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Endogenous TLR4 ligands in tumor metastasis.

Planned Research

Project AreaHomeostatic inflammation: Molecular basis and dysregulation
Project/Area Number 21117008
Research Category

Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionTokyo Women's Medical University

Principal Investigator

MARU Yoshiro  東京女子医科大学, 医学部, 教授 (00251447)

Co-Investigator(Renkei-kenkyūsha) NAKAMURA Sachie  東京女子医科大学, 医学部, 准教授 (60313087)
TSUKAHARA Fujiko  東京女子医科大学, 医学部, 講師 (40119996)
TOMITA Takeshi  東京女子医科大学, 医学部, 助教 (20302242)
DEGUCHI Atsuko  東京女子医科大学, 医学部, 助教 (10422932)
IEGUCHI Katsuaki  東京女子医科大学, 医学部, 助教 (90586348)
TAKITA Morichika  東京女子医科大学, 医学部, 助教 (80533455)
Project Period (FY) 2009-07-23 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥139,490,000 (Direct Cost: ¥107,300,000、Indirect Cost: ¥32,190,000)
Fiscal Year 2013: ¥25,350,000 (Direct Cost: ¥19,500,000、Indirect Cost: ¥5,850,000)
Fiscal Year 2012: ¥28,340,000 (Direct Cost: ¥21,800,000、Indirect Cost: ¥6,540,000)
Fiscal Year 2011: ¥27,300,000 (Direct Cost: ¥21,000,000、Indirect Cost: ¥6,300,000)
Fiscal Year 2010: ¥25,350,000 (Direct Cost: ¥19,500,000、Indirect Cost: ¥5,850,000)
Fiscal Year 2009: ¥33,150,000 (Direct Cost: ¥25,500,000、Indirect Cost: ¥7,650,000)
KeywordsTLR4 / SAA3 / S100A8 / CCL2 / ephrinA1 / 自然免疫 / がん転移 / CCR2 / ADAM12 / 炎症 / 内因性リガンド / TLR / 転移 / がん / 癌 / ケモカイン / 増殖因子
Research Abstract

We focused on five points (1)endogenous ligands for TLR4 (2)homeostasis inflammation (3)pathological condition (4)translational research, and (5)generation of knockout mice. We showed conclusion as below.
(1)We showed binding between TLR4/MD-2 and peptide SAA3 (20-86). Binding site of S100A8 was center domain of TLR4. (2)Bronchial Clara cells contribute to lung metastasis by amplifying SAA3. (3)We found that C1D, a DNA-binding protein, is a novel endogenous ligand for TLR9. We found that TLR4 signaling plays a role in resistance to BCR-ABL kinase inhibitor, imatinib, in Chronic myeloid leukemia. (4)We identified mTOC as a Cerastramycin binding protein. We created human SAA3 ELISA system to quantitate SAA3 protein in culture media. We are investigating whether KB-R7785, an ADAM12 inhibitor, effect on lung metastasis by reduction of cleaved form of ephrin-A1. (5)To examine the homeostasis inflammation related to S100A8 and SAA3, we are trying to establish knockout mouse system.

Report

(6 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (55 results)

All 2014 2013 2012 2011 2010 2009 Other

All Journal Article (32 results) (of which Peer Reviewed: 15 results) Presentation (17 results) (of which Invited: 4 results) Book (3 results) Remarks (3 results)

  • [Journal Article] ADAM12-cleaved ephrin-A1 contributes to lung metastasis2014

    • Author(s)
      Ieguchi K, Tomita T, Omori T, Komatsu A, Deguchi A, Masuda J, Duffy S, Coulthard M, Boyd A, Maru Y
    • Journal Title

      Oncogene

      Volume: 33(17) Pages: 2179-2190

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Journal Article] Connexin43 Functions as a Novel Interacting Partner of Heat Shock Cognate Protein 702013

    • Author(s)
      Hatakeyama T, Dai P, Harada Y, Hino H, Tsukahara F,Maru Y, Otsuji E, Takamatsu T
    • Journal Title

      Sci Rep.

