The study of stromal cells constituting fibrous stroma for the treatment of liver cancer

• Project/Area Number: 26461909
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Kyoto University
• Principal Investigator: IWAISAKO Keiko 京都大学, 医学研究科, 特定講師 (70625300)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 線維化 / 肝癌 / 胆管細胞癌 / 外科総論

Outline of Final Research Achievements

In liver cancer, it is thought that various fibrosis presents and supports the progress of cancer. In this study, we aimed to find a new treatment strategy for liver cancer by analyzing cells constituting fibrous cancer stroma. To analysis of clinical samples, we have discriminated "tumor" and "non-tumor" macroscopically and investigated in bulk. However, the microscopically observation revealed that "tumor" tissue markedly increased fibrosis and infiltration of fibroblasts and immune cells. Therefore, using by laser capture microdissection, we isolated cancer stroma and investigated gene expression. It was found that fibrotic genes and marker genes of immune cells were highly expressed in the stroma of cholangiocellular carcinoma. Stroma cells of cholangiocellular carcinoma can be considered as therapeutic targets.

Research Products

• [Journal Article] Hepatic vagus nerve regulates Kupffer cell activation via α7 nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. (2017)
  • Author(s): Nishio T, Taura K, Iwaisako K, Koyama Y, Tanabe K, Yamamoto G, Okuda Y, Ikeno Y, Yoshino K, Kasai Y, Okuno M, Seo S, Sakurai T, Asagiri M, Hatano E, Uemoto S
  • Journal Title: Journal of Gastroenterology Volume: 印刷中 Issue: 8 Pages: 965-976
  • DOI: 10.1007/s00535-016-1304-z
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Nardilysin promotes hepatocellular carcinoma through activation of signal transducer and activator of transcription 3 (2017)
  • Author(s): Kasai Y, Toriguchi K, *Hatano E, Nishi K, Ohno M, Yoh T, Fukuyaman K, Nishio T, Okuno M, Iwaisako K, Seo S, Taura K, Kurokawa M, Kunichika M, Uemoto S, *Nishi E
  • Journal Title: Cancer Sci. Volume: 108 Issue: 5 Pages: 910-917
  • DOI: 10.1111/cas.13204
  • NAID: 120006333898
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Actin-binding protein coronin 1A controls osteoclastic bone resorption by regulating lysosomal secretion of cathepsin K (2017)
  • Author(s): Ohmae S, Noma N, Toyomoto M, Shinohara M, Takeiri M, Fuji H, Takemoto K, Iwaisako K, Fujita T, Takeda N, Kawatani M, Aoyama M, Hagiwara M, Ishihama Y, Asagiri M
  • Journal Title: Sci Rep Volume: - Issue: 1 Pages: 41710-41710
  • DOI: 10.1038/srep41710
  • NAID: 120006313626
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis. (2016)
  • Author(s): Fujita T, Soontrapa K, Ito Y, Iwaisako K, Moniaga CS, Asagiri M, Majima M, Narumiya S.
  • Journal Title: Hepatology Volume: 63 Issue: 4 Pages: 1325-1339
  • DOI: 10.1002/hep.28112
  • NAID: 120005663256
  • Peer Reviewed / Open Access
• [Journal Article] Diagnostic performance of (18)F-fluorodeoxyglucose PET/CT and bone scintigraphy in breast cancer patients with suspected bone metastasis. (2016)
