The role of a lipid mediator in an interaction between cancer and the host, promoting breast cancer progression

• Project/Area Number: 15H05676
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: General surgery
• Research Institution: Niigata University
• Principal Investigator: Nagahashi Masayuki 新潟大学, 医歯学総合病院, 講師 (30743918)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥23,790,000 (Direct Cost: ¥18,300,000、Indirect Cost: ¥5,490,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2016: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2015: ¥10,660,000 (Direct Cost: ¥8,200,000、Indirect Cost: ¥2,460,000)
• Keywords: 脂質メディエーター / スフィンゴシン-１-リン酸 / スフィンゴシンキナーゼ / 癌と宿主 / リンパ節転移 / 乳癌 / スフィンゴシン-1-リン酸 / 癌間質液 / リンパ液 / 癌 / 血管新生 / リンパ管新生

Outline of Final Research Achievements

Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator. We studied the role of S1P in the interaction between cancer and host (tumor microenvironment) utilizing experiments using genetically modified cancer cells and mice of S1P production responsive enzymes and analysis of clinical specimens. Based on the results of this study, it was revealed that both S1P produced by cancer and that produced by the host are important for the cancer progression. Our data showed that S1P concentration in the tumor of breast cancer patients with lymph node metastasis is higher than that without lymph node metastasis.