      Volume: 3 Pages: 2179-2179

    • Related Report
      2013 Final Research Report
  • [Journal Article] Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci2013

    • Author(s)
      Hiratsuka S, Ishibashi S, Tomita T, Watanabe A, Tamura S, Murakami M, Kijima H, Miyake K, Aburatani H, Maru Y
    • Journal Title

      Nat Commun

      Volume: 4 Pages: 1853-1853

    • Related Report
      2013 Final Research Report
  • [Journal Article] Serum Amyroid A3 binds MD-2 to activates p38 and NF-kB pathway in a MyD88-dependent manner2013

    • Author(s)
      Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, Tanimura N, Akashi-Takamura S, Miyake K, Maru Y
    • Journal Title

      J Immunol. 2013

      Volume: 191, 4, 2013 Pages: 1856-1864

    • Related Report
      2013 Final Research Report
  • [Journal Article] Ephrin-A1 expression induced by S100A8 is mediated by the toll-like receptor 42013

    • Author(s)
      Ieguchi K, Omori T, Komatsu A, Tomita T, Deguchi A, Maru Y
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 440(4) Pages: 623-629

    • Related Report
      2013 Final Research Report
  • [Journal Article] Ephrin-A1 expression induced by S100A8 is mediated by the toll-like receptor 42013

    • Author(s)
      Ieguchi K, Omori T, Komatsu A, Tomita T, Deguchi A, Maru Y
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 440(4) Issue: 4 Pages: 623-629

    • DOI

      10.1016/j.bbrc.2013.09.119

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Serum Amyroid A3 binds MD-2 to activates p38 and NF-kB pathway in a MyD88-dependent manner2013

    • Author(s)
      Deguchi A, Tomita T, Omori T, Komatsu A, Ohto U, Takahashi S, Tanimura N, Akashi-Takamura S, Miyake K, Maru Y
    • Journal Title

      J Immunol

      Volume: 191(4) Issue: 4 Pages: 1856-1864

    • DOI

      10.4049/jimmunol.1201996

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Primary tumours modulate innate immune signalling to create pre-metastatic vascular hyperpermeability foci2013

    • Author(s)
      Hiratsuka S, Ishibashi S, Tomita T, Watanabe A, Tamura SA, Murakami M, Kijima H, Miyake K, Aburatani H, Maru Y
    • Journal Title

      Nat Commun

      Volume: 4 Issue: 1 Pages: 1853-1853

    • DOI

      10.1038/ncomms2856

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Connexin43 Functions as a Novel Interacting Partner of Heat Shock Cognate Protein 702013

    • Author(s)
      Hatakeyama T, Dai P, Harada Y, Hino H, Tsukahara F, Maru Y, Otsuji E, Takamatsu T
    • Journal Title

      Sci Rep

      Volume: 3 Issue: 1 Pages: 2719-2719

    • DOI

      10.1038/srep02719

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular biology of chronic myeloid leukemia2012

    • Author(s)
      Maru Y
    • Journal Title

      Cancer Sci.

      Volume: 103, 9 Pages: 1601-1610

    • NAID

      10007320374

    • Related Report
      2013 Final Research Report
  • [Journal Article] Molecular biology of chronic myeloid leukemia.2012

    • Author(s)
      Maru Yoshiro
    • Journal Title

      Cancer science

      Volume: 103 Issue: 9 Pages: 1601-1610

    • DOI

      10.1111/j.1349-7006.2012.02346.x

    • NAID

      10007320374

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endogenous ligand-induced activation of TLR4 in Pre-metastatic phase is both downstream and upstream of TNF signaling2011

    • Author(s)
      Maru Y
    • Journal Title

      Adv Exp Med Biol.

      Volume: 691 Pages: 261-268

    • Related Report
      2013 Final Research Report
  • [Journal Article] Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation2011

    • Author(s)
      Hiratsuka S, Goel S, Kamoun WS, Maru Y, Fukumura D, Duda DG, Jain RK
    • Journal Title

      Proc Natl Acad Sci USA.

      Volume: 108 Pages: 3725-3730

    • Related Report
      2013 Final Research Report
  • [Journal Article] Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis2011

    • Author(s)
      Tomita T, Sakurai Y, Ishibashi S, Maru Y
    • Journal Title

      Oncogene.