  • Author(s): Niikura N, Hashimoto J, Kazama T, Koizumi J, Ogiya R, Terao M, Oshitanai R, Morioka T, Tsuda B, Okamura T, Saito Y, Iwaisako K, Iwamoto T, Hayashi N, Imai Y, Tokuda Y
  • Journal Title: Breast Cancer Volume: 23 Issue: 4 Pages: 662-667
  • DOI: 10.1007/s12282-015-0621-z
  • Peer Reviewed
• [Journal Article] Pattern of RECK CpG methylation as a potential marker for predicting breast cancer prognosis and drug-sensitivity (2016)
  • Author(s): Gongping Shi , Yoko Yoshida , Kanako Yuki , Tomomi Nishimura , Yukiko Kawata , Masahiro Kawashima , Keiko Iwaisako , Kiyotsugu Yoshikawa , Junichi Kurebayashi , Masakazu Toi
  • Journal Title: Oncotarget Volume: 7 Issue: 50 Pages: 82158-82169
  • DOI: 10.18632/oncotarget.8620
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Controversies over the Epithelial-to-Mesenchymal Transition in Liver Fibrosis. (2016)
  • Author(s): Taura K, Iwaisako K, Hatano E, Uemoto S.
  • Journal Title: J Clin Med. Volume: 5 Issue: 1 Pages: 1-11
  • DOI: 10.3390/jcm5010009
  • NAID: 120005825917
  • Peer Reviewed / Open Access
• [Journal Article] Migration of splenic lymphocytes promotes liver fibrosis through modification of T helper cytokine balance in mice (2015)
  • Author(s): Tanabe K, Taura K, Koyama Y, Yamamoto G, Nishio T, Okuda Y, Nakamura K, Toriguchi K, Takemoto K, Yamanaka K, Iwaisako K, Seo S, Asagiri M, Hatano E, Uemoto S.
  • Journal Title: Journal of Gastroenterology Volume: in press Issue: 10 Pages: 1054-1068
  • DOI: 10.1007/s00535-015-1054-3
  • Peer Reviewed
• [Journal Article] Evaluation of Liver Fibrosis Using Texture Analysis on Combined-Contrast-Enhanced Magnetic Resonance Images at 3.0T. (2015)
  • Author(s): Yokoo T, Wolfson T, Iwaisako K, Peterson MR, Mani H, Goodman Z, Changchien C, Middleton MS, Gamst AC, Mazhar SM, Kono Y, Ho SB, Sirlin CB.
  • Journal Title: Biomed Res Int. Volume: 5 Pages: 387653-387653
  • DOI: 10.1155/2015/387653
  • NAID: 120005745652
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of transcriptome and metabolome analysis in Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma (2015)
  • Author(s): Murakami, Y
  • Journal Title: Scientific Reports Volume: 5 Issue: 1 Pages: 16294-16294
  • DOI: 10.1038/srep16294
  • NAID: 120005820886
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Inhibition of MMP-2-Mediated Mast Cell Invasion by NF-κB Inhibitor DHMEQ in Mast Cells. (2015)
  • Author(s): Noma N, Asagiri M, Takeiri M, Ohmae S, Takemoto K, Iwaisako K, Minato N, Maeda-Yamamoto M, Simizu S, Umezawa K
  • Journal Title: Int Arch Allergy Immunol. Volume: 166 Pages: 84-90
  • Peer Reviewed
• [Journal Article] Intestinal ischemic preconditioning ameliorates hepatic ischemia/reperfusion injury in rats: role of heme oxygenase 1 in the second window of protection. (2015)
  • Author(s): Kageyama S, Hata K, Tanaka H, Hirao H, Kubota T, Okamura Y, Iwaisako K, Takada Y, Uemoto S.
  • Journal Title: Liver Transpl. Volume: 21 Issue: 1 Pages: 112-122
  • DOI: 10.1002/lt.24006
  • NAID: 120005625638
  • Peer Reviewed
• [Journal Article] Strategies to Detect Hepatic Myofibroblasts in Liver Cirrhosis of Different Etiologies. (2014)
