Prostanoid regulates premetastatic niche formation in lung cancers

• Project/Area Number: 15K15056
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Kitasato University
• Principal Investigator: Majima Masataka 北里大学, 医学部, 教授 (70181641)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 前転移ニッチェ / プロスタグランジン / EP3受容体 / SDF-1 / COX-2 / 樹状細胞 / リンパ節 / リンパ管新生 / 腫瘍 / リンパ節転移 / ケモカイン / EP3 / PG

Outline of Final Research Achievements

The lymphatic system is an important route for cancer dissemination, and lymph node metastasis (LNM) serves as a critical prognostic determinant in cancer patients. We investigated the contribution of COX-2-derived prostaglandin E2 (PGE2) in the formation of a premetastatic niche and LNM. A murine model of Lewis lung carcinoma (LLC) cell metastasis revealed that COX-2 is expressed in DCs from the early stage in the lymph node subcapsular regions, and COX-2 inhibition markedly suppressed mediastinal LNM. Stromal cell-derived factor-1 (SDF-1) was elevated in DCs before LLC cell infiltration to the lymph nodes, and a COX-2 inhibitor, an SDF-1 antagonist, and a CXCR4 neutralizing antibody all reduced LNM. Moreover, LNM was reduced in mice lacking the PGE2 receptor EP3, and stimulation of cultured DCs with an EP3 agonist increased SDF-1 production. These results indicate that DCs induce a premetastatic niche during LNM via COX-2/EP3-dependent induction of SDF-1.

Research Products

• [Journal Article] Prostaglandin E Receptors, EP3 and EP4 Facilitates Wound Healing and Lymphangiogenesis with Enhanced Recruitment of M2 Macrophages in Mice. (2016)
  • Author(s): Hosono K, Isonaka R, Kawakami T, Narumiya S, Majima M.
  • Journal Title: PLoS One. Volume: 11 Issue: 10 Pages: e0162532-e0162532
  • DOI: 10.1371/journal.pone.0162532
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Suppression of lymphangiogenesis by soluble vascular endothelial growth factor receptor-2 in a mouse lung cancer model. (2016)
  • Author(s): Maehana S, Nakamura M, Ogawa F, Imai R, Murakami R, Kojima F, Majima M, Kitasato H.
  • Journal Title: Biomed Pharmacother. Volume: 84 Pages: 660-665
  • DOI: 10.1016/j.biopha.2016.09.083
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] RAMP1 suppresses mucosal injury from dextran sodium sulfate-induced colitis in mice. (2016)
  • Author(s): Kawashima-Takeda N, Ito Y, Nishizawa N, Kawashima R, Tanaka K, Tsujikawa K, Watanabe M, Majima M.
  • Journal Title: J Gastroenterol Hepatol. Volume: 32 Issue: 4 Pages: 809-818
  • DOI: 10.1111/jgh.13505
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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: 1 Pages: 153-163
  • DOI: 10.1016/j.jss.2016.04.011
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] BLT1 signalling protects the liver against acetaminophen hepatotoxicity by preventing excessive accumulation of hepatic neutrophils (2016)
  • Author(s): Kojo, K., Ito, Y., Eshima, K., Nishizawa, N., Ohkubo, H., Yokomizo, T., Shimizu, T., Watanabe, M.,Majima, M.
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 29650-29650
  • DOI: 10.1038/srep29650
  • Peer Reviewed / Open Access
• [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 Issue: 6 Pages: 1481-1498
  • DOI: 10.1016/j.ajpath.2016.02.014
  • 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] Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis. (2016)
  • Author(s): Fujita T, Soontrapa K, Ito Y, Iwaisako K, Moniaga CS, Asagiri M, Majima M, Narumiya S.
  • Journal Title: Hepatology Volume: 63 Issue: 4 Pages: 1325-1339
  • DOI: 10.1002/hep.28112
  • NAID: 120005663256
  • Peer Reviewed / Open Access
• [Journal Article] PDGFRα plays a crucial role in connective tissue remodeling. (2015)
  • Author(s): Horikawa S, Ishii Y, Hamashima T, Yamamoto S, Mori H, Fujimori T, Shen J, Inoue R, Nishizono H, Itoh H, Majima M, Abraham D, Miyawaki T, Sasahara M.
  • Journal Title: Scientific Reports Volume: Dec 7;5 Issue: 1 Pages: 17948-17948
  • DOI: 10.1038/srep17948
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Roles of mPGES-1, an inducible prostaglandin E synthase, in enhancement of LPS-induced lymphangiogenesis in a mouse peritonitis model. (2015)
  • Author(s): Matsuda H, Hosono K, Tsuru S, Kurashige C, Sekiguchi K, Akira S, Uematsu S, Okamoto H, Majima M.
  • Journal Title: Life Sci. Volume: 142 Pages: 1-7
  • DOI: 10.1016/j.lfs.2015.10.008
  • 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回日本薬理学会年会 シンポジウム
  • Place of Presentation: 長崎 ブリックホール
  • Year and Date: 2017-03-15
  • Invited
• [Presentation] Roles of RAMP-1 Signalling as a Neuronal Cue of Lymphangiogenesis (2016)
  • Author(s): Masataka Majima
  • Organizer: Gordon Research Conference
  • Place of Presentation: Ventura, CA, USA
  • Year and Date: 2016-03-20
  • Int'l Joint Research / Invited
• [Presentation] Neuronal Cue for Neovascularization; CGRP-RAMP1 Signaling (2015)
  • Author(s): Masataka Majima
  • Organizer: Gordon Research Conference
  • Place of Presentation: Newport, RI, USA
  • Year and Date: 2015-08-02
  • Int'l Joint Research / Invited
• [Book] NEW薬理学第７版 (2017)
  • Author(s): 馬嶋正隆
  • Publisher: 南江堂
• [Book] 標準薬理学第７版、第２３章 免疫炎症系 (2015)
  • Author(s): 馬嶋正隆
  • Total Pages: 50
  • Publisher: 医学書院
• [Remarks] 北里大学医学部薬理学単位
  • URL: http://www.med.kitasato-u.ac.jp/pharm/