Regulation of liver cancer stem cells by cirrhotic liver microenvironment

• Project/Area Number: 26460994
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kanazawa University
• Principal Investigator: YAMASHITA TARO 金沢大学, 附属病院, 准教授 (90377432)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝細胞癌 / 癌幹細胞 / 肝硬変 / 微小環境 / がん幹細胞 / がん微小環境 / エピジェネテッィク制御 / サイトカイン / 抗がん剤感受性 / 肝がん幹細胞 / 可塑性 / エピジェネティック変化

Outline of Final Research Achievements

Recent evidences suggest that hepatocellular carcinoma possesses cancer stem cells that play a pivotal role on local recurrence and distant organ metastasis after radical treatment. In this study, we found that fibroblasts secrets TGF-beta and induce the stemness in EpCAM+ hepatocellular carcinoma. This effect was mediated at least in part through the activation of H3K36 demethylase KDM2B to modify epigenetic memories and induce the population of EpCAM+ cancer stem cells. We further identified the six cytokines, potentially reflecting the activation of microenvironment of hepatocellular carcinoma, to predict the survival outcome of hepatocellular carcinoma patients who received sorafenib treatment.

Research Products

• [Journal Article] De Novo Emergence of Mesenchymal Stem-Like CD105+ Cancer Cells by Cytotoxic Agents in Human Hepatocellular Carcinoma. (2017)
  • Author(s): Nomura Y, Yamashita T, Oishi N, Nio K, Hayashi T, Yoshida M, Hayashi T, Hashiba T, Asahina Y, Okada H, Sunagozaka H, Takatori H, Honda M, Kaneko S.
  • Journal Title: Transl Oncol. Volume: - Issue: 2 Pages: 184-189
  • DOI: 10.1016/j.tranon.2017.01.005
  • Peer Reviewed / Open Access
• [Journal Article] The evolving concept of liver cancer stem cells. (2017)
  • Author(s): K Nio, T Yamashita, S Kaneko.
  • Journal Title: Mol Cancer Volume: 16 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12943-016-0572-9
  • Peer Reviewed / Open Access
• [Journal Article] Stemness of liver cancer: From hepatitis B virus to Wnt activation. (2016)
  • Author(s): Yamashita T, Nault JC
  • Journal Title: J Hepatol. Volume: 65 Issue: 5 Pages: 873-875
  • DOI: 10.1016/j.jhep.2016.07.014
  • NAID: 120005983029
  • Peer Reviewed
• [Journal Article] Defeating EpCAM(+) liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma. (2015)
  • Author(s): Nio K, Yamashita T, Okada H, Kondo M, Hayashi T, Hara Y, Nomura Y, Zeng SS, Yoshida M, Hayashi T, Sunagozaka H, Oishi N, Honda M, Kaneko S
  • Journal Title: J. Hepatology Volume: 5 Issue: 5 Pages: 1164-72
  • DOI: 10.1016/j.jhep.2015.06.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gd-EOB-DTPA-enhanced magnetic resonance imaging and alpha-fetoprotein predict prognosis of early-stage hepatocellular carcinoma. (2014)
  • Author(s): Yamashita T, Kitao A, Matsui O, Hayashi T, Nio K, Kondo M, Ohno N, Miyati T, Okada H, Yamashita T, Mizukoshi E, Honda M, Nakanuma Y, Takamura H, Ohta T, Nakamoto Y, Yamamoto M, Takayama T, Arii S, Wang XW, Kaneko S
  • Journal Title: Hepatology Volume: in press Issue: 5 Pages: 1674-85
  • DOI: 10.1002/hep.27093
  • Peer Reviewed / Open Access
• [Presentation] The role of liver cancer stem cells in hepatocellular carcinoma (2017)
  • Author(s): Taro Yamashita
  • Organizer: APASL
  • Place of Presentation: 上海
  • Year and Date: 2017-02-17
  • Int'l Joint Research / Invited
• [Presentation] Peretinoin prevents DNA damage accumulation and reverts preneoplastic lesions to normal liver-like in platelet derived growth factor-c transgenic mice. (2016)
  • Author(s): Taro Yamashita
  • Organizer: AASLD
  • Place of Presentation: Boston
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] ソラフェニブ抵抗性を獲得した肝細胞癌に対する治療戦略の基礎検討 (2016)
  • Author(s): 山下太郎、羽柴智美、金子周一
  • Organizer: 日本肝臓学会
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] Fibrotic liver microenvironment promotes stemness of liver cancer through the activation of TGF-beta and histone demethylase KDM2B in a p53 dependent manner (2015)
  • Author(s): Taro Yamashita, Mitsumasa Kondo, Hikari Okada, Naoki Oishi, Masao Honda, and Shuichi Kaneko
  • Organizer: AASLD Liver Meeting
  • Place of Presentation: Moscone West Convention Center (San Francisco, California, U.S.A.)
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Exploring the stemness of hepatocellular carcinoma (2015)
  • Author(s): Taro Yamashita
  • Organizer: Global Liver Conference
  • Place of Presentation: University of Hawaii Cancer Center (Honolulu, Hawaii, U.S.A.)
  • Year and Date: 2015-05-22
  • Int'l Joint Research / Invited
• [Presentation] Gd-EOB-DTPA-enhanced MRI and AFP predict prognosis of early-stage hepatocellular carcinoma. Molecular features of MR images and their clinical utilities. (2015)
  • Author(s): Taro Yamashita, Masao Honda, Shuichi Kaneko
  • Organizer: AACR conference Molecular Imaging and Cancer Biology and Therapy
  • Place of Presentation: San Diego
  • Year and Date: 2015-02-11 – 2015-02-14
• [Presentation] Wnt/beta-catenin signaling activates different target genes in hepatocellular carcinoma based on the stem/maturational status and HNF4a (2014)
  • Author(s): Taro Yamashita, Masao Honda, Shuichi Kaneko
  • Organizer: AASLD annual meeting 2014
  • Place of Presentation: Boston
  • Year and Date: 2014-11-07 – 2014-11-11
• [Patent(Industrial Property Rights)] ソラフェニブ応答性予測のための方法 (2016)
  • Inventor(s): 山下太郎、本多政夫、金子周一
  • Industrial Property Rights Holder: 山下太郎、本多政夫、金子周一
  • Industrial Property Rights Type: 特許
  • Filing Date: 2016-12-08