Treatments including liver transplantation against hepatocellular carcinoma based on tumor characteristics

• Project/Area Number: 16K10425
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Osaka University
• Principal Investigator: Umeshita Koji 大阪大学, 医学系研究科, 教授 (60252649)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肝細胞癌 / 癌幹細胞 / 肝移植 / ABO不適合移植 / 移植後再発 / DTCs / CTCs / 再発予測

Outline of Final Research Achievements

Cancer stem cells (CSCs) were reported to be involved in resistance to chemo/radiation therapy. We previously reported that CD13 was both a marker of CSCs and a candidate therapeutic target in hepatocellular carcinoma (HCC). We explored the antitumor effect of a combined therapy, where ubenimex, a CD13 inhibitor, was combined with conventional anticancer drugs. In HCC cell lines, while the expression of CD13 increased after an exposure to each anticancer drug alone, the CD13 expression decreased with ubenimex administration. Next, we focused on c-Met, another CSC marker and transcatheter arterial chemoembolization (TACE). We investigated clinical impact of TACE on c-Met expression. The results showed that c-Met upregulation was observed significantly more frequently in clinical samples of HCC that were treated with preoperative TACE than in samples with no TACE treatment. These results would be useful in treatments against HCC based on tumor characteristics.

Academic Significance and Societal Importance of the Research Achievements

本研究により、癌幹細胞を標的とする治療は肝癌の治療として論理的に効率的なものであり、実際に有効である可能性が確認された．この結果は，移植後の肝癌再発予防につながる可能性を示唆するものであり、非常に意義深いものでと考えられた。

