Identification of the metastatic mechanism of keratin 19 positive cancer stem cells and novel therapeutic targets in hepatocellular carcinoma

• Project/Area Number: 18K16305
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Kawai Takayuki 京都大学, 医学研究科, 客員研究員 (00813867)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝細胞癌 / 癌幹細胞 / 肝臓外科学

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) is one of the most intractable malignancies worldwide. In this study, we investigated the metastatic mechanism of keratin 19 (K19) positive HCC cancer stem cells (CSCs). The results of three-dimensional culture of HCC cells using the decellularized liver derived from normal and fibrotic livers showed that K19-positive HCC-CSCs showed high invasive and metastatic potential in the decellularized fibrotic liver, suggesting that the activation of TGFb/Smad pathway via signals from the fibrotic liver extracellular matrix may be the mechanism. In addition, analysis of HCC clinical specimens revealed that K19 expression was significantly correlated with the progression of liver fibrosis, and mutations in genes involved in the regulation of the TGFb/Smad pathway occurred in K19-positive hepatocellular carcinoma.

Academic Significance and Societal Importance of the Research Achievements

本研究では、K19陽性肝細胞癌癌幹細胞が線維化肝からのシグナルを介したTGFb/Smad pathwayの活性化により高い浸潤・転移形質を示す可能性が示唆された。また、肝細胞癌におけるK19発現は肝線維化進行度と相関しており、K19陽性肝細胞癌ではTGFb/Smad pathwayの調節に関わる遺伝子に変異を有していた。この成果により、K19陽性肝細胞癌の転移メカニズムの一端が明らかになり、TGFb/Smad pathwayという新規治療標的が同定された。肝細胞癌の約15%を占める特に予後不良なK19陽性症例に対する個別化治療の可能性が示されたと考えており、社会的意義を有すると思われる。

