Effect of lipid mediator pumped out by ABC transporter to breast cancer microenvironment

• Project/Area Number: 16K19055
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Yokohama City University
• Principal Investigator: Akimitsu Yamada 横浜市立大学, 医学研究科, 客員研究員 (90567603)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: 乳癌 / ABC輸送体 / S1P / 癌微小環境 / 乳癌幹細胞 / スフィンゴシン１リン酸 / 微小環境 / 脂質メディエーター

Outline of Final Research Achievements

Sphingosine-1-phosphate (S1P), a bioactive sphingolipid mediator, has been implicated in regulation of many processes important for breast cancer progression. We demonstrated that overexpression of ABC transporter that efflux S1P in breast cancer cells enhanced S1P secretion, proliferation and migration of breast cancer cells. Implantation of these cells into the mammary fat pad of mice markedly enhanced tumor growth, angiogenesis and lymphangiogenesis with a concomitant increase in lymph node and lung metastases as well as shorter survival. Furthermore, patients with breast cancers that express both activated SPHK1 and ABC transporter have significantly shorter disease-free survival. These findings suggest that export of S1P via ABC transporter functions in a malicious feed-forward manner to amplify the S1P axis involved in breast cancer progression and metastasis, which has important implications for prognosis of breast cancer patients and for potential therapeutic targets.

Academic Significance and Societal Importance of the Research Achievements

本研究によって、脂質シグナル伝達物質S1Pが生成/排出のサイクルを介して乳癌微小環境に作用し乳癌の増悪に関与していることが示された．現在S1Pシグナルを標的とした治療薬として、S1P受容体修飾薬が，本邦では未承認であるが海外では免疫修飾薬として多発性硬化症に投与されており，潰瘍性大腸炎・関節リウマチなどに対する臨床試験が行われている．今後，S1Pシグナル標的治療が癌治療へ応用される可能性があり，本研究がその一助となることが期待される．

Research Products

• [Int'l Joint Research] Virginia Commonwealth University/Roswell Park Comprehensive Cancer Center(米国)
• [Int'l Joint Research] Roswell Park Cancer Institute/Virginia Commonwealth University(米国)
• [Int'l Joint Research] Virginia Commonwealth University/Roswell Park Cancer Institute(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] Lnc RNA H19 is associated with poor prognosis in breast cancer patients and promotes cancer stemness. (2018)
  • Author(s): Shima H, Kida K, Adachi S, Yamada A, Sugae S, Narui K, Miyagi Y, Nishi M, Ryo A, Murata S, Taniguchi H, Ichikawa Y, Ishikawa T, Endo I.
  • Journal Title: Breast Cancer Res Treat. Volume: 170(3) Issue: 3 Pages: 507-516
  • DOI: 10.1007/s10549-018-4793-z
  • Peer Reviewed
• [Journal Article] Are breast cancer stem cells the key to resolving clinical issues in breast cancer therapy? (2017)
  • Author(s): Shima H，Yamada A, Ishikawa T, Endo I
  • Journal Title: Gland Surgery Volume: 6(1) Issue: 1 Pages: 82-88
  • DOI: 10.21037/gs.2016.08.03
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Operation with less adjuvant therapy for elderly breast cancer (2016)
  • Author(s): Yamada A, Narui K, Sugae S, Shimizu D, Takabe K, Ichikawa Y, Ishikawa T, Endo I
  • Journal Title: J Surg Res Volume: 204 Issue: 2 Pages: 410-417
  • DOI: 10.1016/j.jss.2016.05.031
  • Peer Reviewed
• [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 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] 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
• [Presentation] Sphingosine-1- phosphate Produced by Sphingosine Kinase 1 and Exported via ABCC1 Shortens Survival of Mice and Humans with Breast Cancer (2017)
  • Author(s): Yamada A, Nagahashi M, Aoyagi T, Huang W-C, Lima S, Miyazaki H, Narui K, Ishikawa T, Endo I, Waters MR, Milstien S, Spiegel S, Takabe K
  • Organizer: 40th Annual CTRC-AACR San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] argeting the SphK1/S1P/S1PR1 axis that connects obesity, chronic inflammation, and breast cancer metastasis (2017)
  • Author(s): Nagahashi M, Yamada A, Aoyagi T, Huang W-C, Terracina KP, Hait N, Allegood JC, Tsuchida J, Nakajima M, Katsuta E, Milstien S, Wakai T, Spiegel S, Takabe K
  • Organizer: 40th Annual CTRC-AACR San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] Long non-coding RNA H19 promotes cancer stemness and worsen breast cancer survival (2017)
  • Author(s): Shima H, Kida K, Yamada A, Sugae S, Narui K, Miyagi Y, Ryo A, Ichikawa Y, Ishikawa T, Endo I
  • Organizer: 40th Annual CTRC-AACR San Antonio Breast Cancer Symposium
  • Int'l Joint Research
• [Presentation] ABCC11はスフィンゴシン１リン酸（S1P）を輸送して微小環境を整え，乳癌の増殖に寄与する (2017)
  • Author(s): 5.山田顕光，永橋昌幸，鈴木千穂，足立祥子，島秀栄，菅江貞亨，成井一隆，市川靖史，高部和明，石川孝，遠藤格
  • Organizer: 第26回日本癌病態治療研究会
• [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: 東京国際フォーラム（東京）
  • Year and Date: 2016-06-16
• [Presentation] 当院の超高齢者乳癌に対する集学的治療の現状 (2016)
  • Author(s): 山田顕光、成井一隆、足立祥子、田辺美樹子、島秀栄、喜多久美子、菅江貞亨、市川靖史、石川孝、遠藤格
  • 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）
  • Year and Date: 2016-04-15