Investigation of anti-angiogenesis therapy against hepatocellular carcinoma targeting liver-infiltrating myeloid cells.

• Project/Area Number: 26461028
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Kanto Tatsuya 国立研究開発法人国立国際医療研究センター, その他部局等, 研究センター長 (80372613)
• Co-Investigator(Kenkyū-buntansha): 溝上 雅史 国立研究開発法人国立国際医療研究センター, その他部局等, 肝炎免疫研究センター長 (40166038) ; 是永 匡紹 国立研究開発法人国立国際医療研究センター, その他部局等, その他 (70420536)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝がん / 血管新生 / ミエロイド細胞

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) is a vascular-rich tumor, the development of which is influenced by angiogenesis. The aim of this study is to clarify the mechanisms of the development of myeloid cells (Tie-2-expressing monocytes; TEM and macrophages) in patients with HCC and their impact on the pathogenesis and the response to anti-angiogenesis treatment (sorafenib) against HCC.
The frequency of CD68+ macrophages in the liver and serum YKL-40 (macrophage-derived factor) levels were increased in NAFLD patients with HCC. In patients who underwent sorafenib, the change of TEM frequency at 1 month after the start of therapy (⊿TEM) was well correlated with anti-tumor response and overall survival rate of the treated patients. Therefore, angiogenesis-related myeloid cells are involved in the progression of HCC and could be a therapeutic target. The ⊿TEM index could be a biomarker for predicting better treatment response and good prognosis in patients with advanced HCC under sorafenib.

