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Molecular mechanim of cancer-associated bone pain caused by protons

Research Project

Project/Area Number 23390422
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional basic dentistry
Research InstitutionOsaka University

Principal Investigator

YONEDA Toshiyuki  大阪大学, 歯学研究科(研究院), 招へい教員 (80142313)

Co-Investigator(Renkei-kenkyūsha) HATA Kenji  大阪大学, 歯学研究科, 准教授 (80444496)
TANAKA Soichi  大阪大学, 歯学研究科, 助教 (20548200)
Project Period (FY) 2011-04-01 – 2014-03-31
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000)
Fiscal Year 2013: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2011: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
Keywords口腔生化学 / プロトン / 骨痛 / 骨転移
Research Abstract

Bone pain is one of the most common complications associated with bone metastasis. It causes increased morbidity and undermining QOL in cancer patients with bone metastasis. However, the molecular basis of bone pain remains unclear. We reasoned that acidic conditions contribute to bone pain, because cancer creates acidic extracellular microenvironment and acid is a well-known algesic substance.
We found that extracellular microenvironment of bone-colonizing cancer was acidic due to proton release via V-ATPase proton pump expressed on plasma membrane. Microarray analysis using primary sensory neuron cells isolated from dorsal root ganglions (DRG) demonstrated that acidic microenvironment increased the transcription of several genes including CGRP and Snap25.Our findings suggest that acidic microenvironments created by cancer cells colonizing bone contribute to elicitation of bone pain through regulating the expression of algogenic genes in DRG sensory neurons.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (40 results)

All 2014 2013 2012 2011

All Journal Article (16 results) (of which Peer Reviewed: 15 results) Presentation (16 results) (of which Invited: 10 results) Book (8 results)

  • [Journal Article] Cyclooxygenase-2 expression is associated with vascular endothelial growth factor-c and lymph node metastasis in human oral tongue cancer2014

    • Author(s)
      Morita Y, Morita N, Hata K, Nakanishi M, Kimoto N, Omata T, Nakamura Y, Yoneda T
    • Journal Title

      Oral Surg Oral Med Oral Pathol Oral Radiol

      Volume: 117(4) Issue: 4 Pages: 502-510

    • DOI

      10.1016/j.oooo.2013.12.410

    • Related Report
      2013 Annual Research Report 2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Japanese Society for Bone and Mineral Research and Japan Osteoporosis Society Joint Review Committee for the Revision of the Diagnostic Criteria for Primary Osteoporosis. Diagnostic criteria for primary osteoporosis : year 2012 revision2013

    • Author(s)
      Soen S, Fukunaga M, (他9名) Yoneda T, Tomomitsu T
    • Journal Title

      J Bone Miner Metab

      Volume: 31 Pages: 247-257

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Role of RANKL/RANK in primary and secondary breast cancer2013

    • Author(s)
      Yoneda T, Tanaka S, Hata K
    • Journal Title

      World J Orthop

      Volume: 4(4) Pages: 178-185

    • Related Report
      2013 Final Research Report
  • [Journal Article] Role of RANKL/RANK in primary and secondary breast cancer.2013

    • Author(s)
      Yoneda T, Tanaka S, Hata K
    • Journal Title

      World J Orthop

      Volume: 4(4) Pages: 178-185

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diagnostic criteria for primary osteoporosis: year 2012 revision.2013

    • Author(s)
      Soen S, Fukunaga M, Sugimoto T, Sone T, Fujiwara S, Endo N, Gorai I, Shiraki M, Hagino H, Hosoi T, Ohta H, Yoneda T, Tomomitsu T
    • Journal Title

      J Bone Miner Metab

      Volume: 31(3) Issue: 3 Pages: 245-257

    • DOI

      10.1007/s00774-013-0447-8

    • NAID

      10031176589

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bone-derived IGF mediates crosstalk between bone and breast cancer cells in bony metastases2012

    • Author(s)
      Hiraga T, Myoui A, Hashimoto N, Sasaki A, Hata K, Morita Y, Yoshikawa H, Rosen CJ, Mundy GR, Yoneda T
    • Journal Title

      Cancer Res

      Volume: 72(16) Pages: 4238-4249

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Cyclooxygenase-2 promotes tumor lymphangiogenesis and lymph node metastasis in oral squamous cell carcinoma2012

    • Author(s)
      Morita Y, Nishisho T, et al
    • Journal Title

      Int J Oncol

      Volume: 41(3) Issue: 3 Pages: 885-892

    • DOI

      10.3892/ijo.2012.1529

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Stathmin is involved in the cooperative effect of zoledronic acid and gefitinib on bone homing breast cancer cells in vitro2012

    • Author(s)
      Oda M, Iwaya K, Kikuchi R, Kobayashi T, Yoneda T, Nishikawa, Matsubara O, Kohno N
    • Journal Title

      J Bone Oncol

      Volume: 1 Pages: 40-46

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Bone-derived IGF mediates crosstalk between bone and breast cancer cells in bony metastases.2012

    • Author(s)
      Hiraga T, Myoui A, Hashimoto N, Sasaki A, Hata K, Morita Y, Yoshikawa H, Rosen CJ, Mundy GR, Yoneda T
    • Journal Title

      Cancer Research

      Volume: 72 Pages: 4238-4249

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stathmin is involved in the cooperative effect of zoledronic acid and gefitinib on bone homing breast cancer cells in vitro.2012

    • Author(s)
      Oda M, Iwaya K, Kikuchi R, Kobayashi T, Yoneda T, Nishikawa, Matsubara O, Kohno N.
    • Journal Title

      J Bone Oncol

      Volume: 1 Pages: 40-46

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The a3 isoform vacuolar type H+-ATPase promotes distant metastasis in the mouse B16 melanoma cells2011

    • Author(s)
      Nishisho, et al
    • Journal Title

      Molecular and Cancer Research

      Volume: 9 Issue: 7 Pages: 845-855

    • DOI

      10.1158/1541-7786.mcr-10-0449

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Involvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain.2011

    • Author(s)
      Yoneda T, Hata K, Nakanishi M, Nagae M, Nagayama T, Wakabayashi H, Nishisho T, Sakurai T, Hiraga T.
    • Journal Title

      Bone

      Volume: 48(1) Issue: 1 Pages: 100-5

    • DOI

      10.1016/j.bone.2010.07.009

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Molecular events of acid-induced bone pain2011

    • Author(s)
      Yoneda T, Hata K, Nakanishi M, Nagae M, Nagayama T, Wakabayashi H, Nishisho T, Sakurai T, Hiraga T
    • Journal Title

      IBMS BoneKey

      Volume: 8 Pages: 195-204

    • Related Report
      2013 Final Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD442011

    • Author(s)
      Mandal CC, Ghosh-Choudhury N, Yoneda T, Choudhury GG, Ghosh- Choudhury N
    • Journal Title

      J Biol Chem

      Volume: 286 Pages: 11314-11327

    • Related Report
      2013 Final Research Report
    • Peer Reviewed
  • [Journal Article] Simvastatin prevents skeletal metastasis of breast cancer by an antagonistic interplay between p53 and CD442011

    • Author(s)
      Mandal CC, Ghosh-Choudhury N, Yoneda T, Choudhury GG, Ghosh-Choudhury N
    • Journal Title

      J Biol Chem

      Volume: 286(13) Pages: 11314-11327

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The a3 isoform vacuolar type H^+-ATPase promotes distant meta stasis in the mouse B16 melanoma cells2011

    • Author(s)
      Nishisho T, Hata K, Nakanishi M, Morita Y Yasui N, Yoneda T
    • Journal Title

      Mol Cancer Res

      Volume: 9 Pages: 845-855

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Involvement of ubiquitin/proteasome system in the regulation of epithelial-mesenchymal transition of breast cancer cells in bone2013

    • Author(s)
      Yoneda T, Tanaka S, Hata K, Roodman D, Nishimura R
    • Organizer
      13th International Conference on Cancer-Induced Bone Disease
    • Place of Presentation
      Miami, Florida, USA
    • Year and Date
      2013-11-08
    • Related Report
      2013 Annual Research Report 2013 Final Research Report
  • [Presentation] Zoledronic Acids Inhibits Epithelial-mesenchymal Transition (EMT) of Breast Cancer Cells in Bone via Ubiquitin/Proteasome System2013

    • Author(s)
      Yoneda T, Tanaka S, Hata K, Roodman D, Nishimura R
    • Organizer
      The American Society for Bone and Mineral Research 2012 35th Annual Meeting
    • Place of Presentation
      Baltimore Maryland, USA
    • Year and Date
      2013-10-04
    • Related Report
      2013 Final Research Report
  • [Presentation] Zoledronic Acids Inhibits Epithelial-mesenchymal Transition (EMT) of Breast Cancer Cells in Bone via Ubiquitin/Proteasome System2013

    • Author(s)
      Yoneda T, Tanaka S, Hata K, Roodman D, Nishimura R.
    • Organizer
      The American Society for Bone and Mineral Research 35th Annual Meeting
    • Place of Presentation
      Baltimore, Maryland, USA
    • Related Report
      2013 Annual Research Report
  • [Presentation] 骨転移の分子メカニズム2012

    • Author(s)
      米田俊之
    • Organizer
      第27回日本整形外科学会基礎学術集会
    • Place of Presentation
      名古屋
    • Year and Date
      2012-10-26
    • Related Report
      2013 Final Research Report 2012 Annual Research Report
    • Invited
  • [Presentation] The De ubiquitinating Enzyme USP45 Is Critical to Epithelial-mesenchymal Transition (EMT) in Breast Cancer Cells Colonized Bone2012

    • Author(s)
      Tanaka S, Yoneda T
    • Organizer
      The American Society for Bone and Mineral Research 34th Annual Meeting
    • Place of Presentation
      Minneapolis, Minnesota, USA
    • Year and Date
      2012-10-13
    • Related Report
      2013 Final Research Report
  • [Presentation] 骨微小環境と癌2012

    • Author(s)
      米田俊之
    • Organizer
      第30回日本骨代謝学会
    • Place of Presentation
      東京
    • Year and Date
      2012-07-20
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] The docking protein NEDD9 is a novel regulator of vicious cycle between breast cancer and bone in bone metastasis2012