Research Products

• [Journal Article] Preoperative risk score for prediction of long-term outcomes after hepatectomy for intrahepatic cholangiocarcinoma: Report of a collaborative, international-based, external validation study (2020)
  • Author(s): Brustia R, Langella S, Kawai T, Fonseca GM, Schielke A, Colli F, Resende V, Fleres F, Roulin D, Leyman P, Giacomoni A, Granger B, Fartoux L, De Carlis L, Demartines N, Sommacale D, Sanches MD, Patrono D, Detry O, Herman P, Okumura S, Ferrero A, Scatton O, Uemoto S, Perdigao F, et al.
  • Journal Title: European Journal of Surgical Oncology Volume: 46 Issue: 4 Pages: 560-571
  • DOI: 10.1016/j.ejso.2019.10.041
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of cirrhosis in patients undergoing laparoscopic liver resection in a nationwide multicentre survey (2020)
  • Author(s): Hobeika C, Fuks D, Cauchy F, Goumard C, Soubrane O, Gayet B, Salam E, Cherqui D, Vibert E, Scatton O, Nomi T, Oudafal N, Kawai T, Komatsu S, Okumura S, et al.
  • Journal Title: British Journal of Surgery Volume: 107 Issue: 3 Pages: 268-277
  • DOI: 10.1002/bjs.11406
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Laparoscopic right hepatectomy using the caudal approach is superior to open right hepatectomy with anterior approach and liver hanging maneuver: a comparison of short-term outcomes (2020)
  • Author(s): Yoh Tomoaki、Cauchy Fransois、Kawai Takayuki、Schneck Anne-Sophie、Le Roy Bertrand、Goumard Claire、Sepulveda Ailton、Dokmak Safi、Farges Olivier、Scatton Olivier、Soubrane Olivier
  • Journal Title: Surgical Endoscopy Volume: 34 Issue: 2 Pages: 636-645
  • DOI: 10.1007/s00464-019-06810-1
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pure laparoscopic versus open hemihepatectomy: a critical assessment and realistic expectations - a propensity score-based analysis of right and left hemihepatectomies from nine European tertiary referral centers (2020)
  • Author(s): Cipriani F, Alzoubi M, Fuks D, Ratti F, Kawai T, Berardi G, Barkhatov L, Lainas P, Van der Poel M, Faoury M, Besselink MG, D'Hondt M, Dagher I, Edwin B, Troisi RI, Scatton O, Gayet B, Aldrighetti L, Abu Hilal M.
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences Volume: 27(1) Issue: 1 Pages: 3-15
  • DOI: 10.1002/jhbp.662
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel hybrid three-dimensional artificial liver using human induced pluripotent stem cells and a rat decellularized liver scaffold (2019)
  • Author(s): Takahito Minami, Takamichi Ishii, Kentaro Yasuchika, Ken Fukumitsu, Satoshi Ogiso, Yuya Miyauchi, Hidenobu Kojima, Takayuki Kawai, Ryoya Yamaoka, Yu Oshima, Hiroshi Kawamoto, Maki Kotaka, Katsutaro Yasuda, Kenji Osafune, Shinji Uemoto
  • Journal Title: Regenerative therapy Volume: 10 Pages: 127-133
  • DOI: 10.1016/j.reth.2019.03.002
  • NAID: 120006719314
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of practical recellularized liver graft for blood perfusion using primary rat hepatocytes and liver sinusoidal endothelial cells (2018)
  • Author(s): Kojima H.、Yasuchika K.、Fukumitsu K.、Ishii T.、Ogiso S.、Miyauchi Y.、Yamaoka R.、Kawai T.、Katayama H.、Yoshitoshi-Uebayashi E. Y.、Kita S.、Yasuda K.、Sasaki N.、Komori J.、Uemoto S.
  • Journal Title: American Journal of Transplantation Volume: 印刷中 Issue: 6 Pages: 1351-13559
  • DOI: 10.1111/ajt.14666
  • Peer Reviewed
• [Journal Article] CD90 expression in human intrahepatic cholangiocarcinoma is associated with lymph node metastasis and poor prognosis. (2018)
  • Author(s): Yamaoka R, Ishii T, Kawai T, Yasuchika K, Miyauchi Y, Kojima H, Katayama H, Ogiso S, Fukumitsu K, Uemoto S
  • Journal Title: J Surg Oncol. Volume: 4 Issue: 4 Pages: 664-674
  • DOI: 10.1002/jso.25192
  • Peer Reviewed
• [Presentation] Involvement of liver cirrhosis in keratin 19-positive cancer stem cells associating human hepatocellular carcinoma (2020)
  • Author(s): Takayuki Kawai, Takamichi Ishii, Yuya Miyauchi, Satoshi Ogiso, Ken Fukumitsu, Shinji Uemoto
  • Organizer: The 14th World Congress of the International Hepato-Pancreato-Biliary Association
  • Int'l Joint Research
• [Presentation] Caudal approach in laparoscopic liver resection for tumors in the Segment 1 (2020)
  • Author(s): Takayuki Kawai, Kohta Iguchi, Ryo Kamimura, Hiroaki Terajima
  • Organizer: The 14th World Congress of the International Hepato-Pancreato-Biliary Association
  • Int'l Joint Research
• [Presentation] KRAS野生型大腸癌同時性肝転移に対する系統的肝切除の腫瘍学的有用性 (2020)
  • Author(s): 河合隆之， 石井隆道， 内田洋一朗， 岡本共弘， 井口公太， 上村良， 小木曾聡， 福光剣， 上本伸二 ， 寺嶋宏明
  • Organizer: 第75回日本消化器外科学会総会
• [Presentation] 大腸癌肝転移に対する腹腔鏡下肝切除の腫瘍学的有用性－術後化学療法導入までの期間に関する検討－ (2019)
  • Author(s): 河合隆之、奥村晋也、Claire Goumard、Florence Jeune、Eric Savier、Jean-Christophe Vaillant、 上本伸二、Olivier Scatton
  • Organizer: 第119回日本外科学会定期学術集会、東京
• [Presentation] Impact of liver cirrhosis in keratin 19-positive cancer stem cells associating human hepatocellular carcinoma (2019)
  • Author(s): Takayuki Kawai, Takamichi Ishii, Yuya Miyauchi, Yu Oshima, Hiroshi Kawamoto, Takahito Minami, Hidenobu Kojima, Satoshi Ogiso, Ken Fukumitsu, Kentaro Yasuchika, Shinji Uemoto
  • Organizer: 第31回日本肝胆膵外科学会学術集会、香川
• [Presentation] 両葉多発大腸癌肝転移に対する二期的肝切除－腹腔鏡下アプローチの有用性に関する検討－ (2019)
  • Author(s): 河合隆之、奥村晋也、Claire Goumard、David Fuks、Brice Gayet、Olivier Scatton
  • Organizer: 第74回日本消化器外科学会総会、東京
• [Presentation] Laparoscopic two-stage hepatectomy for bilobar colorectal liver metastases; a multiinstitutional study (2019)
  • Author(s): S.Okumura, C.Goumard, D.Fuks, T.Kawai, J.Danion, O.Soubrane, B.Gayet, O.Scatton
  • Organizer: The 2nd World Congress of the International Laparoscopic Liver Society (ILLS), Tokyo
  • Int'l Joint Research
• [Presentation] Pure laparoscopic versus open hemihepatectomy: a critical assessment and realistic expectations. A propensity score based analysis of right and left hemihepatectomies from 9 European tertiary referral centers (2019)
  • Author(s): F.Cipriani, M.Alzoubi, D.Fuks, F.Ratti, T.Kawai, G.Berardi, L.Barkhatov, P.Lainas, M.Van Der Poel, M.Faoury, M.Besselink, M.D'hondt, I.Dagher, B.Edwin, R.I.Troisi, O.Scatton, B.Gayet, L.Aldrighetti, M.Abu Hilal
  • Organizer: The 2nd World Congress of the International Laparoscopic Liver Society, Tokyo (ILLS)
  • Int'l Joint Research
• [Presentation] Identification of keratin 19-positive cancer stem cells associating human hepatocellular carcinoma using 18FFDGPET and CYFRA 21-1 (2018)
  • Author(s): Takayuki Kawai, Takamichi Ishii, Kentaro Yasuchika, Satoru Seo, Satoshi Ogiso, Takahito Minami, Yuya Miyauchi, Ryoya Yamaoka, Hidenobu Kojima, Ken Fukumitsu, and Shinji Uemoto
  • Organizer: The International Liver Congress (EASL) 2018, Paris, France
  • Int'l Joint Research
• [Presentation] 肝細胞癌におけるkeratin 19陽性癌幹細胞を追跡するバイオマーカーとしての18F-FDGPETおよび血清keratin 19 fragment (CYFRA 21-1)の役割 (2018)
  • Author(s): 河合隆之, 石井隆道, 安近健太郎, 小木曾聡, 南貴人, 宮内雄也, 小島秀信, 山岡竜也, 福光剣, 波多野悦朗, 上本伸二
  • Organizer: 第118回日本外科学会定期学術集会、東京
• [Presentation] Development of precision medicine for keratin 19-positive hepatocellular carcinoma (2018)
  • Author(s): Takayuki Kawai, Takamichi Ishii, Kentaro Yasuchika, Satoru Seo, Satoshi Ogiso, Yuya Miyauchi, Ryoya Yamaoka, Hidenobu Kojima, Ken Fukumitsu, Hideaki Okajima, Toshimi Kaido, and Shinji Uemoto
  • Organizer: The Asian Pacific Association for the Study of the Liver (APASL) Single Topic Conference on HCC 2018, Yokohama, Japan
  • Int'l Joint Research
• [Presentation] Tracking keratin 19-positive cancer stem cells using CYFRA 21-1 in hepatocellular carcinoma (2018)
  • Author(s): Takayuki Kawai, Takamichi Ishii, Kentaro Yasuchika, Satoshi Ogiso, Takahito Minami, Yuya Miyauchi, Hidenobu Kojima, Ken Fukumitsu, Shinji Uemoto
  • Organizer: The 13th World Congress of the International Hepato-Pancreato-Biliary Association (IHPBA) 2018, Geneva, Switzerland
  • Int'l Joint Research
• [Presentation] 肝移植を施行した肝細胞癌症例における癌幹細胞マーカーkeratin 19およびSOX9発現の意義 (2018)
  • Author(s): 河合隆之、石井隆道、安近健太郎、川本浩史、大島侑、南貴人、宮内雄也、小島秀信、小木曾聡、福光剣、岡島英明、海道利美、上本伸二
  • Organizer: 第54回日本移植学会総会、東京