Development of novel therapy for hepatocellular carcinoma targeting of bone marrow-derived angiogenesis precursor

• Project/Area Number: 22590729
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: KANTO Tatsuya 大阪大学, 医学系研究科, 寄附講座准教授 (80372613)
• Co-Investigator(Kenkyū-buntansha): TAKEHARA Tetsuo 大阪大学, 大学院・医学系研究科, 教授 (70335355) ; HIRAMATSU Naoki 大阪大学, 大学院・医学系研究科, 講師 (30362700)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肝癌 / 血管新生 / TIE2 / 骨髄系前駆細胞

Research Abstract

Angiogenesis is a critical step in the development of vascular-rich hepatocellular carcinoma (HCC). 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 and to identify molecules involving in the differentiation of TEMs. In HCC patients, the frequency of TEMs in the periphery and in the liver was significantly higher than those in non-HCC groups. In patients who underwent local ablation of HCC, the frequency of TEMs changed in parallel with the recurrence of HCC. A significant positive correlation was observed between micro-vessel density in HCC tissues and the 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. TEMs were generated from TIE2-negative monocytes in the presence of M-CSF, TNF-α and IL-1β. In conclusion, the frequency of TEMs can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver.

Research Products

• [Journal Article] TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlated with angiogenesis (2013)
  • Author(s): 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.
  • Journal Title: Hepatology Volume: 57 Pages: 1416-1425
• [Journal Article] Incidence of hepatocellular carcinoma in HCV -infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines (2013)
  • Author(s): 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
  • Journal Title: J Gastroenterol
  • NAID: 10031169228
• [Journal Article] TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlated with angiogenesis. (2013)
  • Author(s): Matsubara T
  • Journal Title: Hepatology Volume: 印刷中 Issue: 4 Pages: 1416-1425
  • DOI: 10.1002/hep.25965
  • Peer Reviewed
• [Journal Article] Incidence of hepatocellular carcinoma in HCV-infected patients with normal alanine aminotransferase levels categorized by Japanese treatment guidelines. (2013)
  • Author(s): Harada N
  • Journal Title: Journal of Gastroenterology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: J Gastroenterol Volume: 47 Pages: 169-178
• [Journal Article] Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. (2012)
  • Author(s): Tsunematsu, H., Tatsumi, T., Kohga, K., Yamamoto, M., Aketa, H., Miyagi, T., Hosui, A., Hiramatsu, N., Kanto, T., Hayashi, N. and Takehara, T
  • Journal Title: Int J Cancer Volume: 130 Pages: 356-364
• [Journal Article] Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma: a crucial role of CD25(-) FOXP3(-) T cells (2012)
  • Author(s): 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
  • Journal Title: Int J Cancer Volume: 31 Pages: 2573-2583
• [Journal Article] Fibroblast growth factor-2 enhances NK sensitivity of hepatocellular carcinoma cells. (2012)
  • Author(s): Tsunematsu H
  • Journal Title: International Journal of Cancer Volume: 130 Pages: 356-364
  • Peer Reviewed
• [Journal Article] Comparative analyses of regulatory T cell subsets in patients with hepatocellular carcinoma : A crucial role of CD25-FOXP3-T cells (2012)
  • Author(s): Kakita N., Kanto T., et al
  • Journal Title: International Journal of Cancer Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Kanto T., Inoue M., et al
  • Journal Title: Journal of Gastroenterology Volume: 47 Pages: 169-178
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: Cancer Immunol Immunother Volume: 60 Pages: 1565-1575
• [Journal Article] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma. (2011)
  • Author(s): 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
  • Journal Title: Int J Cancer Volume: 131 Pages: 548-557
• [Journal Article] nvolvement of STAT3-regulated hepatic soluble factors in attenuation of stellate cell activity and liver fibrogenesis in mice (2011)
  • Author(s): 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
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Pages: 614-620
• [Journal Article] Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan (2011)
  • Author(s): 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.
  • Journal Title: J Gastroenterol Volume: 46 Pages: 1031-1037
  • NAID: 10029563329
• [Journal Article] alpha-Galactosylceramide activates antitumor immunity against liver tumor. (2011)
  • Author(s): Tatsumi, T., Takehara, T., Miyagi, T., Sugiyama, T., Aketa, H., Sasakawa, A., Kanto, T., Hiramatsu, N. and Hayashi, N
  • Journal Title: Hepatol Res Volume: 41 Pages: 160-169
• [Journal Article] 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)
  • Author(s): 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
  • Journal Title: J Med Virol Volume: 83 Pages: 419-427
• [Journal Article] 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)
  • Author(s): Sakakibara M., Kanto T., et al
  • Journal Title: Cancer Immunology Immunotherapy Volume: 60 Issue: 11 Pages: 1565-1575
  • DOI: 10.1007/s00262-011-1051-1
  • Peer Reviewed
• [Journal Article] Inhibition of autophagy potentiates the antitumor effect of the multikinase inhibitor sorafenib in hepatocellular carcinoma (2011)
  • Author(s): 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
  • Journal Title: Int.J.Cancer Volume: 131 Issue: 3 Pages: 548-57
  • DOI: 10.1002/ijc.26374
  • Peer Reviewed
• [Journal Article] Involvement of STAT3-regulated hepatic soluble factors in attenuation of stellate cell activity and liver fibrogenesis in mice (2011)
  • Author(s): Shigekawa, M., Takehara, T., et al
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Pages: 614-620
  • Peer Reviewed
