Comprehensive investigation of cancer promotion C5a-C5a receptor system including clinical analysis and application of the system to a cancer therapeutic target.

• Project/Area Number: 16K08741
• 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)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: C5a / 前立腺癌 / グルタミン / 増殖 / 浸潤 / 転移 / アルザス反応 / 受容体拮抗剤 / 癌 / C5a受容体 / PD-L1 / MDSC / 予後

Outline of Final Research Achievements

Cancer cell C5a-receptor (C5aR) expression correlated to invasion, clinical stage advance, metastasis to lymph nodes and liver and poor prognosis. Prostate cancer (PC) C5aR expression did not relate to clinicopathological parameters, but C5a augmented PC cell glutamine consumption, proliferation, invasion in C5aR-depemndent manner. PD-L1 expression increase by C5a suggested a participation of C5a in evasion from the anticancer immune responses. Endogenous C5a generation augmented cancer cell invasion and tumor formation and induced myeloid-derived suppressor cells (MDSC) accumulation. These effects of the C5a-C5aR system on cancer-promoting and anticancer immune response evasion suggested an availability of the system as a therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

C5aが約半分の症例で前立腺癌が発現するC5a受容体を介して癌細胞のグルタミン代謝、増殖や浸潤能を亢進すること、さらにキラーTリンパ球による抗腫瘍免疫応答を抑制するPD-L1の癌細胞発現を増加させることは、生体防御系の補体系の分子C5aの癌促進かつ抗腫瘍免疫抑制への関与を示しており、これまで炎症メディエーターと考えられていたC5aの新たな概念を提示して学術的意義が高い。
C5aやC5a受容体に対する抗体や受容体拮抗剤等によるC5a-C5a受容体シグナルの遮断は癌進行抑制効果が推測され、この系を標的として開発された薬剤は新たな前立腺癌治療として臨床的に有効性が期待されて社会的意義がある。