      Volume: 30 Pages: 3429-3439

    • Related Report
      2013 Final Research Report
  • [Journal Article] p57(Kip2) and p27(Kip1) cooperate to maintain hematopoietic stem cell quiescence through interactions with Hsc702011

    • Author(s)
      Zou P, Yoshihara H, Hosokawa K, Tai I, Shinmyozu K, Tsukahara F, Maru Y, Nakayama K, Nakayama KI, Suda T
    • Journal Title

      Cell Stem Cell

      Volume: 9 Pages: 247-261

    • Related Report
      2013 Final Research Report 2011 Annual Research Report
  • [Journal Article] Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis2011

    • Author(s)
      Tomita T, Sakurai Y, Ishibashi S, Maru Y
    • Journal Title

      Oncogene

      Volume: 30 Issue: 31 Pages: 3429-3439

    • DOI

      10.1038/onc.2011.53

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation2011

    • Author(s)
      Hiratsuka S, Goel S, Kamoun WS, Maru Y, Fukumura D, Duda DG, Jain RK
    • Journal Title

      PNAS (Proceedings of the National Academy of Sciences of the United States of America)

      Volume: 103 Issue: 9 Pages: 3725-3730

    • DOI

      10.1073/pnas.1100446108

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] FOXA1 plays a role in regulating secretoglobin 1a1 expression in the absence of CCAAT/enhancer binding protein activities in lung in vivo2011

    • Author(s)
      Kido T, Tomita T, Okamoto M, Cai Y, Matsumoto Y, Vinson C, Maru Y, Kimura S
    • Journal Title

      American Journal of Physiology-Lung Cellular and Molecular Physiology

      Volume: 300 Issue: 3 Pages: L441-L452

    • DOI

      10.1152/ajplung.00435.2009

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endogenous ligand-induced activation of TLR4 in Pre-metastatic phase is both downstream and upstream of TNF signaling2011

    • Author(s)
      Maru Y
    • Journal Title

      Advances in Experimental Medicine and Biology

      Volume: 691 Pages: 261-268

    • DOI

      10.1007/978-1-4419-6612-4_26

    • ISBN
      9781441966117, 9781441966124
    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Imbalance of Clara cell-mediated homeostatic inflammation is involved in lung metastasis.2011

    • Author(s)
      Tomita T, Sakurai Y, Ishibashi S, Maru Y.
    • Journal Title

      Oncogene

      Volume: (in press)

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] XPB induces C1D expression to counteract UV-induced apoptosis2010

    • Author(s)
      Li G, Liu J, Abu-Asab M, Shibuya M, Maru Y
    • Journal Title

      Mol Cancer Res.

      Volume: 8 Pages: 885-895

    • Related Report
      2013 Final Research Report
  • [Journal Article] Pre-metastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation2010

    • Author(s)
      Maru Y
    • Journal Title

      Cell and Mol Immun.

      Volume: 7 Pages: 94-99

    • Related Report
      2013 Final Research Report
  • [Journal Article] Bag1 directly routes immature BCR-ABL for proteasomal degradation2010

    • Author(s)
      Tsukahara F, Maru Y
    • Journal Title

      Blood.

      Volume: 116 Pages: 3582-3592

    • Related Report
      2013 Final Research Report
  • [Journal Article] Bag1 directly routes immature BCR-ABL for proteasomal degradation.2010

    • Author(s)
      Tsukahara F, Maru Y.
    • Journal Title

      Blood

      Volume: 116 Pages: 3582-3592

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] XPB induces C1D expression to counteract UV-induced apoptosis.2010

    • Author(s)
      Li G, Liu J, Abu-Asab M, Masabumi S, Maru Y.
    • Journal Title

      Molecular Cancer Research

      Volume: 8 Pages: 885-895

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The tumor suppressor LZTS2 functions through the cellular samurai Katanin2009

    • Author(s)
      Maru Y
    • Journal Title

      Cent Eur J Biol.

      Volume: 4 Pages: 1-10

    • Related Report
      2013 Final Research Report
  • [Journal Article] EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility2009

    • Author(s)
      Yamazaki T, Masuda J, Omori T, Usui R, Akiyama H, Maru Y
    • Journal Title

      J Cell Sci.

      Volume: 122 Pages: 243-255

    • Related Report
      2013 Final Research Report
  • [Journal Article] Logical structures extracted from metastasis experiments2009

    • Author(s)
      Maru Y
    • Journal Title

      Cancer Sci.

