Elucidation of molecular mechanism of lipid mediator involved in metastatic ability of biliary tract cancer / pancreatic cancer and clinical application

• Project/Area Number: 15H04927
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Niigata University
• Principal Investigator: WAKAI TOSHIFUMI 新潟大学, 医歯学系, 教授 (50372470)
• Co-Investigator(Kenkyū-buntansha): 永橋 昌幸 新潟大学, 医歯学総合病院, 講師 (30743918) ; 松田 康伸 新潟大学, 医歯学系, 准教授 (40334669) ; 小林 隆 新潟大学, 医歯学総合病院, 講師 (40464010) ; 五十嵐 道弘 新潟大学, 医歯学系, 教授 (50193173) ; 坂田 純 新潟大学, 医歯学系, 講師 (70447605) ; 味岡 洋一 新潟大学, 医歯学系, 教授 (80222610) ; 小杉 伸一 新潟大学, 医歯学総合病院, 特任教授 (90401736)
• Co-Investigator(Renkei-kenkyūsha): Komatsu Masaaki 新潟大学, 医歯学系, 教授 (90356254)
• Research Collaborator: Sarah Spiegel バージニア州立大学, 教授 ; Hylemon Phillip B. バージニア州立大学, 教授 ; Takabe Kazuaki Roswell Park Cancer Institution, 教授
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 脂質メディエーター / 胆道外科学 / 膵臓外科学 / ダブルノックアウトマウス / リンパ管新生 / 細胞外基質 / リンパ管浸潤 / CRISPR/Cas9 / B/6系マウス / 細胞増殖能 / 胆道癌 / 膵癌 / 転移能

Outline of Final Research Achievements

We have developed a method to measure sphingosine-1-phosphate levels in the interstitial fluid that bathes cancer cells in the tumor microenvironment, and reported that high levels of sphingosine-1-phosphate exist in the tumor interstitial fluid. Importantly, sphingosine-1-phosphate can be secreted from cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment. We elucidate the roles of sphingosine-1-phosphate in the interaction between cancer and non-cancer cells in tumor microenvironment, and discuss future possibilities for targeted therapies against sphingosine-1-phosphate signaling for cancer patients.