  • Author(s): Iwaisako K, Taura K, Koyama Y, Takemoto K, Asagiri M.
  • Journal Title: Curr Pathobiol Rep. Volume: 2 Pages: 209-215
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. (2014)
  • Author(s): Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S, Toriguchi K, Tanabe K, Tanaka H, Seo S, Taura K, Machida K, Takeda N, Saji S, Uemoto S, Asagiri M.
  • Journal Title: FEBS Open Bio Volume: 4 Issue: 1 Pages: 777-787
  • DOI: 10.1016/j.fob.2014.08.007
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Origin of myofiblasts in the fibrotic liver in mice (2014)
  • Author(s): K.Iwaisako, C.Jiang, M.Zhang, M.Cong, T.J.Moore-Morris, T.J.Park, X.Liu, J.Xu, P.Wang, Y-H.Paik, F.Meng, M.Asagiri, L.A.Murray, A.F.Hofmann, T.Iida, C.K.Glass, D.A.Brenner, T.Kisseleva
  • Journal Title: Proc. Natl. Acad. Sci. USA. Volume: 111 Issue: 32
  • DOI: 10.1073/pnas.1400062111
  • Peer Reviewed
• [Journal Article] Whey-hydrolyzed peptide-enriched immunomodulating diet prevents progression of liver cirrhosis in rats. (2014)
  • Author(s): Jobara K, Kaido T, Hori T, Iwaisako K, Endo K, Uchida Y, Uemoto S
  • Journal Title: Nutrition Volume: 30 Issue: 10 Pages: 1195-1207
  • DOI: 10.1016/j.nut.2014.02.005
  • Peer Reviewed
• [Journal Article] Cilostazol attenuates hepatic stellate cell activation and protects mice against carbon tetrachloride-induced liver fibrosis. (2014)
  • Author(s): Saito S, Hata K, Iwaisako K, Yanagida A, Takeiri M, Tanaka H, Kageyama S, Hirao H, Ikeda K, Asagiri M, Uemoto S
  • Journal Title: Hepatol Res Volume: 44 Issue: 4 Pages: 460-473
  • DOI: 10.1111/hepr.12140
  • NAID: 120005625637
  • Peer Reviewed
• [Journal Article] Effects of oral intake of hydrogen water on liver fibrogenesis in mice (2013)
  • Author(s): Koyama Y, Taura K, Hatano E, Tanabe K, Yamamoto G, Nakamura K, Yamanaka K, Kitamura K, Narita M, Nagata H, Yanagida A, Iida T, Iwaisako K, Fujinawa H, Uemoto S
  • Journal Title: Hepatol Res Volume: May 20 Issue: 6 Pages: 663-677
  • DOI: 10.1111/hepr.12165
  • Peer Reviewed
• [Presentation] Reconstruction of the hepatic artery in mouse liver transplantation. (2017)
  • Author(s): Iwaisako K, Zhao X, Asagiri M, Kawamoto M, Uermoto S
  • Organizer: 2017 Keystone Symposia Conference C8: Injury, Inflammation and Fibrosis
  • Place of Presentation: Snowbird, USA
  • Year and Date: 2017-03-26
  • Int'l Joint Research
• [Presentation] 肝胆膵領域の悪性腫瘍におけるメソテリンの診断用バイオマーカーとしての意義 (2014)
  • Author(s): 祝迫 恵子、朝霧 成挙、田浦 康二朗、波多野 悦朗、上本 伸二、佐治 重衡
  • Organizer: 第52回 日本癌治療学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2014-08-30
• [Presentation] 繊維化と再生を多臓器に学ぶ (2014)
  • Author(s): 祝迫惠子
  • Organizer: 第57回日本腎臓学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2014-07-05
  • Invited
• [Presentation] 肝線維症における筋線維芽細胞の起源 (2014)
  • Author(s): 祝迫 惠子、河本 宏、佐治 重衡
  • Organizer: 第35回 日本炎症・再生医学会年次集会
  • Place of Presentation: 沖縄
  • Year and Date: 2014-07-01
• [Presentation] 肝臓の筋線維芽細胞の起源 ―肝疾患の治療標的探索― (2014)
  • Author(s): 祝迫 惠子、朝霧 成挙、木下 正彦、濱野 玄弥、野沢 彰紀、西岡 孝芳、浦田 順久、坂田 親治、竹村 茂一、久保 正二
  • Organizer: 114回 日本外科学会定期学術集会
  • Place of Presentation: 京都
  • Year and Date: 2014-04-04