The role of Prostanoid in premetastatic niche in regional lymph nodes.

• Project/Area Number: 26462132
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Kitasato University
• Principal Investigator: Amano Hideki 北里大学, 医学部, 講師 (60296481)
• Co-Investigator(Kenkyū-buntansha): 江島 耕二 北里大学, 医学部, 准教授 (30327324)
• 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: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: プロスタグランジンE2 / 縦隔リンパ節転移 / pre-metastatic niche / EP3 / SDF-1 / プロスタギランジンE2 / EP3受容体 / 肺癌 / PGE2 / mPGES-1 / Treg / MDSC / 樹状細胞 / CXCR4

Outline of Final Research Achievements

Lung cancer has remained one of the most deadliest cancers worldwide accounting for 18% of all cancer deaths. We investigated the contribution of COX-2/PGE2 in the formation of a premetastatic niche and LNM. A murine model of LLC cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node, and COX-2 inhibition suppressed mediastinal LNM. SDF-1 was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, a SDF-1 antagonist, and a CXCR4 antibody reduced LNM. Moreover, LNM was reduced in EP3 knock out mice and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. The injection of EP3-KO CD11c+DCs reduced accumulation of SDF-1+CD11c+DCs in regional LNs and LNM in LLC-injected mice. Accumulation of Tregs and lymph node lymphangiogenesis, was also COX-2/EP3-dependent. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1.