Research Products

• [Int'l Joint Research] Roswell Park Cancer Institute/The State University of New York(米国)
• [Int'l Joint Research] Roswell Park Cancer Institute/University at Buffalo Jacobs School/Virginia Commonwealth University(米国)
• [Int'l Joint Research] Virginia Commonwealth University(米国)
• [Journal Article] 癌と宿主におけるスフィンゴシン-1-リン酸の役割 (2017)
  • Author(s): 永橋 昌幸，若井 俊文
  • Journal Title: BIO Clinica Volume: 32 Pages: 397-404
• [Journal Article] The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications (2017)
  • Author(s): Nakajima M, Nagahashi M, Rashid OM, Takabe K, Wakai T
  • Journal Title: Tumour Biol. Volume: 39 Issue: 4 Pages: 101042-101042
  • DOI: 10.1177/1010428317699133
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Prognostic heterogeneity of the seventh edition of UICC Stage III gallbladder carcinoma: Which patients benefit from surgical resection? (2017)
  • Author(s): Sakata J, Kobayashi T, Ohashi T, Hirose Y, Takano K, Takizawa K, Miura K, Ishikawa H, Toge K, Yuza K, Soma D, Ando T, Wakai T
  • Journal Title: Eur J Surg Oncol. Volume: 43 Issue: 4 Pages: 780-787
  • DOI: 10.1016/j.ejso.2017.01.001
  • Peer Reviewed / Open Access
• [Journal Article] Sphingosine-1-phosphate in the lymphatic fluid determined by novel methods. (2016)
  • Author(s): Nagahashi M, Yamada A, Aoyagi T, Allegood J, Wakai T, Spiegel S, Takabe K
  • Journal Title: Heliyon Volume: 2 Issue: 12 Pages: e00219-e00219
  • DOI: 10.1016/j.heliyon.2016.e00219
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The roles of bile acids and sphingosine-1-phosphate signaling in the hepatobiliary diseases. (2016)
  • Author(s): Nagahashi M, Yuza K, Hirose Y, Nakajima M, Ramanathan R, Hait NC, Hylemon PB, Zhou H, Takabe K, Wakai T.
  • Journal Title: J Lipid Res. Volume: 57 Issue: 9 Pages: 1636-43
  • DOI: 10.1194/jlr.r069286
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Resolvins and omega three polyunsaturated fatty acids: Clinical implications in inflammatory diseases and cancer. (2016)
  • Author(s): Moro K, Nagahashi M, Ramanathan R, Takabe K, Wakai T.
  • Journal Title: World J Clin Cases. Volume: 4 Issue: 7 Pages: 155-64
  • DOI: 10.12998/wjcc.v4.i7.155
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] DNA damage response and sphingolipid signaling in liver diseases (2016)
  • Author(s): Nagahashi M, Matsuda Y, Moro K, Tsuchida J, Soma D, Hirose Y, Kobayashi T, Kosugi SI, Takabe K, Komatsu M, Wakai T
  • Journal Title: Surg Today Volume: 印刷中 Issue: 9 Pages: 995-1005
  • DOI: 10.1007/s00595-015-1270-8
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interstitial Fluid Sphingosine-1-Phosphate in Murine Mammary Gland and Cancer and Human Breast Tissue and Cancer Determined by Novel Methods. (2016)
  • Author(s): Nagahashi M, Yamada A, Miyazaki H, Allegood JC, Tsuchida J, Aoyagi T, Huang WC, Terracina KP, Adams BJ, Rashid OM, Milstien S, Wakai T, Spiegel S, Takabe K.
  • Journal Title: J Mammary Gland Biol Neoplasia Volume: 21 Issue: 1-2 Pages: 9-17
  • DOI: 10.1007/s10911-016-9354-7
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Comparison of Number Versus Ratio of Positive Lymph Nodes in the Assessment of Lymph Node Status in Extrahepatic Cholangiocarcinoma (2016)
  • Author(s): Sakata J, Wakai T, Matsuda Y, Ohashi T, Hirose Y, Ichikawa H, Kobayashi T, Minagawa M, Kosugi S, Koyama Y, Akazawa K, Ajioka Y
  • Journal Title: Ann Surg Oncol Volume: 23 Issue: 1 Pages: 225-234
  • DOI: 10.1245/s10434-015-4609-x
  • Peer Reviewed / Open Access
• [Presentation] Sphingosine-1-phosphate produced by sphingosine kinase type 1 and type 2 works differently in pancreatic cancer (2018)