• [Journal Article] Efficacy of re-treatment with pegylated interferon plus ribavirin combination therapy for patients with chronic hepatitis C in Japan (2011)
  • Author(s): Oze, T., Hiramatsu, N., et al
  • Journal Title: Journal of Gastroenterology Volume: 46 Pages: 1031-1037
  • NAID: 10029563329
  • Peer Reviewed
• [Journal Article] Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin. (2011)
  • Author(s): Inoue, Y., Hiramatsu, N., et al.
  • Journal Title: J Med Virol Volume: 83 Pages: 419-427
  • Peer Reviewed
• [Journal Article] Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet. (2010)
  • Author(s): 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
  • Journal Title: J Gastroenterol Volume: 45 Pages: 1247-1254
  • NAID: 10027700169
• [Journal Article] EphA2-derived peptide vaccine with amphiphilic poly(gamma-glutamic acid) nanoparticles elicits an anti-tumor effect against mouse liver tumor (2010)
  • Author(s): Yamaguchi, S., Tatsumi, T.Takehara, T., et al.
  • Journal Title: Cancer Immunol Immunother Volume: 59 Pages: 759-767
  • Peer Reviewed
• [Journal Article] alpha-Galactosylceramide activates antitumor immunity against liver tumor. (2010)
  • Author(s): Tatsumi, T., Takehara, T., et al.
  • Journal Title: Hepatol Res Volume: 41 Pages: 160-169
  • Peer Reviewed
• [Journal Article] Absence of invariant natural killer T cells deteriorates liver inflammation and fibrosis in mice fed high-fat diet (2010)
  • Author(s): Miyagi, T., Takehara, T., et al.
  • Journal Title: J Gastroenterol Volume: 45 Pages: 1247-1254
  • NAID: 10027700169
  • Peer Reviewed
• [Presentation] TIE2-expressing monocytes are feasible angiogenesis-related cellular diagnostics for hepatocellular carcinoma: Involvement of inflammatory cytokines in the generation (2012)
  • Author(s): Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Miyazaki M, Hiramatsu N, Kasahara A, Takehara T
  • Organizer: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2012-11-10
• [Presentation] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2012)
  • Author(s): Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Kakita N, Miyazaki M, Hiramatsu N, Kasahara A, Takehara T.
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2012-11-10
• [Presentation] TIE2-expressing monocytes are feasible angiogenesis-related cellular diagnostics for hepatocellular carcinoma: Involvement of inflammatory cytokines in the generation. (2012)
  • Author(s): Matsubara T
  • Organizer: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA USA
• [Presentation] 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)
  • Author(s): Kakita N, Kanto T, et al
  • Organizer: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2011-11-08
• [Presentation] 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)
  • Author(s): Kakita N, Kanto T, Miyazaki M, Yoshio S, Kuroda S, Matsubara T, Higashitani K, Sakakibara M, Hiramatsu N, Kasahara S, Takehara T, Hayashi N
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco CA, USA
  • Year and Date: 2011-11-07
• [Presentation] 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)
  • Author(s): 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
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco CA
  • Year and Date: 2011-11-07
• [Presentation] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2011)
  • Author(s): Matsubara T, Kanto T, et al
  • Organizer: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2011-11-07
• [Presentation] Pro-angiogenic receptor TIE2-expressing monocytes/ TEMs as novel diagnostic biomarker for hepatocellular carcinoma. (2010)
  • Author(s): Matsubara T, Kanto T, Higashitani K, Kakita N, Miyazaki M, Inoue M, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N.
  • Organizer: The Liver Meeting AASLD 61stAnnual Meeting and Postgraduate Course
  • Place of Presentation: Boston MA, USA
  • Year and Date: 2010-10-30
• [Presentation] Distinctive roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • Author(s): Kakita N, Kanto T, Matsubara T, Higashitani K, Miyazaki M, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
  • Organizer: The Liver Meeting AASLD 61stAnnual Meeting and Postgraduate Course
  • Place of Presentation: Boston MA, USA
  • Year and Date: 2010-10-30
• [Presentation] Pro-angiogenic receptor TIE2 expressing monocytes/TEMs as novel diagnostic biomarker for hepatocellular carcinoma (2010)
  • Author(s): Matsubara M, Kanto T, et al.
  • Organizer: The Liver Meeting AASLD 61^<st> Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA, USA
• [Presentation] Distinctive roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • Author(s): Kakita N, Kanto T, et al.
  • Organizer: The Liver Meeting AASLD 61^<st> Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA, USA
• [Presentation] Crucial roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • Author(s): Kakita N, Kanto T, et al.
  • Organizer: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama, Japan
• [Presentation] Pro-angiogenic receptor TIE2-expressing monocytes/TEMs as novel diagnostic marker for HCV-infected hepatocellular carcinoma (2010)
  • Author(s): Matsubara M, Kanto T, et al.
  • Organizer: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama, Japan
• [Presentation] 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)
  • Author(s): Miyazaki M, Kanto T, et al.
  • Organizer: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama, Japan
• [Book] Dendritic cells in hepatitis virus infection : a legatus within. IN Current Immunology Reviews (2011)
  • Author(s): Kanto T.
  • Publisher: Bentham Science Publishers
• [Remarks] 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
• [Remarks] 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
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm