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

2012 Fiscal Year Final Research Report

• 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
• Keywords: 肝癌 / 血管新生 / TIE2

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
• [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] 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
• [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] 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
• [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] 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/ 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
• [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