Research Products

• [Journal Article] Prostate Cancer Expression of C5a Receptor and Augmentation of Proliferation, Invasion and PD-L1 Expression by C5a. (2020)
  • Author(s): Imamura, R., Kitagawa, S., Kubo, T., Irie, A., Kariu, T., Kamba, T., & Imamura, T.
  • Journal Title: BIU International Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] A rare mandibular osteosarcoma case of Li-Fraumeni syndrome with a germline p53R273H mutation. (2020)
  • Author(s): Ogi, H., Tanaka, T., Yoshitake, Y., Shinohara, M., Nakayama, H., & Imamura, T.
  • Journal Title: J. Oral Maxillofac. Surg. Med. Pathol. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Metastasis of malignant pleural mesothelioma to maxillary gingiva: a case report and literature review. (2020)
  • Author(s): Tanaka, T., Nakamatsu, K., & Imamura, T.
  • Journal Title: J. Oral Maxillofac. Surg. Med. Pathol. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] A natural anti-periodontitis agent, epimedokoreanin B, inhibits virulence activities of gingipains from Porphyromonas gingivalis (2019)
  • Author(s): Kariu Toru、Ikeda Tsuyoshi、Nakashima Keisuke、Potempa Jan、Imamura Takahisa
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 83 Issue: 7 Pages: 1-3
  • DOI: 10.1080/09168451.2019.1597615
  • Peer Reviewed / Open Access
• [Journal Article] Enhancement of cancer invasion and growth via the C5a-C5a receptor system: Implications for cancer promotion by autoimmune diseases and association with cervical cancer invasion. (2019)
  • Author(s): Yoneda, M., Imamura, R., Nitta, H., Taniguchi, K., Saito, F., Kikuchi, K., Ogi, H., Tanaka, T., Katabuchi, H., Nakayama, H., & Imamuta, T.
  • Journal Title: Oncol. Lett. Volume: 17 Pages: 913-920
  • Peer Reviewed / Open Access
• [Journal Article] A rare mandibular osteosarcoma case of Li-Fraumeni syndrome with a germline p53R273H mutation. (2019)
  • Author(s): Ogi H, Tanaka T, Yoshitake Y, Shinohara M, Nakayama H, and Imamura T.
  • Journal Title: J.ORAL AND MAXILLOFACIAL.SURG, MED, AND PATHOL Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Augmentation of the enhanced permeability and retention effect with nitric oxide-generating agents improves the therapeutic effects of nanomedicines. (2018)
  • Author(s): Islam, W., Fang, J., Imamura, T., Etrych, T., Subr, V., Ulbrich K., & Maeda, H.
  • Journal Title: Mol. Cancer Therap. Volume: 17 Issue: 12 Pages: 2643-2653
  • DOI: 10.1158/1535-7163.mct-18-0696
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Aeromonas sobria serine protease (ASP): a subtilisin family endopeptidase with multiple virulence activities. (2017)
  • Author(s): Imamura, T., Murakami, Y., & Nitta, H.
  • Journal Title: Biol. Chem. Volume: 398 Issue: 10 Pages: 1055-1068
  • DOI: 10.1515/hsz-2016-0344
  • Peer Reviewed / Open Access
• [Journal Article] Accumulation of HLA-DR4 in Colonic Epithelial Cells Causes Severe Colitis in Homozygous HLA-DR4 Transgenic Mice (2017)
  • Author(s): Irie Atsushi、Imamura Takahisa、Michibata Yayoi、Kubo Ttatsuko、Takeda Naoki、Shibuya Isao、Sogo Shinji、Araki Kimi、Nishimura Yasuharu
  • Journal Title: Inflammatory Bowel Diseases Volume: 23 Issue: 12 Pages: 2121-2133
  • DOI: 10.1097/mib.0000000000001282
  • Peer Reviewed / Open Access
• [Journal Article] Inhibition of gingipains and Porphyromonas gingivalis growth and biofilm formation by prenylated flavonoids (2016)
  • Author(s): Toru Kariua, Ryoma Nakao, Tsuyoshi Ikeda, Keisuke Nakashima, Jan Potempa, and Takahisa Imamura
  • Journal Title: Journal of Periodontal Research Volume: 未定 Issue: 1 Pages: 89-96
  • DOI: 10.1111/jre.12372
  • 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] 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
• [Presentation] C5a-C5a受容体系の前立腺癌促進作用. Promotion of prostate cancer by the C5a-C5a receptor system. (2019)
  • Author(s): 今村隆二, 北川さき, 米田雅一, 神波大己,今村隆寿
  • Organizer: 第106回日本病理学会総会
• [Presentation] C5aは前立腺がんの増殖, 浸潤およびPD-L1の発現を促進する. C5a promotes prostate cancer proliferation, invasion and PD-L1 expression. (2019)
  • Author(s): 北川さき, 今村隆二, 神波大巳, 今村隆寿
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 前立腺癌におけるC5a-C5a受容体系の機能解明 (2019)
  • Author(s): 今村隆二, 今村隆寿, 北川さき, 米田雅一, 神波大巳
  • Organizer: 第28回泌尿器分子細胞研究会
• [Presentation] 高感度ELISAによる微量尿トロンビンの検出 (2018)
  • Author(s): 北本康則,小林剛, 今村隆寿,田熊淑男
  • Organizer: 第61回日本腎臓学会学術総会
• [Presentation] 内因性C5aによる癌浸潤亢進と癌C5a受容体発現の臨床的関連性. (2018)
  • Author(s): 今村隆寿, 今村隆二,米田雅一
  • Organizer: 第107回日本病理学会総会
• [Presentation] C5a-C5a受容体系は癌促進に関連し治療標的となる可能性がある (2018)
  • Author(s): 今村隆寿, 米田雅一, 今村隆二, 新田英利
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 前立腺癌進行におけるC5a-C5a受容体系. The C5a-C5a receptor system in prostate cancer progression. (2018)
  • Author(s): 今村隆二, 米田雅一, 神波大巳, 今村隆寿
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Prostate cancer promotion via the C5a-C5a receptor system. (2018)
  • Author(s): Imamura, R., Imamura, T., Kitagawa, S., Yoneda, M., & Kamba, T
  • Organizer: 35th Japan-Korea Urological Congress
  • Int'l Joint Research
• [Presentation] C5aの癌転移促進と内因性C5aによる同種浸潤亢進. Cancer metastasis promotion by C5a and homologous cancer invasion enhancement by endogenous C5a. (2017)
  • Author(s): 米田雅一，中山秀樹，今村隆寿
  • Organizer: 第106回日本病理学会総会
• [Presentation] 糖尿病性腎症早期の患者尿トロンビン濃度測定による糸球体炎症の評価 (2017)
  • Author(s): 北本康則，今村隆寿，有薗健二，北村 洋，小林 剛，田熊淑男
  • Organizer: 第60回日本腎臓学会学術総会
• [Presentation] 癌促進におけるC5a-C5a受容体系：マウスと臨床病理学的データを使った研究 (2017)
  • Author(s): 今村隆寿，米田雅一，今村隆二，中山秀樹
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] アンギオポエチンライク４の発現は口腔扁平上皮癌の予後マーカーとなりうる (2017)
  • Author(s): 田中拓也，尾木秀直，吉田遼司，廣末晃之，福間大喜，川原健太，松岡裕一郎，坂田純基，有田英生，中嶋 光，今村隆寿，中山秀樹
  • Organizer: 第76回日本癌学会学術総会
• [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
• [Book] 救急・集中治療 (2018)
  • Author(s): 今村隆寿
  • Publisher: 総合医学社