Investigation of cancer promotion by a cancer microenvironment factor C5a and establishment of the therapy targeting the C5a-C5a receptor system.

• Project/Area Number: 25460498
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• 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(医), 准教授 (20176499)
• Co-Investigator(Renkei-kenkyūsha): IRIE ATSUSHI 熊本大学, 生命科学研究部, 講師 (30250343)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: C5a / 癌 / 浸潤 / 増殖 / 転移 / プロテアーゼ / 阻害剤 / 受容体拮抗剤 / C5a受容体 / 予後 / Rho / 補体

Outline of Final Research Achievements

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

Research Products

• [Journal Article] Inhibition of gingipains and Porphyromonas gingivalis growth and biofilm formation by prenyl flavonoids. (2017)
  • Author(s): Kariu, T., Nakao, R., Ikeda, T., Nakashima, K., Potempa, J., & Imamura, T.
  • Journal Title: J. Periotont. Res. Volume: 52 Pages: 89-96
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Enhancement of active MMP release and invasive activity of lymph node metastatic tongue cancer cells by elevated signaling via the TNF-α-TNFR1-NF-κB pathway and a possible involvement of angiopoietin-like 4 in lung metastasis. (2016)
  • Author(s): Tanaka, T., Imamura, T., Yoneda, M., Irie, A., Ogi, H., Nagata, M., Yoshida, R., Fukuma, D., Kawahara, K., Shinohara, M, & Nakayama, H.
  • Journal Title: Int. J. Oncol. Volume: 49 Issue: 4 Pages: 1377-1384
  • DOI: 10.3892/ijo.2016.3653
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of anaphylatoxin C5a receptor in gastric cancer: Implications with vascular invasion and patient outcome. (2016)
  • Author(s): Nitta, H., Shimose, T., Emi, Y., Imamura, T., Ohnishi, K., Kusumoto, T., Yamamoto. M., Fukuzawa, K., Takahashi, I., Higashi, H., Tsuji, A., Akagi, Y., Oki, E., Maehara, Y., & Baba, H.
  • Journal Title: Med. Oncol. Volume: 33 Issue: 11 Pages: 118-118
  • DOI: 10.1007/s12032-016-0834-9
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Relation of anaphylatoxin C5a receptor (CD88) expression of urothelial cancer to poor prognosis of patients treated by radical cystectomy or nephroureterectomy. (2016)
  • Author(s): Wada, Y., Maeda, Y., Kubo, T., Kikuchi, K., Eto, M., & Imamura, T.
  • Journal Title: Oncol. Lett. Volume: 12 Issue: 5 Pages: 3995-4000
  • DOI: 10.3892/ol.2016.5137
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] C5a receptor (CD88) promotes motility and invasiveness of gastric cancer by activating RhoA. (2016)
  • Author(s): Kaida, T., Nitta, H., Kitano, Y., Yamamura, K., Arima, K., Izumi, D., Higashi, T., Kurashige, J., Imai, K., Hayashi, H., Iwatsuki, M., Ishimoto, T., Hashimoto, D., Yamashita, Y., Chikamoto, A., Imamura, T., Ishiko, T., Beppu, T., & Baba, H.
  • Journal Title: Oncotarget Volume: 51 Pages: 84798-84809
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Successful treatment of a renal cancer patient with brachial muscle metastasis by sequential molecular targeted therapy. (2016)
  • Author(s): Iwashita, H., Maeda, Y., Murakami, S., Imamura, T., Wada, Y., & Eto, M.
  • Journal Title: J. Med. Case Report Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Relation of anaphylatoxin C5a receptor (CD88) expression of urothelial cancer to poor prognosis of patients treated by radical cystectomy or nephronureterctomy. (2016)
  • Author(s): Wada, Y., Maeda, Y., Kawano, Y., Kubo, T., Kikuchi, K., Eto, M., & Imamura, T.
  • Journal Title: Oncol. Lett. Volume: 印刷中
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Influence of the C5a-C5a receptor system on breast cancer progression and patient prognosis (2015)
  • Author(s): Imamura, T. Yamamoto-Ibusuki, M. Sueta, A. Kubo, T. Irie, A. Kikuchi, K. Kariu, T. Iwase, H.
