Role of sensory nerve in cancer progession

• Project/Area Number: 17H04377
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Osaka University
• Principal Investigator: Yoneda Toshiyuki 大阪大学, 歯学研究科, 招へい教員 (80142313)
• Co-Investigator(Kenkyū-buntansha): 波多 賢二 大阪大学, 歯学研究科, 准教授 (80444496)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2017: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
• Keywords: がん / 知覚神経 / 骨転移 / 骨 / プロトンポンプ / TRPV1 / 骨痛 / 神経

Outline of Final Research Achievements

Majority of cancer patients suffer from cancer pain at advanced and terminal stage of the illness. However, the mechanism underlying cancer pain remains unclear and currently-available therapeutic means are not satisfactorily effective at reducing cancer pain, resulting in decreased survival of cancer patients. In this study, we found that the acidic microenvironment created by breast cancer is responsible for causing bone pain using an animal model of cancer pain. We then showed that a synthetic small compound and a natural substance that block the actions of the acidic microenvironment reduced bone pain, and the progression of breast cancer in bone and metastasis to lung from bone. These results suggest that bone pain and breast cancer progression are reciprocally interactive and that bone pain biologically regulates cancer progression and secondary metastasis from bone and support the notion that the acidic microenvironment associated with cancer is a potential therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

血管の新生はがんの増大に不可欠である。しかし、血管の新生と連動して起こる神経の新生とがんの増大との関係は不明である。本研究は、増大するがん周囲の酸性環境による骨内の知覚神経の興奮、すなわちがん性骨痛、により知覚神経でのがん増殖促進因子の産生が高まり、その結果骨内でのがんの増大、骨からの二次転移が強まることを分子細胞生物学的に明らかにした。本成果は、がん患者を最も苦しめ、その治療を困難にする要因の一つであるがん性骨痛を抑え込むことにより、同時にがん自体の進展に対しても一石二鳥的に抑制効果が得られることを示唆し、今後のがん治療にこれまでになかった視点からのアプローチをもたらすと期待される。

