Investigation and therapeutic application of the cancerauto-activation pathway through generation of anaphylatoxin C5a

• Project/Area Number: 22590363
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Kumamoto University
• Principal Investigator: IMAMURA Takahisa 熊本大学, 大学院・生命科学研究部, 准教授 (20176499)
• Co-Investigator(Renkei-kenkyūsha): NISHINO Norikazu 九州工業大学, 生命体工学研究科, 教授 (40145165) ; IRIE Atsushi 熊本大学, 生命科学研究部, 准教授 (30250343)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2012: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2010: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: C5a / 癌 / 浸潤 / 増殖 / 転移 / プロテアーゼ / 阻害剤 / 受容体拮抗剤 / フューリン / 自己活性化 / 産生 / MMP / 運動性 / CD88 / 受容体 / 血栓症

Research Abstract

Anaphylatoxin C5a receptor (C5aR) was expressed in cancer cellsfrom all organs examined and at various rates in organs. Several cancer cell lines alsoexpressed C5aR. C5a augmented C5aR-expressing cancer cell invasion in a MMP-6 dependentmanner in Matrigel chambers and in implanted nude mouse skin. C5a also enhanced cancercell lung metastasis in a C5aR-dependent manner. By cell membrane-bound furin-like serineprotease cancer cells generated C5a from C5, even it in plasma, augmenting theirinvasiveness. These C5a effects on cancer cells were inhibited by antibodies againsteither C5a or C5aR, and by a C5aR antagonist. These results indicate presence of a cancercell autoactivation pathway via C5a generation and suggest availability of a new cancertherapy targeting the C5a-C5aR axis or the cancer protease.

Research Products

• [Journal Article] Severe bleeding tendencycaused by excessive fibrinolysis withdisseminated intravascular coagulationin a prostate cancer patient: a casereport (2012)
  • Author(s): Wada, Y., Uchiba, M., Kawano, Y., Kai,N., Takahashi, W., Honda, J., Tanoue, K.,Maeda, Y., Murakami, Y., Eto, M., &Imamura, T
  • Journal Title: J. Med. Case Report Volume: 6 Pages: 378-378
  • Peer Reviewed
• [Journal Article] The tail nick augmentsAeromonas sobria serine protease (ASP)activity in plasma through retarding_2-macroglobulin (2012)
  • Author(s): Murakami, Y., Wada, Y., Kobayashi, H.,Hasegawa, M., Okamoto, K., Eto, M., &Imamura, T
  • Journal Title: FEBSLett Volume: 586 Pages: 3613-3617
  • Peer Reviewed
• [Journal Article] Inhibition of Aeromonas sobria serine2-macroglobulin (2012)
  • Author(s): Murakami, Y., Wada, Y., Kobayashi, H.,Irie, A., Hasegawa, M., Yamanaka, H.,Okamoto, K., Eto, M., & Imamura, T
  • Journal Title: Biol. Chem Volume: 393 Pages: 1193-1200
  • Peer Reviewed
• [Journal Article] Inhibition of Aeromonas sobria serine protease (ASP) by α2-macroglobulin. (2012)
  • Author(s): Murakami, Y. et al.
  • Journal Title: Biological Chemistry Volume: 393 Issue: 10 Pages: 1193-1200
  • DOI: 10.1515/hsz-2012-0117
  • Peer Reviewed
• [Journal Article] The tail nick augments Aeromonas sobria serine protease (ASP) activity in plasma through retarding inhibition by α2-macroglobulin. (2012)
  • Author(s): Murakami Y, Wada Y, Kobayashi H, Hasegawa M, Okamoto K, Eto M, Imamura. T
  • Journal Title: FEBS Letters Volume: 586 Issue: 20 Pages: 3613-3617
  • DOI: 10.1016/j.febslet.2012.08.004
  • Peer Reviewed
• [Journal Article] Severe bleeding tendency caused by a rare complication of excessive fibrinolysis with disseminated intravascular coagulation in a 51-year-old Japanese man with prostate cancer:a case report. (2012)
  • Author(s): Wada Y, Uchiba M, Kawano Y, Kai N, Takahashi W, Honda J, Tanoue K, Maeda Y, Murakami Y, Eto M, Imamura T.