  • Journal Title: Breast Cancer Volume: Oct21 Issue: 6 Pages: 1-10
  • DOI: 10.1007/s12282-015-0654-3
  • Peer Reviewed / Open Access
• [Journal Article] C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways. (2015)
  • Author(s): Maeda Y, Kawano Y, Wada Y, Yatsuda J, Motoshima T, Murakami Y, Kikuchi K, Imamura T, Eto M.
  • Journal Title: Oncology Reports Volume: 33 Issue: 4 Pages: 1844-1850
  • DOI: 10.3892/or.2015.3800
  • Peer Reviewed
• [Journal Article] Cleavage of host cytokeratin-6 by lysine-specific gingipain induces gingival inflammation in periodontitis patients. (2015)
  • Author(s): Tancharoen S, Matsuyama T, Kawahara K, Tanaka K, Lee LJ, Machigashira M, Noguchi K, Ito T, Imamura T, Potempa J, Kikuchi K,Maruyama I.
  • Journal Title: PLoS One. Volume: 10 Issue: 2 Pages: e0117775-e0117775
  • DOI: 10.1371/journal.pone.0117775
  • Peer Reviewed / Open Access
• [Journal Article] Urinary thrombin: A novel marker of glomerular inflammation for the diagnosis of crescentic glomerulonephritis. (2015)
  • Author(s): Kitamoto, Y., Arizono, K., Fukui, H., Tomita, K., Kitamura, H., Taguma, Y., & Imamura, T.
  • Journal Title: PLOS ONE. Volume: 10(3) Issue: 3 Pages: e0118704-e0118704
  • DOI: 10.1371/journal.pone.0118704
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Porphyromonas gingivalis-derived lysine gingipain enhances osteoclast differentiation induced by tumor necrosis factor and interleukin-1 but suppresses that by interleukin-17: Importance of proteolytic degradation of osteoprotegerin by lysine gingipain. (2014)
  • Author(s): Tomohito Akiyama, Yoichi Miyamoto, Kentaro Yoshimura, Atsushi Yamada, Masamichi Takami, Tetsuo Suzawa, Marie Hoshino, Takahisa Imamura, Chie Akiyama, Rika Yasuhara, Kenji Mishima, Toshifumi Maruyama, Chikara Kohda, Kazuo Tanaka, Jan Potempa, Hisataka Yasuda, Kazuyoshi Baba, Ryutaro Kamijo.
  • Journal Title: J.Biol.Chem. Volume: 289 Issue: 22 Pages: 1-35
  • DOI: 10.1074/jbc.m113.520510
  • Peer Reviewed / Open Access
• [Journal Article] Staphopains in Staphylococcus aureus bactermia: Virulence activities related to the onset of septic shock, coagulation disorder and infectious endocarditis. (2014)
  • Author(s): Imamura, T.
  • Journal Title: J. Oral Bioscience Volume: 56 Issue: 3 Pages: 81-85
  • DOI: 10.1016/j.job.2014.04.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Discovery of a novel vascular endothelial growth factor (VEGF) with no affinity to heparin in Gloydius tsushimaensis venom. (2014)
  • Author(s): Nakamura H, Murakami T, Imamura T, Toriba M Chijiwa T, Ohno M, Oda-Ueda N
  • Journal Title: Toxicon Volume: 86 Pages: 107-115
  • DOI: 10.1016/j.toxicon.2014.05.003
  • Peer Reviewed / Open Access
• [Journal Article] Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness. (2014)
  • Author(s): Nitta, H., Murakami, Y., Wada, Y., Eto, M., Baba, H., & Imamura, T.： Cancer cells release anaphylatoxin C5a from C5 by serine protease to enhance invasiveness.
  • Journal Title: Oncol. Rep. Volume: 32 Issue: 4 Pages: 1715-1719
  • DOI: 10.3892/or.2014.3341
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 凝固炎症反応と病理組織 特集『徹底ガイド DICのすべて2014-’15』 (2014)
  • Author(s): 今村隆寿
  • Journal Title: 救急・集中治療 Volume: -
• [Journal Article] Enhancement of human cancer cell motility and invasiveness by anaphylatoxin C5a via aberrantly expressed C5a-receptor (CD88). (2013)
  • Author(s): Nitta, H. et al.
