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Development of hybrid therapy using iron chelators and regenerative therapy for advanced hepatocellular carcinoma with decompensated liver cirrhosis

Research Project

Project/Area Number 20K08358
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionYamaguchi University

Principal Investigator

Takami Taro  山口大学, 大学院医学系研究科, 教授 (60511251)

Co-Investigator(Kenkyū-buntansha) 山本 直樹  山口大学, 教育・学生支援機構, 教授 (90448283)
松本 俊彦  山口大学, 大学院医学系研究科, 講師 (70634723)
藤澤 浩一  産業医科大学, 産業生態科学研究所, 教授 (00448284)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords肝硬変症 / 肝細胞癌 / 鉄キレート剤 / 間葉系幹細胞 / 骨髄間葉系幹細胞 / 骨髄細胞
Outline of Research at the Start

非代償性肝硬変症を背景に持つ進行肝細胞癌に対して「抗癌作用としての鉄キレート肝動注治療」と「肝機能サポートとしての培養骨髄MSC肝動脈投与療法」のハイブリット療法は生命予後を改善させるという作業仮説を肝硬変合併肝癌モデルで検証する。

Outline of Final Research Achievements

In rats fed with choline-deficient L-amino acid-defined diet, developing cirrhosis with liver tumors, iron chelator treatment tended to suppress the tumor development, but further investigation of the effects of MSCs including MSC passages was necessary. On the other hand, in the iron chelator-resistant cancer cell line, an increase in lactate production was caused by a metabolic shift to the glycolytic pathway, showing that the anti-tumor effect of iron chelator was enhanced when the lactate concentration in the cancer microenvironment was lower. Therefore, these results suggest that MSCs may have a novel effect of suppressing the glycolytic shift of hepatocellular carcinoma cells in liver cirrhosis.

Academic Significance and Societal Importance of the Research Achievements

肝臓領域のアンメット・メディカルニーズのひとつは「分子標的薬投与ができない肝予備能不良例(Child-Pugh B)における切除不能進行肝細胞癌」である。今回、ラット肝発癌肝硬変モデルおよび細胞共培養系により鉄キレート剤の抗腫瘍メカニズムを検証することができ、新たなMSC抗腫瘍機序を想起することができ、今後のハイブリッド療法の開発につながる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (33 results)

All 2023 2022 2021 2020 Other

All Journal Article (19 results) (of which Peer Reviewed: 19 results,  Open Access: 16 results) Presentation (11 results) (of which Int'l Joint Research: 1 results,  Invited: 2 results) Remarks (3 results)

  • [Journal Article] Double cancer of primary hepatic angiosarcoma and hepatocellular carcinoma treated with atezolizumab plus bevacizumab. Hepatol Res. 2023 Feb 24.2023

    • Author(s)
      Yamauchi Y, Saeki I, Yamasaki T, Egusa M, Nishiyama N, Fujioka T, Kawamoto D, Nishimura T, Tanabe N, Oono T, Matsumoto T, Ishikawa T, Marumoto Y, Matsukuma S, Shindo Y, Tokumitsu Y, Yoshimine S, Murakami J, Tanaka T, Kimura S, Hoshii Y, Hamano K, Nagano H, Takami T.
    • Journal Title

      Hepatol Res.

      Volume: - Issue: 7 Pages: 681-686

    • DOI

      10.1111/hepr.13894

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Optimizing the Seeding Density of Human Mononuclear Cells to Improve the Purity of Highly Proliferative Mesenchymal Stem Cells2023

    • Author(s)
      Nagai Hiroyuki、Miwa Akihiro、Yoneda Kenji、Fujisawa Koichi、Takami Taro
    • Journal Title

      Bioengineering

      Volume: 10 Issue: 1 Pages: 102-102

    • DOI

      10.3390/bioengineering10010102

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A combination of liver stiffness and international normalized ratio is an ideal prognostic predictor of portosystemic shunt occlusion in patients with portal hypertension2022

    • Author(s)
      Ishikawa Tsuyoshi、Egusa Maho、Fujioka Tsuyoshi、Nishiyama Natsuko、Kawamoto Daiki、Sasaki Ryo、Nishimura Tatsuro、Tanabe Norikazu、Oono Takashi、Saeki Issei、Takami Taro
    • Journal Title

      Journal of Gastroenterology

      Volume: 58 Issue: 3 Pages: 246-256

    • DOI

      10.1007/s00535-022-01947-8

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Evaluation of the Effects of Microgravity on Activated Primary Human Hepatic Stellate Cells2022

    • Author(s)
      Fujisawa Koichi、Nishimura Yuto、Sakuragi Akino、Duponselle Jolien、Matsumoto Toshihiko、Yamamoto Naoki、Murata Tomoaki、Sakaida Isao、Takami Taro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 13 Pages: 7429-7429

    • DOI

      10.3390/ijms23137429

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Diagnostic criteria for acute-on-chronic liver failure and related disease conditions in Japan2022

    • Author(s)
      Mochida S, Nakayama N, Terai S, Yoshiji H, Shimizu M, Ido A, Inoue K, Genda T, Takikawa Y, Takami T, Kato N, Abe M, Abe R, Inui A, Ohira H, Kasahara M, Chayama K, Hasegawa K, Tanaka A.
    • Journal Title

      Hepatol Res.

      Volume: 52 Issue: 5 Pages: 417

    • DOI

      10.1111/hepr.13763

    • URL

      https://pure.teikyo.jp/en/publications/aedc574f-2ab8-4827-9859-818e6eb64564

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An iron chelation-based combinatorial anticancer therapy comprising deferoxamine and a lactate excretion inhibitor inhibits the proliferation of cancer cells2022

    • Author(s)
      Fujisawa Koichi、Takami Taro、Matsumoto Toshihiko、Yamamoto Naoki、Yamasaki Takahiro、Sakaida Isao
    • Journal Title

      Cancer Metabolism

      Volume: 10 Issue: 1 Pages: 8-16

    • DOI

      10.1186/s40170-022-00284-x

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Adenylate Kinase Isozyme 3 Regulates Mitochondrial Energy Metabolism and Knockout Alters HeLa Cell Metabolism2022

    • Author(s)
      Fujisawa Koichi、Wakazaki Maina、Matsuzaki Aya、Matsumoto Toshihiko、Yamamoto Naoki、Noma Takafumi、Takami Taro
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 8 Pages: 4316-4319

    • DOI

      10.3390/ijms23084316

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Long-term efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A multicenter retrospective study2022

    • Author(s)
      Kawaratani H, Kondo Y, Tatsumi R, Kawabe N, Tanabe N, Sakamaki A, Okumoto K, Uchida Y, Endo K, Kawaguchi T, Oikawa T, Ishizu Y, Hige S, Takami T, Terai S, Ueno Y, Mochida S, Takikawa Y, Torimura T, Matsuura T, Ishigami M, Koike K, Yoshiji H
    • Journal Title

      J Clin Med.

      Volume: 11(6) Issue: 6 Pages: 1571-1571

    • DOI

      10.3390/jcm11061571

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Screening for portopulmonary hypertension using computed tomography-based measurements of the main pulmonary artery and ascending aorta diameters in patients with portal hypertension.2022

    • Author(s)
      Ishikawa T, Egusa M, Kawamoto D, Nishimura T, Sasaki R, Saeki I, Sakaida I, Takami T.
    • Journal Title

      Hepatol Res.

      Volume: 52(3) Issue: 3 Pages: 255-268

    • DOI

      10.1111/hepr.13735

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment of an Adult Medaka Fatty Liver Model by Administration of a Gubra-Amylin-Nonalcoholic Steatohepatitis Diet Containing High Levels of Palmitic Acid and Fructose2021

    • Author(s)
      Fujisawa K, Takami T, Okubo S, Nishimura Y, Yamada Y, Kondo K, Matsumoto T, Yamamoto N, Sakaida I.
    • Journal Title

      Int J Mol Sci.

      Volume: 22(18) Issue: 18 Pages: 9931-9941

    • DOI

      10.3390/ijms22189931

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Skeletal Muscle Volume Is an Independent Predictor of Survival after Sorafenib Treatment Failure for Hepatocellular Carcinoma2021

    • Author(s)
      Saeki Issei、Yamasaki Takahiro、Yamauchi Yurika、Takami Taro、Kawaoka Tomokazu、Uchikawa Shinsuke、Hiramatsu Akira、Aikata Hiroshi、Kawano Reo、Kobayashi Kazufumi、Kondo Takayuki、Ogasawara Sadahisa、Chiba Tetsuhiro、Chayama Kazuaki、Kato Naoya、Sakaida Isao
    • Journal Title

      Cancers

      Volume: 13 Issue: 9 Pages: 2247-2247

    • DOI

      10.3390/cancers13092247

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Successful Management With Dual Therapy of Lenvatinib and Macitentan for HCC With Portopulmonary Hypertension2021

    • Author(s)
      Ishikawa Tsuyoshi、Sasaki Ryo、Matsuda Takashi、Saeki Issei、Takami Taro、Wada Yasuaki、Yano Masafumi、Sakaida Isao
    • Journal Title

      Hepatology

      Volume: 74 Issue: 4 Pages: 2300-2303

    • DOI

      10.1002/hep.31865

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Splenic non-infarction volume determines a clinically significant hepatic venous pressure gradient response to partial splenic embolization in patients with cirrhosis and hypersplenism2021

    • Author(s)
      Ishikawa Tsuyoshi、Sasaki Ryo、Nishimura Tatsuro、Matsuda Takashi、Iwamoto Takuya、Saeki Issei、Hidaka Isao、Takami Taro、Sakaida Isao
    • Journal Title

      Journal of Gastroenterology

      Volume: 56 Issue: 4 Pages: 382-394

    • DOI

      10.1007/s00535-021-01762-7

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Albumin-bilirubin score as a useful predictor of energy malnutrition in patients with hepatocellular carcinoma2020

    • Author(s)
      Kotoh Yurika、Saeki Issei、Yamasaki Takahiro、Sasaki Ryo、Tanabe Norikazu、Oono Takashi、Maeda Masaki、Hidaka Isao、Ishikawa Tsuyoshi、Takami Taro、Sakaida Isao
    • Journal Title

      Clinical Nutrition

      Volume: - Issue: 5 Pages: 3585-3591

    • DOI

      10.1016/j.clnu.2020.12.023

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Trans-portal hepatic infusion of cultured bone marrow-derived mesenchymal stem cells in a steatohepatitis murine model2020

    • Author(s)
      Sasaki R, Takami T, Fujisawa K, Matsumoto T, Ishikawa T, Yamamoto N, Sakaida I.
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 67 Issue: 3 Pages: 274-282

    • DOI

      10.3164/jcbn.20-88

    • NAID

      130007934155

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Invasion inhibition in pancreatic cancer using the oral iron chelating agent deferasirox2020

    • Author(s)
      Amano Shogo、Kaino Seiji、Shinoda Shuhei、Harima Hirofumi、Matsumoto Toshihiko、Fujisawa Koichi、Takami Taro、Yamamoto Naoki、Yamasaki Takahiro、Sakaida Isao
    • Journal Title

      BMC Cancer

      Volume: 20 Issue: 1 Pages: 681-681

    • DOI

      10.1186/s12885-020-07167-8

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bone marrow-derived humoral factors suppress oxidative phosphorylation, upregulate TSG-6, and improve therapeutic effects on liver injury of mesenchymal stem cells2020

    • Author(s)
      Miyaji Takashi、Takami Taro、Fujisawa Koichi、Matsumoto Toshihiko、Yamamoto Naoki、Sakaida Isao
    • Journal Title

      Journal of Clinical Biochemistry and Nutrition

      Volume: 66 Issue: 3 Pages: 213-223

    • DOI

      10.3164/jcbn.19-125

    • NAID

      130007839286

    • ISSN
      0912-0009, 1880-5086
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Metabolic Alterations in Spheroid-Cultured Hepatic Stellate Cells.2020

    • Author(s)
      Fujisawa K, Takami T, Sasai N, Matsumoto T, Yamamoto N, Sakaida I.
    • Journal Title

      Int J Mol Sci.

      Volume: 21(10) Issue: 10 Pages: 3451-3455

    • DOI

      10.3390/ijms21103451

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] MIG and I309 Accelerates Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells.2020

    • Author(s)
      Aibe Y, Takami T, Fujisawa K, Matsumoto T, Sakaida I.
    • Journal Title

      Bull Yamaguchi Med Sch.

      Volume: 50(10) Pages: 1201-1208

    • NAID

      120006869715

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Conducting clinical trial for decompensated liver cirrhosis using cultured autologous bone marrow derived mesenchymal stem cells -Self-contained cirrhosis regeneration therapy-2022

    • Author(s)
      Taro Takami
    • Organizer
      The 13th Meeting of Asian Cellular Therapy Organization (ACTO 2022)
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 鉄キレート剤(DFO)投与により変化した代謝をターゲットとした併用療法の検討2022

    • Author(s)
      藤澤 浩一、松本 俊彦、山本 直樹、高見 太郎
    • Organizer
      第58回日本肝臓学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 医師主導治験「自己完結型肝硬変再生療法」の開発とNASHモデル有効性評価2022

    • Author(s)
      高見 太郎
    • Organizer
      第12回肥満と消化器疾患研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 医師主導治験「自己完結型肝硬変再生療法」の開発とNASH肝硬変への有効性評価2022

    • Author(s)
      高見太郎、松本俊彦、大田久美江、児玉雅季、藤村瑠意、小島奈緒美、山本直樹、坂井田 功
    • Organizer
      第21回日本再生医療学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 培養自己骨髄間葉系幹細胞肝動脈投与による医師主導治験「自己完結型肝硬変再生療法」の開発2021

    • Author(s)
      高見太郎、松本俊彦、坂井田 功
    • Organizer
      第107回日本消化器病学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 骨髄間葉系幹細胞肝動脈投与による「自己完結型肝硬変再生療法」の開発と併用療法に向けた作用機序の解明2021

    • Author(s)
      松本俊彦、高見太郎、坂井田 功
    • Organizer
      第57回日本肝臓学会総会
    • Related Report
      2021 Research-status Report
  • [Presentation] 肝硬変に対する医師主導治験「自己完結型肝硬変再生療法」の開発とNASH肝硬変モデルに対する有効性評価2021

    • Author(s)
      高見太郎、松本俊彦、坂井田 功
    • Organizer
      第28回日本消化器関連学会週間
    • Related Report
      2021 Research-status Report
  • [Presentation] 再生医療用ロボット自動培養システムとの 融合による自己完結型肝硬変再生療法2021

    • Author(s)
      高見太郎
    • Organizer
      第3回日本再生医療とリハビリテーション学会学術大会
    • Related Report
      2021 Research-status Report
    • Invited
  • [Presentation] 非代償性肝硬変に対する自己完結型肝硬変再生療法の開発2020

    • Author(s)
      高見太郎, 松本俊彦, 坂井田 功
    • Organizer
      第106回日本消化器病学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 非代償性肝硬変に対する培養自己骨髄間葉系幹細胞による自己完結型肝硬変再生療法2020

    • Author(s)
      高見太郎, 松本俊彦, 坂井田 功
    • Organizer
      第56回日本肝臓学会総会
    • Related Report
      2020 Research-status Report
  • [Presentation] 培養自己骨髄間葉系幹細胞肝動脈投与による「自己完結型肝硬変再生療法」の医師主導治験に向けた取り組み2020

    • Author(s)
      高見太郎, 松本俊彦, 坂井田 功
    • Organizer
      第28回日本消化器関連学会週間
    • Related Report
      2020 Research-status Report
  • [Remarks] 医師主導治験「自己完結型肝硬変再生療法」

    • URL

      https://www.ichinai-yamaguchi.jp/news/381

    • Related Report
      2021 Research-status Report
  • [Remarks] 肝細胞研究会 研究交流「自己完結型肝硬変再生療法」

    • URL

      http://hepato.umin.jp/kouryu/kouryu62.html

    • Related Report
      2021 Research-status Report
  • [Remarks] 医師主導治験「自己完結型肝硬変再生療法」

    • URL

      http://www.hosp.yamaguchi-u.ac.jp/news/news/post_375.html

    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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