  • Journal Title: Journal of Medical Case Reports Volume: 6 Issue: 1 Pages: 378-378
  • DOI: 10.1186/1752-1947-6-378
  • Peer Reviewed
• [Journal Article] 凝固反応：感染・炎症の病態と制御-;細菌と好中球プロテアーゼ- (2012)
  • Author(s): 今村隆寿
  • Journal Title: 日本血栓止血学会誌 Volume: 23 Pages: 268-285
  • NAID: 130002077020
• [Journal Article] 凝固炎症反応関連の病理学 (2012)
  • Author(s): 今村隆寿
  • Journal Title: Coagulation & Inflammation Volume: 6 Pages: 6-14
• [Journal Article] 進行性腎盂尿管癌の臨床において手術に役立つ腎盂尿管の解剖(Gerota筋膜) (2012)
  • Author(s): 和田孝浩, 今村隆寿, 高橋渡, 河野吉昭, 本多次朗, 田上憲一郎, 仲西寿朗, 谷川史城, 前田喜寛, 中村圭輔, 江藤正俊, 桑原朋広
  • Journal Title: 泌尿器外科 Volume: 25 Pages: 667-672
• [Journal Article] Inhibition of Aeromonas sobria serine protease(ASP) by α2-macrogluburin (2012)
  • Author(s): Murakami, Y., Imamura, T.
  • Journal Title: Biological Chemistry Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] 凝固反応:感染・炎症の病態と制御-細菌と好中球プロテアーゼ (2012)
  • Author(s): 今村隆寿
  • Journal Title: 日本血栓止血学会誌 Volume: (印刷中)
  • NAID: 130002077020
• [Journal Article] Degradation of fibrinogen and collagenby staphopains, cysteine proteasesreleased from Staphylococcus aureus (2011)
  • Author(s): Ohbayashi, T., Irie, A., Murakami, Y.,Nowak, M., Potempa, J., Nishimura, Y.,Shinohara, M., & Imamura, T
  • Journal Title: Microbiology Volume: 157 Pages: 786-792
  • Peer Reviewed
• [Journal Article] Degadation of fibrinogen and collagen by staphopains, cysteine proteass from Staphylococcus aureus (2011)
  • Author(s): Ohbayashi, T., Imamura, T.
  • Journal Title: Microbiology Volume: 157 Pages: 786-792
  • Peer Reviewed
• [Journal Article] Degadation of fibrinogen and collagen by staphopains, cysteine protease from Staphylococcus aureus. (2011)
  • Author(s): Ohbayashi, T., Imamura, T.
  • Journal Title: Microbiology Volume: 157 Pages: 786-792
  • Peer Reviewed
• [Journal Article] AL-アミロイドーシスと線溶異常 (2010)
  • Author(s): 内場光浩, 今村隆寿
  • Journal Title: 日本血栓止血学会誌 Volume: 21 Pages: 9-15
  • NAID: 10026118462
• [Journal Article] Enhancement of human cancer cellmotility and invasiveness byanaphylatoxin C5a via aberrantlyexpressed C5a-receptor (CD88)
  • Author(s): Nitta, H., Wada, Y., Kawano, Y.,Murakami, Y., Irie, A., Taniguchi, K.,Kikuchi, K., Yamada, G., Suzuki, K.,Honda, J., Wilson-Morifuji, M., Araki,N., Eto, M., Baba, H., & Imamura, T
  • Journal Title: Clin.Cancer Res Volume: (in press)
  • Peer Reviewed
• [Presentation] 転移性腎細胞癌におけるC5a受容体の発現及び生物学的意義について (2013)
  • Author(s): 前田喜寛、和田孝浩、河野吉昭、菊池健、高橋渡、本多次朗、田上憲一郎、仲西寿朗、谷川史城、中村圭輔、矢津田旬二、今村隆寿、江藤正俊
  • Organizer: 第22回泌尿器科分子・細胞研究会
  • Place of Presentation: 高知：ホテル日航高知旭ロイヤル
• [Presentation] Enhancement of human cancer cell migration and invasion by anaphylatoxin C5a vvia aberrantly expressed C5a-receptor. (2012)
  • Author(s): Nitta, H., Imamura, T., & Baba, H.