  • Journal Title: Clinical Cancer Reseach Volume: 19 Issue: 8 Pages: 2004-2013
  • DOI: 10.1158/1078-0432.ccr-12-1204
  • Peer Reviewed
• [Journal Article] 凝固炎症反応の病理組織 (2013)
  • Author(s): 今村隆寿
  • Journal Title: Thrombosis Medicine Volume: 3 Pages: 48-52
• [Presentation] Endoplasmic reticulum causes ulcerative colitis-like severe colitis in the homozygotes of HLA-DR4 transgenic mice. (2016)
  • Author(s): Irie. A., Michibata, Y., Kubo, T., Imamura, T., Takeda, N., Araki, K., Shibuya, I., Sogo, S., & Nishimura, Y.
  • Organizer: 第45回日本免疫学会学術集会
  • Place of Presentation: 宜野湾市，沖縄コンベンションセンター，ラグナガーデンホテル
  • Year and Date: 2016-12-22
• [Presentation] 大腸上皮細胞の小胞体ストレスがHLA-DR4トランスジェニックマウスのホモ接合体に発症する大腸炎の病因である (2016)
  • Author(s): 入江 厚，今村隆寿，道端弥生，久保多津子，竹田直樹，澁谷 功，十河真司，荒木喜美，西村泰治
  • Organizer: 第25回日本組織適合性学会大会
  • Place of Presentation: 札幌市，北海道大学学術交流会館
  • Year and Date: 2016-10-22
• [Presentation] C5a-C5a受容体は癌転移を促進し、癌微小環境C5aは癌浸潤を亢進する. (2016)
  • Author(s): 今村隆寿，米田雅一，河野吉昭，中山秀樹
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜市，パシフィコ横浜
  • Year and Date: 2016-10-06
• [Presentation] Aberrant accumulation of HLA-DR and reduced mucin production in colonic epithelial cells of HLA-DR4 transgenic mice and ulcerative colitis patients. (2016)
  • Author(s): Irie. A., Imamura, T., Michibata, Y., Kubo, T., Takeda, N., Shibuya, I., Sogo, S., Araki, K., & Nishimura, Y.
  • Organizer: 16th International Congress of Immunology.
  • Place of Presentation: Melbourne, Australia, Melbourne Convention and Exhibition Centre
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] 糖尿病性腎症進行期におけるトロンビン尿増加は糸球体炎症の腎傷害進行への関与を示唆する (2016)
  • Author(s): 北本康則，今村隆寿，北村 洋，田熊淑男，有薗健二
  • Organizer: 第59回日本腎臓学会学術総会
  • Place of Presentation: 横浜市，パシフィコ横浜
  • Year and Date: 2016-06-17
• [Presentation] 尿上皮癌アナフィラトキシンC5a受容体発現は根治手術後患者の予後不良を示唆する (2016)
  • Author(s): 今村隆寿，前田喜寛，和田孝浩
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台市，仙台国際センター会議棟
  • Year and Date: 2016-05-12
• [Presentation] C5a受容体は根治手術を受けた侵襲性尿上皮癌患者の補助療法の必要性を示唆する (2015)
  • Author(s): 今村隆寿, 新田英利, 和田孝浩, 河野吉昭, 村上洋嗣, 江藤正俊, 馬場秀夫
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市 名古屋国際会議場
  • Year and Date: 2015-09-25
• [Presentation] 前立腺癌細胞におけるWnt/β-catenin-Survivin axis の生物学的意義 (2015)
  • Author(s): 河野吉昭, 中田小百合, 入江 厚, 元島崇信, 前田喜寛, 鹿瀬島裕, 今村隆寿, Robert Kypta, 江藤正俊
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋市 名古屋国際会議場
  • Year and Date: 2015-09-25
• [Presentation] 大腸上皮細胞の小胞体ストレスがHLA-DR4トランスジェニックマウスのホモ接合体に発症する大腸炎の原因である (2015)