Research Products

• [Journal Article] The role of angiotensin II in liver metastasis formation from colorectal cancer (2017)
  • Author(s): Yuki Shimizu, Hideki Amano, Yoshiya Ito, Tomohiro Betto, Sakiko Yamane, Tomoyoshi Inoue, Nobuyuki Nishizawa, Mariko Kamata, Wasaburo Koizumi, Masataka Majima
  • Journal Title: Kitasato Med J Volume: 47 Pages: 43-51
  • Peer Reviewed
• [Journal Article] Thromboxane A synthase enhances blood flow recovery from hindlimb ischemia. (2016)
  • Author(s): Amano H, Nakamura M, Ito Y, Kakutani H, Eshima K, Kitasato H, Narumiya S, Majima M.
  • Journal Title: J Surg Res Volume: 204 Issue: 12 Pages: 153-163
  • DOI: 10.1016/j.clinthera.2016.10.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages. (2016)
  • Author(s): Okizaki S, Ito Y, Hosono K, Oba K, Ohkubo H, Kojo K, Nishizawa N, Shibuya M, Shichiri M, Majima M.
  • Journal Title: Am J Pathol. Volume: 186 Pages: 1481-1498
  • DOI: 10.1016/j.biopha.2016.01.005
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Anti-tumor effects of interferon-beta cell therapy in murine model of melanoma. (2016)
  • Author(s): Nakamura M, Kagawa L, Nakada N, Satoh M, Maehara S, Kojima F, Amano H, Murakumo Y, Iwabuchi K, Majima M, Kitasato H.
  • Journal Title: Int J Cancer Ther Oncol. Volume: 4 Pages: 4412-4422
  • Peer Reviewed / Open Access
• [Journal Article] Thromboxane A2 induces blood flow recovery via platelet adhesion to ischaemic regions. (2015)
  • Author(s): Amano H, Ito Y, Eshima K, Kato S, Ogawa F, Hosono K, Oba K, Tamaki H, Sakagami H, Shibuya M, Narumiya S, Majima M.
  • Journal Title: Cardiovasc Res. Volume: 107 Issue: 4 Pages: 509-521
  • DOI: 10.1093/cvr/cvv139
  • Peer Reviewed / Open Access
• [Journal Article] The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia. (2015)
  • Author(s): Amano H, Kato S, Ito Y, Eshima K, Ogawa F, Takahashi R, Sekiguchi K, Tamaki H, Sakagami H, Shibuya M, Majima M.
  • Journal Title: PLoS One Volume: 10(7) Issue: 7 Pages: e0131445-e0131445
  • DOI: 10.1371/journal.pone.0131445
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The role of vascular endothelial growth factor receptor-1 signaling in compensatory lung growth following unilateral pneumonectomy (2015)
  • Author(s): Masui Y, Amano H, Ito Y, Eshima K et al
  • Journal Title: Labaratory investigation Volume: 95 Pages: 456-68
  • Peer Reviewed / Open Access
• [Journal Article] Prostanoid induces premetastatic niche in regional lymph nodes. (2014)
  • Author(s): Ogawa F, Amano H, Eshima Y, Ito Y, Matsui Y, Hosono K, Kitasato H, Iyoda A, Iwabuchi K, Kumagai Y, Satoh Y, Narumiiya S, Majima M.
  • Journal Title: J. Clin. Invest. Volume: 124 Issue: 11 Pages: 4882-4894
  • DOI: 10.1172/jci73530
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] An inducible mPGES-1 promotes lung metastasis via SDF-1/CXCR4-mediated recruitment of MDSCs (2017)
  • Author(s): Hideki Amano, Ryo Takahashi, Masataka Majima
  • Organizer: 第90回日本薬理学会
  • Place of Presentation: 長崎ブリックホール(長崎県長崎市)
  • Year and Date: 2017-03-15
  • Invited
• [Presentation] 大腸癌の肝転移形成におけるAT1aシグナリングの解析 (2016)
  • Author(s): 清水裕貴、天野英樹、伊藤義也、別當朝広、山根早紀子、井上智仁、西澤伸晃、小泉和三郎、馬嶋正隆
  • Organizer: 第75回日本癌学会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2016-10-06
• [Presentation] COX-2 /mPGES-1 axis induces blood flow recovery by accumulating Treg. (2016)
  • Author(s): 天野英樹、江島耕二、伊藤義也、審良静男、馬嶋正隆
  • Organizer: 第41回日本微小循環学会
  • Place of Presentation: コクヨホール（東京都品川区）
  • Year and Date: 2016-09-23
• [Presentation] 急性下肢循環障害における膜結合型プロスタグランジンE2合成酵素の虚血改善メカニズムの解析 (2016)
  • Author(s): 天野英樹、江島耕二、伊藤義也、審良静男、馬嶋正隆
  • Organizer: 第37回日本炎症再生医学会
  • Place of Presentation: みやこめっせ（京都府京都市)
  • Year and Date: 2016-06-16
• [Presentation] Microsomal prostaglandin E synthase-1 facilitates mobilization of MDSCs from bone marrow and induces lung metastasis formation (2016)
  • Author(s): Ryo Takahashi、Hideki Amano、Koji Eshima、Takefumi Satoh、Masatsugu Iwamura、Akira Shizuo、Masataka Majima
  • Organizer: アメリカ胸部学会
  • Place of Presentation: サンフランシスコ(U.S.A)
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] リンパ組織の可塑性を制御するプロスタグランジンの役割 (2016)
  • Author(s): 馬嶋正隆、細野加奈子、天野英樹、藤田朋恵
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-03-09
• [Presentation] 下肢虚血の改善におけるCOX-2/mPGES-1の役割 (2016)
  • Author(s): 天野英樹、高橋亮、伊藤義也、中村正樹、北里英郎、審良静男、馬嶋正隆
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: パシフィコ横浜 (神奈川県横浜市)
  • Year and Date: 2016-03-09
• [Presentation] Microsomal prostaglandin E synthase-1 up-regulates COX-2 derived PGE2 in endothelial cell under hypoxia condition in mouse ischemic hind limb model (2015)
  • Author(s): Hideki Amano, Yoshiya Ito, Ryo Takahashi, Koji Eshima, Shizuo Akira, Masataka Majima
  • Organizer: 第10回国際微小循環学会
  • Place of Presentation: 京都国際会議場（京都府京都市）
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] マウス肺転移腫瘍モデルにおける膜型PGE2合成酵素の関与の解析 (2015)
  • Author(s): 高橋亮、天野英樹、小川史洋、審良静男、馬嶋正隆
  • Organizer: 第115回日本外科学会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-16
• [Presentation] pre-metastatic niche 形成における樹状細胞PGE2-EP3 signaling, SDF-1/TGFbの役割 (2014)
  • Author(s): 小川史洋、天野英樹、江島耕二、馬嶋正隆
  • Organizer: 第35回日本炎症・再生医学会
  • Place of Presentation: 万国津梁館（沖縄県名護市）
  • Year and Date: 2014-07-01
• [Presentation] 肺癌リンパ節転移及びpre-metastatic niche形成におけるプロスタグランジンの役割 (2014)
  • Author(s): 小川史洋、天野英樹、江島耕二、馬嶋正隆
  • Organizer: 第38回リンパ学会
  • Place of Presentation: 北里大学白金キャンパス（東京都港区）
  • Year and Date: 2014-06-20 – 2014-06-22
• [Book] 実験医学 (2017)
  • Author(s): 馬嶋正隆、天野英樹、細野加奈子
  • Total Pages: 4
  • Publisher: 羊土社
• [Remarks] 北里大学医学部薬理学教室
  • URL: http://www.med.kitasato-u.ac.jp/pharm/member.html
• [Remarks] 北里大学医学部薬理学ホームページ
  • URL: http://www.med.kitasato-u.ac.jp/pharm/index.html