Research Products

• [Journal Article] Serum YKL-40 as a marker of liver fibrosis in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Kumagai E, Mano Y, Yoshio S, Shoji H, Sugiyama M, Korenaga M, Ishida T, Arai T, Itokawa N, Atsukawa M, Hyogo H, Chayama K, Ohashi T, Ito K, Yoneda M, Kawaguchi T, Torimura T, Nozaki Y, Watanabe S, Mizokami M, Kanto T*.
  • Journal Title: Scientific Reports Volume: 6:35282 Issue: 1 Pages: 1-11
  • DOI: 10.1038/srep35282
  • Peer Reviewed
• [Journal Article] Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Shoji H, Yoshio S, Mano Y, Kumagai E, Sugiyama M, Korenaga M, Arai T, Itokawa N, Atsukawa M, Aikata H, Hyogo H, Chayama K, Ohashi T, Ito K, Yoneda M, Nozaki Y, Kawaguchi T, Torimura T, Abe M, Hiasa Y, Kamiyama T, Fukai M, Taketomi A, Mizokami M, Kanto T*
  • Journal Title: Scientific Reports Volume: 6:28814 Issue: 1 Pages: 1-10
  • DOI: 10.1038/srep28814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of PNPLA3 and JAZF1 on hepatocellular carcinoma in non-viral hepatitis patients with type 2 diabetes mellitus (2016)
  • Author(s): Ueyama, M., Nishida, N., Korenaga, M., Korenaga, K., Kumagai, E., et al.
  • Journal Title: Journal of Gastroenterology Volume: 51 Issue: 4 Pages: 370-379
  • DOI: 10.1007/s00535-015-1116-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Host-virus interactions in hepatitis B and hepatitis C infection. (2016)
  • Author(s): Yoshio, S., Kanto, T.
  • Journal Title: Journal of Gastroenterology Volume: 51 Issue: 5 Pages: 409-420
  • DOI: 10.1007/s00535-016-1183-3
  • Peer Reviewed
• [Journal Article] Geographic distribution and characteristics of genotype A hepatitis B virus infection in acute and chronic hepatitis B patients in Japan. (2016)
  • Author(s): Ito, K, Yotsuyanagi H, Sugiyama M, Yatsuhashi H, Karino Y, Takikawa Y, Saito T, Arase Y, Imazeki F, Kurosaki M, Umemura T, Ichida T, Toyoda H, Yoneda M, Tanaka Y, Mita E, Yamamoto K, Michitaka K, Maeshiro T, Tanuma J, Korenaga M, Murata K, Masaki N, Koike K, Mizokami M.
  • Journal Title: J Gastroenterology and Hepatology Volume: 31 Issue: 1 Pages: 180-189
  • DOI: 10.1111/jgh.13030
  • Peer Reviewed
• [Journal Article] Association of serum IFN-λ3 with inflammatory and fibrosis markers in patients with chronic hepatitis C virus infection. (2014)
  • Author(s): Aoki Y, Sugiyama M, Murata K, Yoshio S, Kurosaki M, Hashimoto S, Yatsuhashi H, Nomura H, Kang JH, Takeda T, Naito S, Kimura T, Yamagiwa Y, Korenaga M, Imamura M, Masaki N, Izumi N, Kage M, Mizokami M, Kanto T.
  • Journal Title: J Gastroenterol Volume: - Issue: 8 Pages: 894-902
  • DOI: 10.1007/s00535-014-1023-2
  • Peer Reviewed
• [Presentation] Interleukin-34 as a fibroblast-derived marker of liver fibrosis in patients with non-alcoholic fatty liver disease. (2016)
  • Author(s): Shoji H, Yoshio S, Mano Y, Kumagai E, Doi H, Sugiyama M, Korenaga M, Arai T, Itokawa N, Atsukawa M, Aikata H, Hyogo H, Chayama K, Ohashi T, Ito K, Yoneda M, Nozaki Y, Kawaguchi T, Torimura T, Abe M, Hiasa Y, Fukai M, Kamiyama T, Taketomi A, Mizokami M and Kanto T.
  • Organizer: The Liver Meeting 2016: The 67th Annual Meeting of AASLD.
  • Place of Presentation: Boston, USA
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] 非アルコール性脂肪性肝疾患におけるマクロファージ関連肝線維化マーカーIL-34の検討 (2016)
  • Author(s): 正司裕隆, 溝上雅史, 考藤達哉.
  • Organizer: 第24回日本消化器関連学会週間 (JDDW2016)
  • Place of Presentation: 神戸市
  • Year and Date: 2016-11-03
• [Presentation] Pro-angiogenic Tie2-expressing monocytes/TEMs as a biomarker of the response to sorafenib in patients with advanced hepatocellular carcinoma. (2016)
  • Author(s): Shoji H, Yoshio S, Mano Y, Kumagai E, Doi H, Sugiyama M, Osawa Y, Kimura K, Arai T, Itokawa N, Atsukawa M, Fukai M, Taketomi A, Mizokami M and Kanto T.
  • Organizer: Japan Society of Hepatology, Single Topic Conference, Hepatocellular carcinoma
  • Place of Presentation: 金沢市
  • Year and Date: 2016-09-22
  • Int'l Joint Research
• [Presentation] 非アルコール性脂肪性肝疾患におけるIL-34 新規マクロファージ関連肝線維化マーカー. (2016)
  • Author(s): 正司裕隆, 由雄祥代, 間野洋平, 熊谷恵理奈, 土肥弘義, 杉山真也, 是永匡紹, 武冨紹信, 溝上雅史, 考藤達哉.
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉県
  • Year and Date: 2016-05-19
• [Presentation] Effects of HLA-DPB1 genotypes on chronic hepatitis B infection in Japanese. (2015)
  • Author(s): Nishida N, Ohashi J, Sugiyama M, Tsuchiura T, Yamamoto K, Hino K, Honda M, Kaneko S, Yatsuhashi H, Koike K, Yokosuka O, Tanaka E, Taketomi A), Kurosaki M, Izumi N, Sakamoto N, Eguchi Y, Sasazuki T, Tokunaga K, Kanto T, Mizokami M
  • Organizer: The American Association for the Study of Liver Diseases (AASLD), 66th Annual Meeting and Postgraduate Course,
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] 肝細胞癌における血管新生関連細胞（Tie2-expressing monocytes）誘導因子の探索 (2015)
  • Author(s): 正司裕隆、考藤達哉、間野洋平、青木孝彦、由雄祥代、杉山真也、武冨紹信、溝上雅史
  • Organizer: 2)第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本（熊本）
  • Year and Date: 2015-05-21 – 2015-05-22
• [Presentation] Cancer-associated or cirrhosis fibroblasts recovered from hepatocellular carcinoma promote macrophages and cancer cells to progressive phenotype. (2015)
  • Author(s): Mano Y, Kanto T, Shoji H, Yoshio S, Sugiyama M, Osawa Y, Kimura K, Shirabe K, Maehara Y, Mizokami M.
  • Organizer: Annual Meeting of American Association of Cancer Research (AACR)
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-04-19
  • Int'l Joint Research
• [Presentation] Comprehensive analyses of serum biomarkers associating with the increase of pro-angiogenic Tie2-expressing monocytes in patients with hepatocellular carcinoma. (2015)
  • Author(s): Hirotaka Shoji, Tatsuya Kanto, Sachiyo Yoshio, Yohei Mano, Masaya Sugiyama, Yoshihiko Aoki, Akinobu Taketomi, Masashi Mizokami
  • Organizer: 1)Annual Meeting American Association for Cancer Research(AACR)
  • Place of Presentation: Philadelphia (USA)
  • Year and Date: 2015-04-18 – 2015-04-22
• [Remarks] 国立国際医療研究センター 肝炎免疫研究センター 肝疾患研究部
  • URL: http://www.ncgmkohnodai.go.jp/kanen_meneki/
• [Remarks] 肝炎・免疫研究センター 肝疾患研究部
  • URL: http://www.ncgmkohnodai.go.jp/kanen_meneki/rchi/index.html