Research Products

• [Int'l Joint Research] インディアナ大学(米国)
• [Journal Article] Subcommittee for CTIBL in the JSBMR.Management manual for cancer treatment-induced bone loss (CTIBL): positionstatement of the JSBMR. (2020)
  • Author(s): Fukumoto S, Soen S, Taguchi T, Ishikawa T, Matsushima H, Terauchi M, Horie S, Yoneda T, Sugimoto T, Matsumoto T
  • Journal Title: J Bone Miner Metab Volume: 38 Issue: 2 Pages: 141-144
  • DOI: 10.1007/s00774-020-01087-0
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial. (2019)
  • Author(s): Takeuchi T, Tanaka Y, Soen S, Yamanaka H, Yoneda T, Tanaka S, Nitta T, OkuboN, Genant HK, van der Heijde D.
  • Journal Title: Ann Rheum Dis Volume: 78 Issue: 7 Pages: 899-907
  • DOI: 10.1136/annrheumdis-2018-214827
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bone pain associated with acidic cancer microenvironment. (2018)
  • Author(s): Yoneda T, Hiasa M, Okui T
  • Journal Title: Curr Mol Biol Rep Volume: 4(2) Issue: 2 Pages: 59-68
  • DOI: 10.1007/s40610-018-0089-7
  • Peer Reviewed
• [Journal Article] Crosstalk between sensory nerves and cancer in bone. (2018)
  • Author(s): Yoneda T, Hiasa M, Okui T.
  • Journal Title: Curr Osteopor Rep Volume: 16(6) Issue: 6 Pages: 648-656
  • DOI: 10.1007/s11914-018-0489-x
  • Peer Reviewed
• [Journal Article] Japanese expert panel meeting for the management of prostate cancer with bone metastases. (2018)
  • Author(s): 3.Takahashi S, Kinuya S, Nonomura N, Shinohara N, Suzuki K, Suzuki H, Nakamura K, Satoh T, Tateishi U, Yoneda T, Horikoshi H, Igawa T, Kamai T, Koizumi M, Kosaka T, Matsubara N, Miyake H, Mizokami A, Mizowaki T, Nakamura N, Nozawa M, Takahashi T, Uemura H, Uemura M, Yokomizo A, Yoshimura M, Kakehi Y.
  • Journal Title: Oncol Therap Volume: 6 Pages: 157-171
  • Peer Reviewed
• [Journal Article] Decreased sensory nerve excitation and bone pain associated with mouse Lewis lung cancer in TRPV1-deficient mice. (2018)
  • Author(s): Wakabayashi H, Wakisaka S, Hiraga T, Hata K, Nishimura R, Tominaga M, Yoneda T.
  • Journal Title: J Bone Miner Metab Volume: 36(3) Issue: 3 Pages: 274-285
  • DOI: 10.1007/s00774-017-0842-7
  • Peer Reviewed
• [Journal Article] Disruption of the Cx43/miR21 pathway leads to osteocyte apoptosis and increased osteoclastogenesis with aging (2017)
  • Author(s): Davis HM, Pacheco-Costa R, Atkinson EG, Brun LR, Gortazar AR, Harris J, Hiasa M, Bolarinwa SA, Yoneda T, Ivan M, Bruzzaniti A, Bellido T, Plotkin LI.
  • Journal Title: Aging Cell Volume: 16(3) Issue: 3 Pages: 551-563
  • DOI: 10.1111/acel.12586
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Bone Pain Induced by Multiple Myeloma Is Reduced by Targeting V-ATPase and ASIC3. (2017)
  • Author(s): Hiasa M, Okui T, Allette YM, Ripsch MS, Sun-Wada GH, Wakabayashi H, Roodman GD, White FA, Yoneda T
  • Journal Title: Cancer Research Volume: 77(6) Issue: 6 Pages: 1283-1295
  • DOI: 10.1158/0008-5472.can-15-3545
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Antiresorptive agent-related osteonecrosis of the jaw: Position Paper 2017 of the Japanese Allied Committee on Osteonecrosis of the Jaw. (2017)
  • Author(s): Japanese Allied Committee on Osteonecrosis of the Jaw, Yoneda T, Hagino H, Sugimoto T, Ohta H, Takahashi S, Soen S, Taguchi A, Nagata T, Urade M, Shibahara T, Toyosawa S.
  • Journal Title: J Bone Miner Metab Volume: 35(1) Issue: 1 Pages: 6-19
  • DOI: 10.1007/s00774-016-0810-7
  • Peer Reviewed
• [Presentation] 骨転移における知覚神経とがんのクロストーク (2019)
  • Author(s): 奥井達雄 日浅雅博 米田俊之
  • Organizer: 第37回日本骨代謝学会
• [Presentation] Bone pain associated with acidic cancer microenvironment. (2018)
  • Author(s): Yoneda T
  • Organizer: The International Association for the Study of Pain World Congress of Pain
  • Int'l Joint Research / Invited
• [Presentation] 知覚神経による骨痛とがんの増大、転移の制御. (2018)
  • Author(s): 奥井達雄、日浅雅弘、米田俊之.
  • Organizer: 第36回日本骨代謝学会
  • Invited
• [Presentation] 顎骨壊死最近の動向. (2018)
  • Author(s): 米田俊之
  • Organizer: 第63回日本口腔外科学会総会・学術大会
  • Invited
• [Presentation] Effects of denosumab, a subcutaneous RANKL inhibitor, on the progression of structural damage in Japanese patients with rheumatoid arthritis treated with csDMARDS: Result from the long-term treatment of phase 3, DESIRABLE study. (2018)
  • Author(s): Takeuchi T, Tanaka Y, Soen S, Yamanaka H, Yoneda T, Tanaka S, Nitta T, Okubo N, Genant H, van der Heijde D.
  • Organizer: Annual European Congress of Rheumatology
  • Int'l Joint Research
• [Presentation] Bone pain-modifying actions of osteocytes via Connexin43-mediated communications with sensory nerves (2017)
  • Author(s): Hiasa M, Okui T, Delgado-Calle J, Bellido T, Roodman GD, Plotkin L, White FA, Yoneda T
  • Organizer: 44th European Calcified Tissue Society Congress
  • Int'l Joint Research
• [Presentation] Neuronal HGF regulates breast cancer progression and bone pain induction (2017)
  • Author(s): Okui T, Hiasa M, White FA, Roodman GD,Yoneda T
  • Organizer: 44th European Calcified Tissue Society Congress
  • Int'l Joint Research
• [Presentation] V-ATPaseプロトンポンプおよび酸感受性イオンチャンネルASIC3阻害は多発性骨髄腫の骨痛を緩和する (2017)
  • Author(s): 日浅雅博、奥井達雄、米田俊之
  • Organizer: 第35回日本骨代謝学会学術集会
• [Presentation] TRPV1を通じて興奮した知覚神経はHGF産生により骨内でのがんの進展および骨からの二次転移を促進する (2017)
  • Author(s): 奥井 達雄，日浅 雅博，志茂 剛，佐々木 朗，米田 俊之
  • Organizer: 第35回日本骨代謝学会学術集会