  • Author(s): 入江厚,道端弥生, 久保多津子, 今村隆寿, 竹田直樹, 荒木喜美, 江藤正俊, 渋谷功, 十河真司, 西村泰治
  • Organizer: 第24回日本組織適合性学会大会
  • Place of Presentation: 水戸市 ホテルレイクビュー水戸
  • Year and Date: 2015-09-10
• [Presentation] 癌治療標的標的分子の探索-C5a受容体とプロテアーゼ (2015)
  • Author(s): 米田雅一, 中山秀樹, 岩瀬弘敬, 今村隆寿
  • Organizer: 日本プロテオーム学会2015年会JHUPO第13回大会
  • Place of Presentation: 熊本市 くまもと森都心プラザ
  • Year and Date: 2015-07-23
• [Presentation] 糸球体腎炎における尿トロンビン濃度と血漿thrombin-antithrombin複合体濃度の乖離. (2015)
  • Author(s): 北本康則, 有薗健二, 今村隆寿, 北村洋, 菅井久子, 田熊淑男
  • Organizer: 第58回日本腎臓学会学術総会
  • Place of Presentation: 名古屋市 名古屋国際会議場
  • Year and Date: 2015-06-05
• [Presentation] 乳癌アナフィラトキシンC5a受容体発現と癌進展・患者低生存率との関係. (2015)
  • Author(s): 今村隆寿，指宿睦子, 末田愛子, 岩瀬弘敬
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市 名古屋国際会議場
  • Year and Date: 2015-04-30
• [Presentation] 病理組織にみる血液凝固反応と炎症・免疫反応のクロストーク (2015)
  • Author(s): 今村隆寿
  • Organizer: 急性期管理血漿分画フォーラム in Nagoya
  • Place of Presentation: 名古屋市 メルパルク名古屋
  • Year and Date: 2015-03-14
  • Invited
• [Presentation] Positive-relation of breast cancer cell anaphylatoxin C5a-receptor expression to cancer progression (乳癌アナフィラトキシンC5a受容体発現の癌進展への正の関連性) (2014)
  • Author(s): 今村隆寿, 指宿(山本)睦子, 山本豊, 岩瀬弘敬
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市 パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Wnt/β-catenin signaling pathway is a potential target for castrate-resistant prostate cancer therapy(去勢抵抗性前立腺癌におけるWnt/β-catenin シグナルの意義) (2014)
  • Author(s): 河野吉昭, 前田喜寛, 元島崇信, 入江厚, 今村隆寿, 江藤正俊
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜市 パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 副腎皮質ステロイドによる糸球体腎炎治療効果の尿トロンビン測定によるモニタリング (2014)
  • Author(s): 北本康則, 有薗健二, 田熊淑男, 今村隆寿
  • Organizer: 第36回日本血栓止血学会学術総会
  • Place of Presentation: 大阪市 大阪国際交流センター
  • Year and Date: 2014-05-29 – 2014-05-31
• [Presentation] 胃癌細胞アナフィラトキシンC5a受容体発現と癌進展との関係 (2014)
  • Author(s): 今村隆寿，新田英利
  • Organizer: 第103回日本病理学会総会
  • Place of Presentation: 広島市 国際会議場
  • Year and Date: 2014-04-25 – 2014-04-27
• [Presentation] 去勢不応型前立腺癌特異的プロテアーゼの探索. (2013)
  • Author(s): 今村隆寿，村上洋嗣, 和田孝浩
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: 札幌市；ロイトン札幌
• [Presentation] アナフィラトキシンC5aの癌進展に有利な活性. (2013)
  • Author(s): 今村隆寿, 新田英利, 和田孝浩, 河野吉昭, 村上洋嗣, 江藤正俊, 馬場秀夫
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市；パシフィコ横浜
• [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, 杉山豊, 田上憲一郎, 矢津田旬二, 今村隆寿, 江藤正俊
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜市；パシフィコ横浜
• [Book] 救急・集中治療 (2014)
  • Author(s): 今村隆寿 編集：丸藤 哲
  • Total Pages: 391
  • Publisher: 総合医学社