Research Products

• [Int'l Joint Research] ロズウェルパーク癌研究所/バージニア州立大学(米国)
• [Int'l Joint Research] バージニア州立大学/ロズウェルパーク癌研究所(米国)
• [Int'l Joint Research] Virginia Commonwealth University(米国)
• [Journal Article] 1.ABCC1-Exported Sphingosine-1-phosphate, Produced by Sphingosine Kinase 1, Shortens Survival of Mice and Patients with Breast Cancer (2018)
  • Author(s): Yamada A, Nagahashi M, Aoyagi T, Huang WC, Lima S, Hait NC, Maiti A, Kida K, Terracina KP, Miyazaki H, Ishikawa T, Endo I, Waters MR, Qi Q, Yan L, Milstien S, Spiegel S, Takabe K.
  • Journal Title: Mol Cancer Res Volume: 印刷中 Issue: 6 Pages: 1059-1070
  • DOI: 10.1158/1541-7786.mcr-17-0353
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting the SphK1/S1P/S1PR1 Axis That Links Obesity, Chronic Inflammation, and Breast Cancer Metastasis (2018)
  • Author(s): Nagahashi Masayuki、Yamada Akimitsu、Katsuta Eriko、Aoyagi Tomoyoshi、Huang Wei-Ching、Terracina Krista P.、Hait Nitai C.、Allegood Jeremy C.、Tsuchida Junko、Yuza Kizuki、Nakajima Masato、Abe Manabu、Sakimura Kenji、Milstien Sheldon、Wakai Toshifumi、Spiegel Sarah、Takabe Kazuaki
  • Journal Title: Cancer Research Volume: 78 Issue: 7 Pages: 1713-1725
  • DOI: 10.1158/0008-5472.can-17-1423
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer (2017)
  • Author(s): Tsuchida Junko、Nagahashi Masayuki、Takabe Kazuaki、Wakai Toshifumi
  • Journal Title: Mediators of Inflammation Volume: 2017 Pages: 1-9
  • DOI: 10.1155/2017/2076239
  • Peer Reviewed / Int'l Joint Research
• [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] High levels of sphingolipids in human breast cancer (2016)
  • Author(s): Nagahashi M, Tsuchida J, Moro K, Hasegawa M, Tatsuda K, Woelfel IA, Takabe K, Wakai T
  • Journal Title: J Surg Res Volume: 204 Issue: 2 Pages: 435-444
  • DOI: 10.1016/j.jss.2016.05.022
  • Peer Reviewed / 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] 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] Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans (2016)
  • Author(s): Huang WC, Liang J, Nagahashi M, Avni D, Yamada A, Maceyka M, Wolen AR, Kordula T, Milstien S, Takabe K, Oravecz T, Spiegel S
  • Journal Title: FASEB J Volume: 30 Issue: 8 Pages: 2945-2958
  • DOI: 10.1096/fj.201600394r
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Breast cancer sphingosine-1-phosphate is associated with phospho-sphingosine kinase 1 and lymphatic metastasis (2016)
  • Author(s): Tsuchida J, Nagahashi M, Nakajima M, Moro K, Tatsuda K, Ramanathan R, Takabe K, Wakai T
  • Journal Title: J Surg Res Volume: 205 Issue: 1 Pages: 85-94
  • DOI: 10.1016/j.jss.2016.06.022
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans (2016)
  • Author(s): Wei-Ching Huang, Jie Liang, Masayuki Nagahashi, Dorit Avni, Akimitsu Yamada, Michael Maceyka, Aaron R. Wolen, Tomasz Kordula, Sheldon Milstien, Kazuaki Takabe, Tamas Oravecz, Sarah Spiegel
  • Journal Title: The FASEB Journal Volume: 未定
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 癌における脂質メディエーター・スフィンゴシン-1-リン酸の働き (2015)
  • Author(s): 永橋 昌幸
  • Journal Title: 新潟県医師会報 Volume: 789 Pages: 1-7
• [Presentation] The roles of sphingosine-1-phosphate produced by sphingosine kinases in tumor and its microenvironment (2018)
  • Author(s): Miura K, Nagahashi M, Nakajima M, Yuza K, Tsuchida J, Hirose Y, Abe M, Sakimura K, Wakai T
  • Organizer: The 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] Sphingosine-1-phosphate affects tumor-associated immune cells in human breast cancer patients (2018)
  • Author(s): Tsuchida J, Nagahashi M, Moro K, Otani A, Endo M, Ikarashi M, Nakajima M, Koyama Y, Sakata J, Kobayashi T, Kameyama H, Yan Q, Yan L, Takabe K, Wakai T
  • Organizer: The 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] Sphingosine-1-phosphate in the Lymphatic Fluid Determined by Novel Methods (2017)
  • Author(s): Nagahashi M, Yamada A, Aoyagi T, Allegood J, Wakai T, Spiegel S, Takabe K
  • Organizer: The 12th Annual Academic Surgical Congress
  • Place of Presentation: Las Vegas, USA
  • Year and Date: 2017-02-07
  • Int'l Joint Research
• [Presentation] Peri-tumor Sphingosine-1-phosphate Levels Are Affected by the Tumor. (2017)
  • Author(s): Tsuchida J, Moro K, Ohtani A, Endo M, Niwano T, Tatsuda K, Toshikawa C, Hasegawa M, Ikarashi M, Nakajima M, Y. Koyama1, Sakata J, Kobayashi T, Kameyama H, Takabe K, Wakai T, Nagahashi M
  • Organizer: The 12th Annual Academic Surgical Congress
  • Place of Presentation: Las Vegas, USA
  • Year and Date: 2017-02-07
  • Int'l Joint Research