      Volume: 100 Pages: 2006-2013

    • NAID

      10027196385

    • Related Report
      2013 Final Research Report
  • [Journal Article] A Concept of Homeostatic Inflammation Provided by Endogenous TLR4 Agonists that Function Before and After Danger Signal for Metastasis2009

    • Author(s)
      Maru Y
    • Journal Title

      Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry

      Volume: 8 Pages: 337-347

    • Related Report
      2013 Final Research Report
  • [Journal Article] EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility.2009

    • Author(s)
      Tohru Yamazaki
    • Journal Title

      Journal of Cell Science 122

      Pages: 243-255

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A concept of homeostatic inflammation provided by endogenous TLR4 a gonists that function before and after danger signal for metastasis.2009

    • Author(s)
      Yoshiro Maru
    • Journal Title

      Anti-Inflamm. & Anti-Allerg Agents in Medicinal Chemistry 8

      Pages: 337-347

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Logical structures extracted from metastatic experiments.2009

    • Author(s)
      Yoshiro Maru
    • Journal Title

      Cancer Science 100

      Pages: 2006-2013

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] Identification of calcineurin as a novel therapeutic target in multiple myeloma.2013

    • Author(s)
      IMAI Yoichi, OHTA Eri, WANG Yanhua, KITAGAWA Yukiko, DING Ye, YAMADA Osamu, MARU Yoshiro, MOTOJI Toshiko
    • Organizer
      14th International Myeloma Workshop
    • Place of Presentation
      Kyoto, Japan
    • Related Report
      2013 Annual Research Report
  • [Presentation] How premetastatic milieu is established2013

    • Author(s)
      Maru Yoshiro
    • Organizer
      6th international Singapore Symposium of Immunology
    • Place of Presentation
      Singapore
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] The endogenous TLR4 ligand-mediated vaso-permeability is required for lung metastasis2013

    • Author(s)
      Maru Yoshiro
    • Organizer
      10th International Conference on Innate Immunity
    • Place of Presentation
      Kos, Greece
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] ADAM12-cleaved ephrin-A1 contributes to lung metastasis.2013

    • Author(s)
      Ieguchi Katsuaki, Tomita Takeshi, Yoshiro Maru
    • Organizer
      第72回日本癌学会学術総会
    • Place of Presentation
      横浜、日本
    • Related Report
      2013 Annual Research Report
  • [Presentation] Identification of PPP3CA, catalytic subunit of Calcineurin as a target of multiple myeloma therapy.2013

    • Author(s)
      今井陽一, 太田瑛里, 王艶華, テインイエ, 丸義朗, 泉二登志子
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      札幌、日本
    • Related Report
      2013 Annual Research Report
  • [Presentation] S100A8, amyloid A3, and TLR4 in tumor metastasis2012

    • Author(s)
      Maru Yoshiro
    • Organizer
      4th International Muenster Meeting on Danger Signaling in Autoinflammation
    • Place of Presentation
      Muenster, Germany
    • Year and Date
      2012-04-20
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] S100A8 amyloid A3 and TLR4 in tumor metastasis2012

    • Author(s)
      Maru Y
    • Organizer
      4th International Muenster Meeting on Danger Signaling in Autoinflammation
    • Place of Presentation
      Muenster, Germany
    • Related Report
      2013 Final Research Report
  • [Presentation] Regulation of mature versus immature conformation of BCR-ABL2011

    • Author(s)
      Maru Y
    • Organizer
      13th International Conference on chronic myeloid leukemia : Biology and Therapy
    • Place of Presentation
      Estoril, Portugal(招待講演)
    • Year and Date
      2011-09-24
    • Related Report
      2011 Annual Research Report
  • [Presentation] Dysregulated lung homeostasis involving the TLR4-SAA3 system establishes lung metastasis2011

    • Author(s)
      Maru Y
    • Organizer
      Kennedy Institute of Rheumatology, University of Oxford
    • Place of Presentation
      London, UK(招待講演)
    • Year and Date
      2011-09-21
    • Related Report
      2011 Annual Research Report
  • [Presentation] Dysregulated lung homeostasis involving the TLR4-SAA3 system in Clara cells and Eph-ephrin signaling establishes lung metastasis2011

