic poly(gamma-glutamic acid) nanoparticles elicits an anti-tumor effect against mouse liver tumor (2010)
  • 著者名/発表者名: Yamaguchi, S., Tatsumi, T.Takehara, T., et al.
  • 雑誌名: Cancer Immunol Immunother 巻: 59 ページ: 759-767
  • 査読あり
• [雑誌論文] alpha-Galactosylceramide activates antitumor immunity against liver tumor. (2010)
  • 著者名/発表者名: Tatsumi, T., Takehara, T., et al.
  • 雑誌名: Hepatol Res 巻: 41 ページ: 160-169
  • 査読あり
• [雑誌論文] Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet (2010)
  • 著者名/発表者名: Miyagi, T., Takehara, T., et al.
  • 雑誌名: J Gastroenterol 巻: 45 ページ: 1247-1254
  • NAID: 10027700169
  • 査読あり
• [学会発表] TIE2-expressing monocytes are feasible angiogenesis-related cellular diagnostics for hepatocellular carcinoma: Involvement of inflammatory cytokines in the generation (2012)
  • 著者名/発表者名: Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Miyazaki M, Hiramatsu N, Kasahara A, Takehara T
  • 学会等名: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 2012-11-10
• [学会発表] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2012)
  • 著者名/発表者名: Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Kakita N, Miyazaki M, Hiramatsu N, Kasahara A, Takehara T.
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 2012-11-10
• [学会発表] TIE2-expressing monocytes are feasible angiogenesis-related cellular diagnostics for hepatocellular carcinoma: Involvement of inflammatory cytokines in the generation. (2012)
  • 著者名/発表者名: Matsubara T
  • 学会等名: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA USA
• [学会発表] Enhanced ability of IL28A and IL28B induction in plasmacytoid dendritic cells in chronic hepatitis C patients with major allele of IL28B single nucleotide polymorphism (2011)
  • 著者名/発表者名: Kakita N, Kanto T, et al
  • 学会等名: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco, CA, USA
  • 年月日: 2011-11-08
• [学会発表] Enhanced ability of IL28A and IL28B induction in plasmacytoid dendritic cells in chronic hepatitis C patients with major allele of IL28B single nucleotide polymorphism. (2011)
  • 著者名/発表者名: Kakita N, Kanto T, Miyazaki M, Yoshio S, Kuroda S, Matsubara T, Higashitani K, Sakakibara M, Hiramatsu N, Kasahara S, Takehara T, Hayashi N
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco CA, USA
  • 年月日: 2011-11-07
• [学会発表] Viral suppression at week 4 exceeds the IL28B SNP for predicting SVR in pegylated interferon plus ribavirin combination therapy of genotype 1 infected patients with chronic hepatitis. (2011)
  • 著者名/発表者名: Oze T, Hiramatsu N, Yakushijin T, Doi Y, Ogawa H, Hagiwara H, Mita E, Kaneko A, Katayama K, Hijioka T, Tamura S, Yoshihara H, Inoue A, Imai Y, Hayashi E, Hosui A, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Hayashi N, Takehara T
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco CA
  • 年月日: 2011-11-07
• [学会発表] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2011)
  • 著者名/発表者名: Matsubara T, Kanto T, et al
  • 学会等名: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco, CA, USA
  • 年月日: 2011-11-07
• [学会発表] Pro-angiogenic receptor TIE2-expressing monocytes/ TEMs as novel diagnostic biomarker for hepatocellular carcinoma. (2010)
  • 著者名/発表者名: Matsubara T, Kanto T, Higashitani K, Kakita N, Miyazaki M, Inoue M, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N.
  • 学会等名: The Liver Meeting AASLD 61stAnnual Meeting and Postgraduate Course
  • 発表場所: Boston MA, USA
  • 年月日: 2010-10-30
• [学会発表] Distinctive roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • 著者名/発表者名: Kakita N, Kanto T, Matsubara T, Higashitani K, Miyazaki M, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
  • 学会等名: The Liver Meeting AASLD 61stAnnual Meeting and Postgraduate Course
  • 発表場所: Boston MA, USA
  • 年月日: 2010-10-30
• [学会発表] Pro-angiogenic receptor TIE2 expressing monocytes/TEMs as novel diagnostic biomarker for hepatocellular carcinoma (2010)
  • 著者名/発表者名: Matsubara M, Kanto T, et al.
  • 学会等名: The Liver Meeting AASLD 61^<st> Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
• [学会発表] Distinctive roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • 著者名/発表者名: Kakita N, Kanto T, et al.
  • 学会等名: The Liver Meeting AASLD 61^<st> Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
• [学会発表] Crucial roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • 著者名/発表者名: Kakita N, Kanto T, et al.
  • 学会等名: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama, Japan
• [学会発表] Pro-angiogenic receptor TIE2-expressing monocytes/TEMs as novel diagnostic marker for HCV-infected hepatocellular carcinoma (2010)
  • 著者名/発表者名: Matsubara M, Kanto T, et al.
  • 学会等名: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama, Japan
• [学会発表] Type-I and type-III interferon induction from myeloid and plasmacytoid dendritic cells in chronic hepatitis C patients ; lack of association with single nucleotide polymorphism near IL28B gene (2010)
  • 著者名/発表者名: Miyazaki M, Kanto T, et al.
  • 学会等名: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama, Japan
• [図書] Dendritic cells in hepatitis virus infection : a legatus within. IN Current Immunology Reviews (2011)
  • 著者名/発表者名: Kanto T.
  • 出版者: Bentham Science Publishers
• [備考] 大阪大学大学院医学系研究科消化器内科学ホームページ
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [備考] 大阪大学大学院医学系研究科消化器内科学
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [備考]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [備考]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm