肝癌幹細胞の維持・免疫寛容機構の解明と治療最適化の検討

• Project/Area Number: 21K07953
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Hokkaido University
• Principal Investigator: 荘 拓也 北海道大学, 大学病院, 助教 (50581104)
• Co-Investigator(Kenkyū-buntansha): 坂本 直哉 北海道大学, 医学研究院, 教授 (10334418) ; 須田 剛生 北海道大学, 大学病院, 特任助教 (20447460)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); 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)
• Keywords: HCC / 肝癌幹細胞 / FGF / 肝がん / 癌幹細胞 / 腫瘍免疫 / cancer stem like cells / 免疫寛容

Outline of Research at the Start

本研究では、申請者らが独自に樹立・明らかにした肝癌CSCsとＦＧFシグナルの関連が免疫寛容機構に及ぼす影響の解明を目指す。これら申請者らにより今までに明らかにしてきた肝癌幹細胞に対する知見と今研究で明らかにする肝癌幹細胞免疫寛容機構の解明により得られる知見を発展させ、肝癌幹細胞をターゲットとした免疫チェックポイント阻害剤を含む治療最適化探索の萌芽となる知見の獲得を目指す。

Outline of Annual Research Achievements

世界における肝がんはがん関連死亡原因の第 2 位と公衆衛生上、大きな問題となる。研究代表者らは、肝癌関連死の減少を目指し、肝癌治療の多施設共同臨床研究を行うとともに、肝癌の難治性の原因の一旦に肝癌幹細胞（CSCs）が関与するとの仮説ものもと、肝癌幹細胞の研究を行ってきた。その中で、肝癌幹細胞維持に重要なファクターとしてKLF5が強く関与する事を明らかにし、その恒常発現細胞を樹立、同細胞株を用いて検討を行い肝癌CSCs維持にFGFR1-3シグナルが重要である事を初めて報告した。本研究はこれら、独自に樹立・明らかにした知見に基づき肝癌CSCsの免疫寛容機構解明を目指す。これら研究代表者らにより今までに明らかにしてきた肝癌幹細胞に対する知見と今研究で明らかにする肝癌幹細胞免疫寛容機構の解明により得られる知見を発展させ、肝癌幹細胞をターゲットとした免疫チェックポイント阻害剤を含む治療最適化探索の萌芽となる知見の獲得を目指す研究となる。更に、研究代表者らは予備的な検討にての肝癌幹細胞において免疫寛容機構が他癌の今までの報告と同様に強く働いている可能性を見出した。 肝癌幹細胞の維持機構については、Wnt/β-catenin, Notch, TGF-β,の関与が報告されているがFGFR1-3シグナルの関与は我々が初めて明らかにした。 肝癌幹細胞をターゲットとした多剤併用療法についての知見は現在まで十分にはあきらかとなっていない。肺がん、乳癌のCSCsにおいては、我々が肝がんCSCsの表面マーカーとして使用しているとCD44発現がPDL-1発現との関連が報告されている。一方で、肝癌についての報告は十分でない。以上の知見に基づき、肝癌幹細胞の免疫寛容維持機構とそれを治療ターゲットとしての可能性を探索し、臨床応用の基盤形成を目指す研究となる。

Research Products

• [Journal Article] Coexistence of muscle atrophy and high subcutaneous adipose tissue radiodensity predicts poor prognosis in hepatocellular carcinoma (2023)
  • Author(s): Ohara Masatsugu、Suda Goki、Kohya Risako、Sasaki Takashi、Yoda Tomoka、Yoshida Sonoe、Fu Qingjie、Yang Zijian、Hosoda Shunichi、Maehara Osamu、Ohnishi Shunsuke、Tokuchi Yoshimasa、Kitagataya Takashi、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Ogawa Koji、Sakamoto Naoya
  • Journal Title: Frontiers in Nutrition Volume: 10 Pages: 1-10
  • DOI: 10.3389/fnut.2023.1272728
  • Peer Reviewed / Open Access
• [Journal Article] Potential Correlation between Changes in Serum FGF21 Levels and Lenvatinib-Induced Appetite Loss in Patients with Unresectable Hepatocellular Carcinoma (2023)
  • Author(s): Kohya Risako、Suda Goki、Kawagishi Naoki、et.al.,
  • Journal Title: Cancers Volume: 15 Issue: 12 Pages: 3257-3257
  • DOI: 10.3390/cancers15123257
  • Peer Reviewed / Open Access
• [Journal Article] Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan (2023)
  • Author(s): Sasaki Takashi、Kawagishi Naoki、et.al.,
  • Journal Title: Hepatology Research Volume: 53 Issue: 10 Pages: 960-967
  • DOI: 10.1111/hepr.13936
  • Peer Reviewed
• [Journal Article] Neutrophil gelatinase-associated lipocalin predicts the efficacy of tolvaptan for ascites in patients with liver cirrhosis (2023)
  • Author(s): Nakai Masato、Morikawa Kenichi、Sasaki Takashi、Kohya Risako、Yoshida Sonoe、Hosoda Shunichi、Kubo Akinori、Tokuchi Yoshimasa、Kitagataya Takashi、Yamada Ren、Ohara Masatsugu、Sho Takuya、Suda Goki、Ogawa Koji、Sakamoto Naoya
  • Journal Title: Journal of Gastroenterology Volume: 58 Issue: 7 Pages: 656-667
  • DOI: 10.1007/s00535-023-01993-w
  • Peer Reviewed
• [Journal Article] Identification of Atezolizumab Plus Bevacizumab Prognostic Index via Recursive Partitioning Analysis in HCC: The ABE Index (2023)
  • Author(s): PERSANO MARA、RIMINI MARGHERITA、Sho Takuya et al.,
  • Journal Title: Anticancer Research Volume: 43 Issue: 4 Pages: 1599-1610
  • DOI: 10.21873/anticanres.16310
  • Peer Reviewed
• [Journal Article] Survival outcomes from atezolizumab plus bevacizumab versus Lenvatinib in Child Pugh B unresectable hepatocellular carcinoma patients (2023)
  • Author(s): Rimini M, Persano M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa J, Salani F, Lonardi S, Piscaglia F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Schirripa M, Montes M, Vivaldi C, Solda C, Hiraoka A, Sho T, Niizeki T, Nishida N, et al.
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: ー Issue: 10 Pages: 7565-7577
  • DOI: 10.1007/s00432-023-04678-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hepatitis C virus eradication by direct‐acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low‐density lipoprotein cholesterolemia without an increase in body weight (2023)
  • Author(s): Tokuchi Yoshimasa、Sho Takuya et al.,
  • Journal Title: Hepatology Research Volume: in press Issue: 7 Pages: 595-606
  • DOI: 10.1111/hepr.13899
  • Peer Reviewed
• [Journal Article] Real-World Data for Atezolizumab Plus Bevacizumab in Unresectable Hepatocellular Carcinoma: How Does Adherence to the IMbrave150 Trial Inclusion Criteria Impact Prognosis? (2023)
  • Author(s): Rimini M, Persano M, Tada T, Suda G, Shimose S, Kudo M, Cheon J, Finkelmeier F, Lim HY, Presa J, Masi G, Yoo C, Lonardi S, Piscaglia F, Kumada T, Sakamoto N, Iwamoto H, Aoki T, Chon HJ, Himmelsbach V, Pressiani T, Montes M, Vivaldi C, Solda C, Hiraoka A, Sho T, Niizeki T, Nishida N, et al.
  • Journal Title: Targeted Oncology Volume: 18 Issue: 2 Pages: 221-233
  • DOI: 10.1007/s11523-023-00953-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Efficacy and Effect on Liver Functional Reserve of Atezolizumab and Bevacizumab for Unresectable Hepatocellular Carcinoma in Patients Who Do Not Meet Eligibility Criteria of IMbrave150 (2022)
  • Author(s): Sho Takuya et al.,
  • Journal Title: Cancers Volume: 14 Issue: 16 Pages: 3938-3938
  • DOI: 10.3390/cancers14163938
  • Peer Reviewed / Open Access
• [Journal Article] Overestimated Renal Function in Patients with Liver Cirrhosis Predicts Poor Prognosis (2022)
  • Author(s): Yoshida Sonoe、Suda Goki、et al.,
  • Journal Title: Hepatology Research Volume: in press Issue: 7 Pages: 603-613
  • DOI: 10.1111/hepr.13765
  • Peer Reviewed
• [Journal Article] Changes in the estimated renal function after hepatitis C virus eradication with direct-acting antiviral agents: Impact of changes in skeletal muscle mass (2021)
  • Author(s): Tokuchi Y, Suda G, Kimura M, Maehara O, Kitagataya T, Ohara M, Yamada R, Shigesawa T, Suzuki K, Kawagishi N, Nakai M, Sho T, Natsuizaka M, Morikawa K, Ogawa K, Sakamoto N.
  • Journal Title: J Viral Hepat. Volume: in press Issue: 5 Pages: 755-763
  • DOI: 10.1111/jvh.13484
  • Peer Reviewed
• [Journal Article] Baseline elevated serum angiopoietin-2 predicts long-term non-regression of liver fibrosis after direct-acting antiviral therapy for hepatitis C (2021)
  • Author(s): Kawagishi Naoki、Suda Goki、Kimura Megumi、Maehara Osamu、Yamada Ren、Tokuchi Yoshimasa、Kubo Akinori、Kitagataya Takashi、Shigesawa Taku、Suzuki Kazuharu、Ohara Masatsugu、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Kudo Yusuke、Nishida Mutsumi、Sakamoto Naoya
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 9207-9207
  • DOI: 10.1038/s41598-021-88632-7
  • Peer Reviewed / Open Access
• [Journal Article] FGFR2 maintains cancer cell differentiation via AKT signaling in esophageal squamous cell carcinoma (2021)
  • Author(s): Maehara Osamu、Suda Goki、Natsuizaka Mitsuteru、Shigesawa Taku、Kanbe Gouki、Kimura Megumi、Sugiyama Masaya、Mizokami Masashi、Nakai Masato、Sho Takuya、Morikawa Kenichi、Ogawa Koji、Ohashi Shinya、Kagawa Shingo、Kinugasa Hideaki、Naganuma Seiji、Okubo Naoto、Ohnishi Shunsuke、Takeda Hiroshi、Sakamoto Naoya
  • Journal Title: Cancer Biology & Therapy Volume: 22 Issue: 5-6 Pages: 372-380
  • DOI: 10.1080/15384047.2021.1939638
  • Peer Reviewed
• [Journal Article] Early response and safety of atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in patients who do not meet IMbrave150 eligibility criteria (2021)
  • Author(s): Sho Takuya、Suda Goki、et al.,
  • Journal Title: Hepatology Research Volume: 51 Issue: 9 Pages: 979-989
  • DOI: 10.1111/hepr.13693
  • Peer Reviewed
• [Journal Article] Characteristics and Lenvatinib Treatment Response of Unresectable Hepatocellular Carcinoma with Iso-High Intensity in the Hepatobiliary Phase of EOB-MRI (2021)
  • Author(s): Kubo Akinori、Suda Goki、Kimura Megumi、Maehara Osamu、Tokuchi Yoshimasa、Kitagataya Takashi、Ohara Masatsugu、Yamada Ren、Shigesawa Taku、Suzuki Kazuharu、Kawagishi Naoki、Nakai Masato、Sho Takuya、Natsuizaka Mitsuteru、Morikawa Kenichi、Ogawa Koji、Ohnishi Shunsuke、Sakamoto Naoya
  • Journal Title: Cancers Volume: 13 Issue: 14 Pages: 3633-3633
  • DOI: 10.3390/cancers13143633
  • Peer Reviewed / Open Access
• [Journal Article] Prospect of lenvatinib for unresectable hepatocellular carcinoma in the new era of systemic chemotherapy (2021)
  • Author(s): Sho Takuya、Morikawa Kenichi、Kubo Akinori、Tokuchi Yoshimasa、Kitagataya Takashi、Yamada Ren、Shigesawa Taku、Kimura Mugumi、Nakai Masato、Suda Goki、Natsuizaka Mitsuteru、Ogawa Koji、Sakamoto Naoya
  • Journal Title: World Journal of Gastrointestinal Oncology Volume: 13 Issue: 12 Pages: 2076-2087
  • DOI: 10.4251/wjgo.v13.i12.2076
  • Peer Reviewed / Open Access