  • Organizer: Digestive Disease Week (DDW)
  • Place of Presentation: San Diego Convention Center, San Diego, USA.
• [Presentation] Abberant expression C5aR in metastatic renal cell carcinoma. (2012)
  • Author(s): Maeda, Y., Wada Y., Kawano, Y., Kikuchi, K., Takahashi, W., Honda, J., Nakanishi, J., Imamura, T., & Eto, M.
  • Organizer: 107th American Urological Association (AUA) Annual Meeting
  • Place of Presentation: Georgia World Congress Center, Atlanta, USA.
• [Presentation] Aberrant expression of C5aR in metastatic renal cell carcinoma. (2012)
  • Author(s): Maeda, Y.,, Wada, Y., Kawano, Y., Kikuchi, K., Takahashi, W., Honda, J., Nakanishi, J., Yatsuda, J., Murakami, Y., Imamura, T., & Eto, M.
  • Organizer: The 29th Japan-Korea Urological Congress
  • Place of Presentation: 鹿児島市：城山観光ホテル
• [Presentation] Frequent Expression of C5aR in Metastatic Renal Cell Carcinoma. (2012)
  • Author(s): Maeda, Y.,, Wada, Y., Kawano, Y., Kikuchi, K., Takahashi, W., Honda, J., Nakanishi, J., Yatsuda, J., Murakami, Y., Imamura, T., & Eto, M.
  • Organizer: 32nd SIU Congress 2012
  • Place of Presentation: 福岡市：福岡国際会議場
• [Presentation] Anaphylatoxin C5a enhances human cancer cell motility and invasiveness via aberrantly expressed C5a-receptor (CD88). (2012)
  • Author(s): Imamura, T., Murakami, Y., Wada, Y., Kawano, Y., & Nitta, H.
  • Organizer: 2012 Annual Meeting of The American Society for Cell Biology
  • Place of Presentation: The Moscone Center, San Francisco, USA
• [Presentation] Urine of AKI patients promotes metanephrotic cell growth and recovery of renal function after ischemic-reperfusion injury in mouse. (2012)
  • Author(s): Kitamoto, Y., Kitamura, H., Sugai, H., Taguma, Y., Imamura, T., & Yorinaga, H.
  • Organizer: 2012 Annual Meeting of The American Society for Cell Biology
  • Place of Presentation: The Moscone Center, San Francisco, USA
• [Presentation] 癌細胞のアナフィラトキシンC5a受容体発現とC5aによる癌細胞運動性活性化および浸潤亢進. (2012)
  • Author(s): 今村隆寿，村上洋嗣, 新田英利
  • Organizer: 第101回日本病理学会総会
  • Place of Presentation: 東京：京王プラザホテル
• [Presentation] AKI患者尿中の腎傷害回復促進活性―胎仔腎器官培養と動物モデルを用いた解析. (2012)
  • Author(s): 北本康則, 北村洋, 菅井久子, 田熊淑男, 今村隆寿, 頼仲方一
  • Organizer: 第55回日本腎臓学会学術総会
  • Place of Presentation: 横浜：パシフィコ横浜
• [Presentation] 血漿中での細菌プロテアーゼ-α2-マクログロブリン複合体形成の測定-Fluorescence Correlation Spectroscopy (FCS)- (2012)
  • Author(s): 今村隆寿, 村上洋嗣, 小林秀丈, 長谷川慎
  • Organizer: 第17回日本病態プロテアーゼ学会学術集会
  • Place of Presentation: 浜松市：オークラアクトシティホテル浜松
• [Presentation] 黄色ブドウ球菌プロテアーゼ・スタホパインのフィブリノゲンとコラーゲン分解作用. (2012)
  • Author(s): 大林武久, 今村隆寿, 入江厚, 村上洋嗣, 篠原正徳
  • Organizer: 第57回日本口腔外科学会総会・学術大会
  • Place of Presentation: 横浜：パシフィコ横浜
• [Presentation] AKI患者尿中の腎傷害回復促進活性. (2012)
  • Author(s): 北本康則, 北村,洋, 菅井久子, 田熊淑男, 今村隆寿, 駒場秀春, 頼仲方一
  • Organizer: 第59回日本臨床検査医学会学術総会
  • Place of Presentation: 京都：京都国際会館
• [Presentation] Degadation of fibrinogen and collagen by staphopains : Implications in impaired plasma clotting and tissue destruction caused by Staphylococcus aureus infection (2011)
  • Author(s): Ohbayshi, T., Imamura, T.