    • Author(s)
      Maru Y
    • Organizer
      3rd International Kloster Seeon Meeting "Cellular and Molecular Mechanisms of Tumor Progression and Metastasis"
    • Place of Presentation
      Kloster Seeon, Germany(招待講演)
    • Year and Date
      2011-09-20
    • Related Report
      2011 Annual Research Report
  • [Presentation] Homeostatic regulation of endotoxin response by endogenous TLR4 ligands is hijacked by metastatic tumor cells2011

    • Author(s)
      Maru Y
    • Organizer
      8th international conference on innate immunity
    • Place of Presentation
      Crete, Greek(招待講演)
    • Year and Date
      2011-06-18
    • Related Report
      2011 Annual Research Report
  • [Presentation] Bag1 regulates chaperone-mediated triage decisions on degradation of chronic myelogenous leukemia oncoprotein, BCR-ABL.2010

    • Author(s)
      Fujiko Tsukahara, Yoshiro Maru
    • Organizer
      16th World congress on basic and clinical pharmacology
    • Place of Presentation
      Copenhagen, Denmark
    • Year and Date
      2010-07-22
    • Related Report
      2010 Annual Research Report
  • [Presentation] The endogenous TLR4 ligands regulate pre-metastatic soil.2009

    • Author(s)
      Yoshiro Maru
    • Organizer
      2nd International Kloster Seeon Meeting "Cellular and Molecular Mechanisms of Tumor Progression and Metastasis"
    • Place of Presentation
      Kloster Seeon, Germany
    • Year and Date
      2009-09-20
    • Related Report
      2009 Annual Research Report
  • [Presentation] CHIP works in concert with an Hsc70 co-chaperone to degrade BCR-ABL.2009

    • Author(s)
      Yoshiro Maru
    • Organizer
      EUROPEAN SCHOOL OF HAEMATOLOGY11 th International Conference CHRONIC MYELOID LEUKEMIA
    • Place of Presentation
      Palais des Congres, Bordeaux, France
    • Year and Date
      2009-09-11
    • Related Report
      2009 Annual Research Report
  • [Presentation] How organ-specific pre-metastatic soil is prepared.2009

    • Author(s)
      Yoshiro Maru
    • Organizer
      EUROPEAN SCHOOL OF HAEMATOLOGY Interdisciplinary Conference on Angiogenesis
    • Place of Presentation
      Hilton Kalastajatorppa, Helsinki, Finland
    • Year and Date
      2009-06-06
    • Related Report
      2009 Annual Research Report
  • [Presentation] Endogenous ligand-induced activation of TLR4 in pre-metastatic phase is both downstream and upstream of TNF signaling.2009

    • Author(s)
      Yoshiro Maru
    • Organizer
      12th INTERNATIONAL TNF CONFERENCEAPRIL 27
    • Place of Presentation
      San Lorenzo De El Escorial, Madrid, Spain
    • Year and Date
      2009-04-27
    • Related Report
      2009 Annual Research Report
  • [Presentation] S100A8 and lung metastasis

    • Author(s)
      Maru Yoshiro
    • Organizer
      Seminar in German Cancer Research Center
    • Place of Presentation
      Heidelberg, Germany
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Book] 医学のあゆみ2014

    • Author(s)
      塚原富士子、丸義朗
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2013 Annual Research Report
  • [Book] 細胞工学2014

    • Author(s)
      富田毅、丸義朗
    • Publisher
      株式会社 学研メディカル秀潤社
    • Related Report
      2013 Annual Research Report
  • [Book] がん転移先微小環境を「見直す」2012

    • Author(s)
      丸義朗
    • Publisher
      ニューサイエンス社,東京,日本
    • Related Report
      2013 Final Research Report
  • [Remarks] 東京女子医科大学医学部薬理学教室

    • URL

      http://www.twmu.ac.jp/Basic/yakuri/

    • Related Report
      2013 Final Research Report
  • [Remarks] http://www.twmu.ac.jp/Basic/yakuri//index.html

    • Related Report
      2012 Annual Research Report
  • [Remarks]

    • URL

      http://www.twmu.ac.jp/Basic/yakuri/index.html

    • Related Report
      2011 Annual Research Report

URL: 

Published: 2009-04-01   Modified: 2018-03-28  

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