The role of sphingosine-1-phosphate in interstitial fluid promoting the breast cancer progression

• Project/Area Number: 16K19888
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Niigata University
• Principal Investigator: Tsuchida Junko 新潟大学, 医歯学総合病院, 医員 (90769415)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 脂質メディエーター / スフィンゴシン-1-リン酸 / 乳癌 / 癌間質液 / スフィンゴシン-1リン酸

Outline of Final Research Achievements

Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates processes important for cancer progression. We studied the role of S1P in the tumor microenvironment utilizing the experiments using our improved centrifugation method to collect breast tumor and normal tissue interstitial fluid (IF). Importantly, levels of S1P in IF from mammary tumors were reduced when tumor growth was suppressed by oral administration of FTY720/fingolimod. S1P levels were significantly higher in human breast tumor tissue IF than in the normal breast tissue IF. S1P tumor IF measurement illuminates new aspects of the role of S1P in the tumor microenvironment.

Academic Significance and Societal Importance of the Research Achievements

癌間質液中のS1P濃度を定量する方法がこれまでになく、研究はなされてこなかった。我々は、低速遠心分離による組織間質液抽出法を開発し、質量分析装置を用いて、間質液中のS1P濃度を定量することに成功した。癌間質液中のS1Pが癌の発育進展に関わっていることが示唆される結果が得られた。本研究はS1Pの癌微小環境における役割を検討する上で新たな視点をもたらしたと言える。

Research Products

• [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] Ceramide species are elevated in human breast cancer and are associated with less aggressiveness. (2018)
  • Author(s): Moro K，Kawaguchi T，Tsuchida J，Gabriel E，Qi Q，Yan L，Wakai T，Takabe K，Nagahashi M
  • Journal Title: Oncotarget Volume: 9 Issue: 28 Pages: 19874-19890
  • DOI: 10.18632/oncotarget.24903
  • Peer Reviewed / Open Access
• [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] 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] 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] 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
• [Presentation] Levels of sphingolipids in plasma are elevated in breast cancer patients with lymph node metastasis (2019)
  • Author(s): Junko Tsuchida, Masayuki Nagahashi, Kazuki Moro, Mayuko Ikarashi, Yu Koyama, Hiroshi Ichikawa, Yoshifumi Shimada, Jun Sakata, Takashi Kobayashi, Hitoshi Kameyama, Kazuaki Takabe, Toshifumi Wakai
  • Organizer: The 14th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] 肥満が引き起こす慢性炎症による乳癌の転移促進と脂質メディエーターの役割 (2018)
  • Author(s): 永橋 昌幸，土田 純子，油座 築，中島 真人，高部 和明，若井 俊文
  • Organizer: 第25回外科侵襲とサイトカイン研究会
• [Presentation] ヒト乳癌組織では全てのCeramide主合成経路が活性化されている (2018)
  • Author(s): 諸 和樹，永橋 昌幸，遠藤 麻巳子，大溪 彩香，土田 純子，庭野 稔之，山浦 久美子，長谷川 美樹，利川 千絵，五十嵐 麻由子，中島 真人，廣瀬雄己，坂田 純，亀山 仁史，小林 隆，川口 耕，高部 和明，若井 俊文
  • Organizer: 第118回日本外科学会定期学術集会
• [Presentation] Sphingosine-1-phosphate Affects Tumor-associated Immune Cells in Human Breast Cancer Patients (2018)
  • Author(s): Junko Tsuchida，Masayuki. Nagahashi，Kazuki. Moro，Ayaka Otani，Maiko Endo，Mayuko Ikarashi，Masato Nakajima，Yu Koyama，Jun Sakata，Takashi Kobayashi，Hitoshi Kameyama，Qianya Qi，Li Yan，Kazuaki Takabe，Toshifumi Wakai
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] The Roles of Sphingosine-1-phosphate Produced by Sphingosine Kinases in Tumor and Its Microenvironment (2018)
  • Author(s): Kohei Miura，Masayuki Nagahashi，Masato Nakajima，Kizuki. Yuza，Junko Tsuchida，Yuki Hirose，Manabu Abe，Kenji Sakimura，Toshifumi Wakai
  • Organizer: 13th Annual Academic Surgical Congress
  • Int'l Joint Research
• [Presentation] 乳がん患者における脂質メディエーター・スフィンゴシン-１-リン酸の定量と臨床的意義 (2017)
  • Author(s): 土田 純子，永橋 昌幸，遠藤 麻巳子，大溪 彩香，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，坂田 純，小林 隆，亀山 仁史，高部 和明，若井 俊文
  • Organizer: 第117 回日本外科学会定期学術集会
• [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] 乳癌患者における腫瘍のスフィンゴシン-1-リン酸産生と腫瘍関連免疫細胞に対する役割 (2017)
  • Author(s): 土田 純子，永橋 昌幸，中島真人，高部 和明，若井 俊文
  • Organizer: 第24回外科侵襲とサイトカイン研究会
• [Presentation] Sphingosine-1-phosphate and tumor-associated immune cells in the tumor microenvironment (2017)
  • Author(s): Junko Tsuchida，Masayuki Nagahashi，Masato Nakajima，Kazuaki Takabe，Toshifumi Wakai
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] The levels of Sphingosine-1-phosphate and its related gene expressions in breast cancer patients (2017)
  • Author(s): Junko Tsuchida，Masayuki Nagahashi，Masato Nakajima，Kazuaki Takabe，Toshifumi Wakai
  • Organizer: 2017 San Antonio Breast Cancer Symposium
  • 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. 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
  • Int'l Joint Research
• [Presentation] Obesity-induced Sphingosine-1-phosphate in Breast Cancer Interstitial Fluid Promotes Angiogenesis (2017)
  • Author(s): Tsuchida J, Nakajima M, Moro K, Ohtani A, Endo M, Niwano T, Tatsuda K, Toshikawa C, Hasegawa M, Ikarashi M, Koyama Y, Sakata J, Kobayashi T, Kameyama H, Wakai T, Takabe K, Nagahashi M
  • Organizer: The 12th Annual Academic Surgical Congress
  • Place of Presentation: Las Vegas, USA
  • 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)
• [Presentation] 肥満によって促進される乳癌の血管新生に対する抗スフィンゴシン-1-リン酸受容体治療 (2016)
  • 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，山田 顕光，青柳 智義，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)
• [Presentation] 乳がん手術検体におけるスフィンゴリン脂質の定量 (2016)
  • Author(s): 中島 真人，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，小山 諭，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)
• [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] 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、小山 諭、高部 和明、若井 俊文
  • Organizer: 第78回臨床外科学会総会
  • Place of Presentation: グランドプリンスホテル新高輪(東京都港区)