• [Presentation] High Levels of Ceramide in Breast Cancer and Its Microenvironment. (2017)
  • Author(s): Moro K, Tsuchida J, Ohtani A, Endo M, Niwano T, Tatsuda K, Toshikawa C, Hasegawa M, Ikarashi M, Nakajima M, Y. Koyama Y, Sakata J, Kobayashi T, Kameyama H, Takabe K, Wakai T, Nagahashi M
  • Organizer: The 12th Annual Academic Surgical Congress
  • Place of Presentation: Las Vegas, USA
  • Year and Date: 2017-02-07
  • Int'l Joint Research
• [Presentation] Immune-modulator FTY720 potentiate Doxorubicin in obesity-related breast cancer. (2017)
  • Author(s): Takabe K, Katsuta E, Nagahashi M
  • Organizer: The 12th Annual Academic Surgical Congress
  • Place of Presentation: Las Vegas, USA
  • Year and Date: 2017-02-07
  • Int'l Joint Research
• [Presentation] CRISPR/Cas9によるスフィンゴシン-1-リン酸産生酵素の乳癌発育進展における役割解明 (2017)
  • Author(s): 三浦要平，中島真人，永橋昌幸，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，若井俊文
  • Organizer: 第117回日本外科学会定期学術集会
• [Presentation] 乳がんのがん細胞と宿主におけるスフィンゴシン-1-リン酸産生酵素の機能解析 (2017)
  • Author(s): 中島真人，永橋昌幸，大谷彩香，遠藤麻已子，土田純子，諸 和樹，庭野稔之，山浦久美子，利川千絵，長谷川美樹，五十嵐麻由子，小山 諭，坂田 純，亀山仁史，小林 隆，若井俊文
  • Organizer: 第25回日本乳癌学会学術集会
• [Presentation] シンポジウム15 私たちが日本で行うべき乳癌研究 基礎から臨床まで 日本だからこそできるトランスレーショナルリサーチの実践を目指して (2017)
  • Author(s): 永橋昌幸，大渓彩香，遠藤麻巳子，土田純子，諸和樹，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25回日本乳癌学会学術集会
• [Presentation] Symposia S1：New trends for studying cancer invasion and metastasis The role of sphingosine-1-phosphate in tumor microenvironment and metastasis (2017)
  • Author(s): Nagahashi M, Tsuchida J, Nakajima M, Takabe K, Wakai T
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Targeting the SphK1/S1P/S1PR1 axis that connects obesity, chronic inflammation, and breast cancer metastasis (2017)
  • Author(s): Nagahashi M, Yamada A, Aoyagi T, Huang WC, Terracina KP, Hait N, Allegood JC, Tsuchida J, Nakajima M, Katsuta E, Milstien S, Wakai T, Spiegel S, Takabe K
  • Organizer: 2017 San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] 乳がん患者における腫瘍内スフィンゴシン-1-リン酸濃度と臨床病理学的因子の関連について (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24回日本乳癌学会学術総会
  • Place of Presentation: 東京ビックサイト（東京都江東区）
  • Year and Date: 2016-06-16
• [Presentation] Targeting sphingosine-1-phosphate in obesity-induced angiogenesis in breast cancer progression (2016)
  • Author(s): Masayuki Nagahashi, Kazuki Moro, Junko Tsuchida, Toshiyuki Niwano, Kumiko Tatsuda, Chie Toshikawa, Miki Hasegawa, Yu Koyama, Takashi Kobayashi, Shin-ichi Kosugi, Hitoshi Kameyama, Akimitsu Yamada, Tomoyoshi Aoyagi, Kazuaki Takabe, Toshifumi Wakai
  • Organizer: The 11th Annual Academic Surgical Congress
  • Place of Presentation: Jacksonville, USA
  • Year and Date: 2016-02-02
  • Int'l Joint Research
• [Presentation] Very Long Acyl Chain (C24:0 and C22:0) Ceramides are Associated with Obesity and Breast Cancer Progression (2016)
  • Author(s): Kazuki Moro, Masayuki Nagahashi, Junko Tsuchida, Toshiyuki Niwano, Kumiko Tatsuda, Chie Toshikawa, Miki Hasegawa, Yu Koyama, Takashi Kobayashi, Shin-ichi Kosugi, Hitoshi Kameyama, Hiroaki Aoki, Kazuaki Takabe, Toshifumi Wakai
  • Organizer: The 11th Annual Academic Surgical Congress
  • Place of Presentation: Jacksonville, USA
  • Year and Date: 2016-02-02
  • Int'l Joint Research
• [Presentation] Roles of sphingosine-1-phosphate produced by sphingosine kinases in cancer progression (2016)
  • Author(s): Masato Nakajima, Masayuki Nagahashi, Junko Tsuchida, Toshifumi Wakai
  • 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）
• [Presentation] FTY720 decreases levels of lipid mediator in tumor microenvironment and suppresses breast cancer progression (2015)
  • Author(s): Masayuki Nagahashi, Kazuki Moro, Junko Tsuchida, Kumiko Tatsuda, Jun Sakata, Takashi Kobayashi, Kazuaki Takabe, Toshifumi Wakai
  • Organizer: 46th World Congress of Surgery
  • Place of Presentation: Bangkok, Thailand
  • Year and Date: 2015-08-23
  • Int'l Joint Research
• [Presentation] A lipid mediator, sphingosine-1-phosphate as a promising target for colitis-associated cancer (2015)
  • Author(s): Masayuki Nagahashi, Yoshifumi Shimada, Jun Sakata, Hitoshi Kameyama, Takashi Kobayashi, Kazuaki Takabe, Yasuo Saijo, Toshifumi Wakai
  • Organizer: 第13回日本臨床腫瘍学会学術集会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2015-07-16
• [Presentation] がん微小環境中にはスフィンゴシン -1-リン酸（S1P）が高濃度で存在する (2015)
  • Author(s): 永橋 昌幸，土田 純子，諸 和樹，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，山田 顕光，青柳 智義，高部 和明，若井 俊文
  • Organizer: 第23回日本乳癌学会学術集会
  • Place of Presentation: 東京国際フォーラム（東京都千代田区）
  • Year and Date: 2015-07-02