    • Author(s)
      Hata K, Morita Y, Nakanishi M, Nishisyo T, Yoneda T
    • Organizer
      2nd Joint Meeting of the International Bone and Mineral Society and The Japanese Society for Bone and Mineral Research
    • Place of Presentation
      Kobe, Japan
    • Year and Date
      2012-05-30
    • Related Report
      2013 Final Research Report
  • [Presentation] 骨転移メカニズムとそのマネージメント2012

    • Author(s)
      米田俊之
    • Organizer
      第57回日本口腔外科学会総会・学術大会
    • Place of Presentation
      横浜
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 骨微小環境と癌2012

    • Author(s)
      米田俊之
    • Organizer
      第30回日本骨代謝学会
    • Place of Presentation
      東京
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 骨は癌の隠れ家2012

    • Author(s)
      米田俊之
    • Organizer
      第112回日本外科学会定期学術集会
    • Place of Presentation
      千葉
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Crosstalk between metastatic cancer cells and bone microenvironment2011

    • Author(s)
      Yoneda T
    • Organizer
      Traditional Chinese Medicine International Forum 2011 in Shanghai
    • Place of Presentation
      Shanghai, Republic of China
    • Year and Date
      2011-11-17
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] Molecular events involved in bone pain2011

    • Author(s)
      Yoneda T
    • Organizer
      2nd World University Network Symposium in Oral Health Sciences
    • Place of Presentation
      Leeds, UK
    • Year and Date
      2011-11-06
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] Bone pain associated with cancer metastasis to bone. Plenary lecture at ANZBMS/ JSBMR Joint Meeting and IOF Regionals2011

    • Author(s)
      Yoneda T
    • Organizer
      2nd Asia-Pacific Osteoporosis and Bone Meeting
    • Place of Presentation
      Gold Coast, Queensland, Australia
    • Year and Date
      2011-09-06
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] 骨は癌のチューター2011

    • Author(s)
      米田俊之
    • Organizer
      第29回日本骨代謝学会
    • Place of Presentation
      大阪
    • Year and Date
      2011-07-30
    • Related Report
      2013 Final Research Report
    • Invited
  • [Presentation] 骨はがん細胞のチューター2011

    • Author(s)
      米田俊之
    • Organizer
      第29回日本骨代謝学会
    • Place of Presentation
      東京(招待講演)
    • Year and Date
      2011-07-30
    • Related Report
      2011 Annual Research Report
  • [Presentation] Role of acid micro environment in bone pain associated with bone metastasis2011

    • Author(s)
      Yoneda T
    • Organizer
      Skeletal Biology Workshop in Shanghai
    • Place of Presentation
      Shanghai, China
    • Year and Date
      2011-06-26
    • Related Report
      2013 Final Research Report
    • Invited
  • [Book] 骨転移の成立-1. 癌の進展と血流循環性腫瘍細胞/播種性腫瘍細胞との関連 米田俊之, 松本俊夫編「癌と骨」2013

    • Author(s)
      米田俊之
    • Publisher
      メディカルレビュー社
    • Related Report
      2013 Final Research Report
  • [Book] 上皮間葉転換と骨転移「癌と骨」(米田俊之, 松本俊夫 編)2013

    • Author(s)
      田中宗一, 波多賢二, 米田俊之
    • Publisher
      メディカルレビュー社
    • Related Report
      2013 Final Research Report
  • [Book] 骨転移の骨病変形成メカニズム 1. 乳癌 「癌と骨」(米田俊之, 松本俊夫 編)2013

    • Author(s)
      波多賢二, 田中宗一, 米田俊之
    • Publisher
      メディカルレビュー社
    • Related Report
      2013 Final Research Report
  • [Book] 骨転移による疼痛の分子メカニズ 米田俊之, 松本俊夫 編 「癌と骨」2013

    • Author(s)
      中西雅子, 波多賢二, 米田俊之
    • Publisher
      メディカルレビュー社
    • Related Report
      2013 Final Research Report
  • [Book] 癌に伴う骨病変の発症機序松本俊夫, 萩野浩 編「ファーマナビゲーター ビスホスホネート編②」2013

    • Author(s)
      波多賢二
    • Publisher
      メディカルレビュー社
    • Related Report
      2013 Final Research Report
  • [Book] 「癌と骨」2013

    • Author(s)
      松本俊夫、米田俊之
    • Total Pages
      347
    • Publisher
      メディカルレビュー社
    • Related Report
      2013 Annual Research Report
  • [Book] がん骨転移のバイオロジーとマネージメント2012

    • Author(s)
      米田俊之 編
    • Publisher
      医薬ジャーナル社
    • Related Report
      2013 Final Research Report
  • [Book] がん骨転移のバイオロジーとマネージメント2012

    • Author(s)
      米田俊之、田中宗一、波多賢二
    • Total Pages
      399
    • Publisher
      医薬ジャーナル
    • Related Report
      2012 Annual Research Report

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Published: 2011-04-06   Modified: 2019-07-29  

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