Research Products

• [Journal Article] Exosomal miR-155 Derived from Hepatocellular Carcinoma Cells Under Hypoxia Promotes Angiogenesis in Endothelial Cells (2019)
  • Author(s): Matsuura Y, Wada H, Eguchi H, Gotoh K, Kobayashi S, Kinoshita M, Kubo M, Hayashi K, Iwagami Y, Yamada D, Asaoka T, Noda T, Kawamoto K, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M.
  • Journal Title: Dig Dis Sci Volume: 64 Issue: 3 Pages: 792-802
  • DOI: 10.1007/s10620-018-5380-1
  • Peer Reviewed
• [Journal Article] “Real-time” risk models of postoperative morbidity and mortality for liver transplants (2018)
  • Author(s): Marubashi Shigeru, Ichihara Naoaki, Kakeji Yoshihiro, Miyata Hiroaki, Taketomi Akinobu, Egawa Hiroto, Takada Yasutsugu, Umeshita Koji, Seto Yasuyuki, Gotoh Mitsukazu
  • Journal Title: Annals of Gastroenterological Surgery Volume: 3 Issue: 1 Pages: 75-95
  • DOI: 10.1002/ags3.12217
  • Peer Reviewed / Open Access
• [Journal Article] Hypoxia-Induced PLOD2 is a Key Regulator in Epithelial-Mesenchymal Transition and Chemoresistance in Biliary Tract Cancer (2018)
  • Author(s): Okumura Y, Noda T, Eguchi H, Sakamoto T, Iwagami Y, Yamada D, Asaoka T, Wada H, Kawamoto K, Gotoh K, Kobayashi S, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M
  • Journal Title: Ann Surg Oncol Volume: 25 Issue: 12 Pages: 3728-3737
  • DOI: 10.1245/s10434-018-6670-8
  • Peer Reviewed / Open Access
• [Journal Article] Short- and Long-term Outcomes of De Novo Liver Transplant Patients Treated With Once-Daily Prolonged-Release Tacrolimus.rent status of surgical incisions used in donors during living related liver transplantation - a nationwide survey in Japan. (2017)
  • Author(s): Okumura Y, Noda T, Eguchi H, Iwagami Y, Yamada D, Asaoka T, Wada H, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Marubashi S, Umeshita K, Doki Y, Mori M.
  • Journal Title: Transplant Direct Volume: e207 Issue: 8 Pages: 1293-1299
  • DOI: 10.1097/tp.0000000000002126
  • Peer Reviewed
• [Journal Article] Risk factors for recurrence of primary biliary cholangitis after liver transplantation in female patients: A Japanese multicenter retrospective study. (2017)
  • Author(s): Kogiso T, Egawa H, Teramukai S, Taniai M, Hashimoto E, Tokushige K, Sakisaka S, Sakabayashi S, Yamamoto M, Umeshita K, Uemoto S.
  • Journal Title: Hepatol Commun Volume: 1(5) Issue: 5 Pages: 394-405
  • DOI: 10.1002/hep4.1037
  • Peer Reviewed
• [Journal Article] Liver transplantation for biliary atresia: a systematic review. (2017)
  • Author(s): Kasahara M, Umeshita K, Sakamoto S, Fukuda A, Furukawa H, Uemoto S.
  • Journal Title: Pediatr Surg Int Volume: 33(12) Issue: 12 Pages: 1289-1295
  • DOI: 10.1007/s00383-017-4173-5
  • Peer Reviewed
• [Journal Article] Expression of carbonic anhydrase IX is associated with poor prognosis through regulation of the epithelial-mesenchymal transition in hepatocellular carcinoma. (2017)
  • Author(s): Hyuga S, Wada H, Eguchi H, Otsuru T, Iwgami Y, Yamada D, Noda T, Asaoka T, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Umeshita K, Doki Y, Mori M.
  • Journal Title: Int J Oncol Volume: 51(4) Issue: 4 Pages: 1179-1190
  • DOI: 10.3892/ijo.2017.4098
  • Peer Reviewed / Open Access
• [Journal Article] Two cases of resectable pancreatic cancer diagnosed by open surgical biopsy after endoscopic ultrasound fine-needle aspiration failed to yield diagnosis: case reports. (2017)
  • Author(s): Toshiyama R, Noda T, Eguchi H, Iwagami Y, Yamada D, Asaoka T, Wada H, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Morii E, Umeshita K, Mori M, Doki Y.
  • Journal Title: Surg Case Rep Volume: 3(1) Issue: 1 Pages: 39-39
  • DOI: 10.1186/s40792-017-0314-2
  • Peer Reviewed / Open Access
• [Journal Article] Optimal dosage regimen for rituximab in ABO-incompatible living donor liver transplantation. (2017)
  • Author(s): Egawa H, Umeshita K, Uemoto S.
  • Journal Title: J Hepatobiliary Pancreat Sci Volume: 24(2) Issue: 2 Pages: 89-94
  • DOI: 10.1002/jhbp.419
  • Peer Reviewed
• [Journal Article] Outcomes of Living Donor Liver Transplantation Alone for Patients on Maintenance Renal Replacement Therapy in Japan: Results of a Nationwide Survey. (2016)
  • Author(s): Eguchi S, Furukawa H, Uemoto S, Umeshita K, Imamura H, Soyama A, Shimamura T, Isaji S, Ogura Y, Egawa H, Kawachi S, Kasahara M, Nagano H, Ku Y, Ohdan H, Maehara Y, Sato S, Inomata Y.
  • Journal Title: Transplant Direct. Volume: 2(6) Issue: 6 Pages: e74-e74
  • DOI: 10.1097/txd.0000000000000587
  • Peer Reviewed
• [Journal Article] A CD13 inhibitor, ubenimex, synergistically enhances the effects of anticancer drugs in hepatocellular carcinoma. (2016)
  • Author(s): Yamashita M, Wada H, Eguchi H, Ogawa H, Yamada D, Noda T, Asaoka T, Kawamoto K, Gotoh K, Umeshita K, Doki Y, Mori M.
  • Journal Title: Int J Oncol. Volume: 49819 Issue: 1 Pages: 89-98
  • DOI: 10.3892/ijo.2016.3496
  • Peer Reviewed
• [Journal Article] Liver transplantation in Japan: Registry by the Japanese Liver Transplantation Society. (2016)
  • Author(s): Umeshita K, Inomata Y, Furukawa H, Kasahara M, Kawasaki S, Kobayashi E, Kokudo N, Sakisaka S, Shimada M, Tanaka E, Uemoto S, for the Japanese Liver Transplantation Society
  • Journal Title: Hepatol Res Volume: 46 Issue: 12 Pages: 1171-1186
  • DOI: 10.1111/hepr.12676
  • Peer Reviewed / Open Access
• [Journal Article] Minimum graft size calculated from preoperative recipient status in living donor liver transplantation. (2016)
  • Author(s): Marubashi, S., Nagano, H., Eguchi, H., Wada, H., Asaoka, T., Tomimaru, Y., Tomokuni, A., Umeshita, K., Doki, Y., Mori, M.
  • Journal Title: Liver Transpl Volume: 22 Issue: 5 Pages: 599-606
  • DOI: 10.1002/lt.24388
  • Peer Reviewed / Open Access