  • Organizer: 7th International Symposium of Proteolysis
  • Place of Presentation: ヒルトン・サンディェゴ・リゾートスパ(San Diego, USA)
  • Year and Date: 2011-10-18
• [Presentation] 電気化学的歯周病関連酵素ジンジパインの検出:新しい歯周病診断法 (2011)
  • Author(s): 長田真一郎, 今村隆寿
  • Organizer: 日本分析化学会第60年会
  • Place of Presentation: 名古屋大学東山キャンパス(愛知県名古屋市)
  • Year and Date: 2011-09-28
• [Presentation] 切れ目のあるAeromonas sobriaセリンプロテアーゼ(ASP)はα2-MGに抵抗性である (2011)
  • Author(s): 今村隆寿, 岡本敬の介
  • Organizer: 第16回日本病態プロテアーゼ学会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府豊中市)
  • Year and Date: 2011-08-26
• [Presentation] RPGNの診断マーカーとしての尿トロンビンの評価 (2011)
  • Author(s): 北本康則, 今村隆寿
  • Organizer: 第54回日本腎臓学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2011-06-17
• [Presentation] 黄色ブドウ球菌病原因子staphopainsの病原作用解析-フィブリノゲンおよびコラーゲン分解作用 (2011)
  • Author(s): 今村隆寿, 村上洋嗣
  • Organizer: 第100回日本病理学会総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
  • Year and Date: 2011-04-28
• [Presentation] 黄色ブドウ球菌システインプロテアーゼの凝固系および結合織破壊作用の研究-フィブリノゲンとコラーゲン分解作用解析 (2011)
  • Author(s): 大林武久, 今村隆寿
  • Organizer: 第65回日本口腔科学会学術集会
  • Place of Presentation: タワーホール船堀(東京都江戸川区)
  • Year and Date: 2011-04-22
• [Presentation] 癌細胞プロテアーゼのアナフィラトキシンC5a産生を介した癌自己活性化機構の解析 (2010)
  • Author(s): 今村隆寿, 新田英利
  • Organizer: 第99回日本病理学会総会
  • Place of Presentation: 京王プラザホテル(東京都)
• [Presentation] 尿トロンビン-急速進行性糸球体腎炎(RPGN)活動性め新規分子マーカー- (2010)
  • Author(s): 北本康則, 今村隆寿
  • Organizer: 第53回日本腎臓学会学術総会
  • Place of Presentation: 神戸国際会議場(神戸市)
• [Presentation] Aeromonas sobriaセリンプロテアーゼ(ASP)のフィブリノゲン分解による血漿凝固能低下誘導 (2010)
  • Author(s): 今村隆寿, 新田英利
  • Organizer: 第15回日本病態プロテアーゼ学会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪市)
• [Book] Proteasesand their receptors in inflammation (2011)
  • Author(s): Imamura, T., & Potempa, J
  • Publisher: Microbial protases: Relevance to theinflammatory response
• [Book] Proteases and their receptors in inflammation (2011)
  • Author(s): Imamura, T., Potempa, J.
  • Publisher: Springer, Basel, Switzerland
• [Book] Proteases and their receptors in inflammation (2011)
  • Author(s): Imamura, T., Potempa, J.
  • Publisher: Springer, Basel, Switzerland(in press)
• [Book] 救急・集中治療 (2010)
  • Author(s): 今村隆寿、丸藤哲
• [Book] 救急・集中治療 (2010)
  • Author(s): 今村隆寿
  • Publisher: 総合医学社,東京
• [Remarks]
  • URL: http://www.kumamoto-u.ac.jp/seeds/seeds/61580016/index.html