  • Author(s): M. Nakajima, K. Yuza, J. Tsuchida, Y. Hirose, K. Miura, H. Ichikawa, Y. Shimada, T. Kobayashi, J. Sakata, H. Kameyama, M. Abe, K. Sakimura, T. Wakai, M. Nagahashi
  • Organizer: The 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] High levels of sphingolipids in human pancreatic cancer (2018)
  • Author(s): K. Yuza, M. Nagahashi, Y. Hirose, M. Nakajima, K. Miura, H. Ichikawa, Y. Shimada, J. Sakata, H. Kameyama, T. Kobayashi, K. Takabe, T. Wakai
  • Organizer: The 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] 膵がんにおけるCRISPR/Cas9を用いたスフィンゴシン-1-リン酸産生酵素の機能解析 (2017)
  • Author(s): 中島 真人，永橋 昌幸，三浦 要平，安藤 拓也，油座 築，土田 純子，田島 陽介，坂田 純，小林 隆，亀山 仁史，阿部 学，崎村 建司，若井 俊文
  • Organizer: 第117回日本外科学会定期学術集会
• [Presentation] 膵癌細胞におけるスフィンゴシン-1-リン酸産生酵素の働きとその代謝動態制御の解析 (2017)
  • Author(s): 中島 真人，永橋 昌幸，三浦 要平，安藤 拓也，油座 築，土田 純子，田島 陽介，坂田 純，小林 隆，亀山 仁史，阿部 学，﨑村 建司，曽我 朋義，若井 俊文
  • Organizer: 日本外科代謝栄養学会第54回学術集会
• [Presentation] Function Analysis of Sphingosine-1-Phosphate Produced by Sphingosine Kinases in Pancreatic Cancer Progression. (2017)
  • Author(s): Masato Nakajima，Masayuki Nagahashi，Junko Tsuchida，Hiroshi Ichikawa，Yoshifumi Shimada，Toshifumi Wakai
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 肥満を伴う乳癌患者における血清スフィンゴシン-1-リン酸の定量 (2016)
  • Author(s): 土田 純子, 永橋 昌幸, 遠藤 麻巳子, 大溪 彩香, 庭野 稔之, 辰田 久美子, 利川 千絵, 長谷川 美樹, 五十嵐 麻由子, 中島 真人, 小山 諭, 高部 和明, 若井 俊文
  • Organizer: 第78回 日本臨床外科学会総会
  • Place of Presentation: グランドプリンスホテル新高輪（東京都港区）
  • Year and Date: 2016-11-24
• [Presentation] スフィンゴシンキナーゼ欠損細胞の開発とその機能解析 (2016)
  • Author(s): 中島 真人, 永橋 昌幸, 土田 純子, 市川 寛, 島田 能史, 若井 俊文
  • Organizer: 第75回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] 検診発見および自己発見乳癌の臨床病理学的特徴と長期成績 (2016)
  • Author(s): 土田 純子, 永橋 昌幸, 諸 和樹, 庭野 稔之, 辰田 久美子, 利川 千絵, 長谷川 美樹, 萬羽 尚子, 五十嵐 麻由子, 小山 諭, 市川 寛, 中島 真人, 島田 能史, 坂田 純, 小林 隆, 亀山 仁史, 若井 俊文
  • Organizer: 第116回 日本外科学会定期学術集会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2016-04-14
• [Presentation] 肝胆膵「肝胆膵外科診療の最前線」 (2015)
  • Author(s): 若井俊文
  • Organizer: 第53回日本癌治療学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-10-30
  • Invited
• [Presentation] 胆汁酸はスフィンゴシン-1-リン酸シグナル伝達系を介して 肝臓における脂質代謝を調節している (2015)
  • Author(s): 永橋 昌幸，廣瀬 雄己，須藤 翔，大橋 拓，滝沢 一泰，高野 可赴，坂田 純，小林 隆，若井 俊文
  • Organizer: 第51日本胆道学会学術集会
  • Place of Presentation: ホテル東日本宇都宮（栃木県宇都宮市）
  • Year and Date: 2015-09-17
• [Presentation] IMPACT OF SURGICAL RESECTION AND CHEMOTHERAPY ON LONG-TERM OUTCOMES IN PATIENTS WITH LOCALLY ADVANCED GALLBLADDER CARCINOMA (2015)
  • Author(s): T. Wakai, J. Sakata, Y. Hirose, N. Sudo, T. Katada, K. Takizawa, M. Nagahashi, T. Kobayashi
  • Organizer: 46th World Congress of Surgery
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-08-26
  • Int'l Joint Research
• [Presentation] LONG-TERM OUTCOMES OF SURGICAL RESECTION FOR EARLY GALLBLADDER CARCINOMA (2015)
  • Author(s): T. Wakai, J. Sakata, Y. Hirose, N. Sudo, T. Katada, K. Takizawa, M. Nagahashi, T. Kobayashi
  • Organizer: 46th World Congress of Surgery
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-08-26
  • Int'l Joint Research
• [Presentation] SymposiumⅢ Laparoscopic cholecystectomy with LN dissection (2015)
  • Author(s): Toshifumi Wakai
  • Organizer: The 36th Annual Meeting of the Korean Society of Endoscopic & Laparoscopic Surgeons, 2015 International Symposium
  • Place of Presentation: Jeju, Korea
  • Year and Date: 2015-05-29
  • Int'l Joint Research / Invited
• [Presentation] 肥満はスフィンゴシン-1-リン酸を癌微小環境において増加させる (2015)
  • Author(s): 永橋 昌幸，諸 和樹，土田 純子，辰田 久美子，利川 千絵，長谷川 美樹，萬羽 尚子，五十嵐 真由子，坂田 純，小林 隆，亀山 仁史，皆川 昌広，小杉 伸一，小山 諭，高部 和明，若井 俊文
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-16