Elucidation of cancer growth mechanisms by C5a-C5aR axis

• Project/Area Number: 17K11679
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Nagoya City University
• Principal Investigator: Imai Masaki 名古屋市立大学, 医薬学総合研究院(医学), 講師 (30440936)
• Co-Investigator(Kenkyū-buntansha): 太田 里永子 愛知県がんセンター(研究所), その他部局等, 研究員 (30452460) ; 山崎 小百合 名古屋市立大学, 医薬学総合研究院(医学), 教授 (70567255)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: C5a / 補体 / 制御性T細胞 / 頭頸部癌 / 口腔癌

Outline of Final Research Achievements

C5a receptor (C5aR) is overexpressed in many cancer tissues, and binding of C5a to C5aR causes cancer growth, invasion and metastasis. We first examined whether C5aR expresses of the oral cancer cell lines or not, mRNA level of C5aR was highly detected. On the other hand, it has been reported that the C5a-C5aR system induces the differentiation of regulatory T cells (Treg cells) and invasion of Treg cells into cancer tissues. However, despite the reports that the C5a-C5aR system acts Treg cells, expression level of C5aR was very low on Treg cells.

Academic Significance and Societal Importance of the Research Achievements

多くの癌組織でC5a-C5aRシステムが癌の浸潤や転移に関わっているが、本研究では今まで明らかにされていない『口腔癌とC5a-C5aRシステムの関係』を明らかできることが特徴である。本研究で口腔癌の増殖にC5a-C5aRシステムの関与が示唆されたが、免疫系を制御するが制御性 T細胞の分化、浸潤に関与しなかったことから、腫瘍特異的なC5aR阻害剤を作成できれば副作用が少なく、高い抗腫瘍効果が得られると予想され、臨床応用への可能性がある。

Research Products

• [Journal Article] Hyperglycemia is associated with psoriatic inflammation in both humans and mice (2019)
  • Author(s): Ikumi K, Odanaka M, Shime H, Imai M, Osaga S, Taguchi O, Nishida E, Hemmi H, Kaisho T, Morita A, Yamazaki S
  • Journal Title: Journal of Investigative Dermatology Volume: 印刷中 Issue: 6 Pages: 1329-1338
  • DOI: 10.1016/j.jid.2019.01.029
  • Peer Reviewed / Open Access
• [Journal Article] Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer. (2019)
  • Author(s): Matoba T, Imai M, Ohkura N, Kawakita D, Ijichi K, Toyama T, Morita A, Murakami S, Sakaguchi S, Yamazaki S.
  • Journal Title: International Journal of Cancer Volume: 144(11) Issue: 11 Pages: 2811-2822
  • DOI: 10.1002/ijc.32024
  • Peer Reviewed / Open Access
• [Journal Article] Ultraviolet B?Induced Maturation of CD11b-Type Langerin?Dendritic Cells Controls the Expansion of Foxp3+Regulatory T Cells in the Skin (2017)
  • Author(s): Yamazaki Sayuri、Odanaka Mizuyu、Nishioka Akiko、Kasuya Saori、Shime Hiroaki、Hemmi Hiroaki、Imai Masaki、Riethmacher Dieter、Kaisho Tsuneyasu、Ohkura Naganari、Sakaguchi Shimon、Morita Akimichi
  • Journal Title: The Journal of Immunology Volume: 200 Issue: 1 Pages: 119-129
  • DOI: 10.4049/jimmunol.1701056
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Skin dendritic cells expressing a unique set of genes associated with immunological tolerance are specialized to expand thymus-derived Foxp3+ regulatory T cells upon ultraviolet B exposure (2019)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: Japan-Singapore Skin International Conference
  • Int'l Joint Research
• [Presentation] Dermal dendritic cells present neo-self antigens induced by ultraviolet B exposure to expand Foxp3+ regulatory T cells (2019)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: 77th annual meeting of Society for investigative dermatology
  • Int'l Joint Research
• [Presentation] Regulatory T cells with a distinctive feature expand through dermal dendritic cells in the ultraviolet B exposed skin (2019)
  • Author(s): Sayuri Yamazaki, Mizuyu Odanaka, Hiroaki Shime, Masaki Imai, Hiroaki Hemmi, Tsuneyasu Kaisho, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita
  • Organizer: 16th international workshop on Langerhans cells
• [Presentation] Functional characterization of regulatory T (Treg) cells in UVB-irradiated skin (2019)
  • Author(s): Hiroaki Shime, Mizuyu Odanaka, Masaki Imai, Naganari Ohkura, Shimon Sakaguchi, Akimichi Morita, Sayuri Yamazaki
  • Organizer: 第48回 日本免疫学会学術集会
• [Presentation] Expression of complement anaphylatoxin receptor in the various subsets of dendritic cells (2019)
  • Author(s): Masaki Imai, Rieko Ohta, Sayuri Yamazaki
  • Organizer: 第48回 日本免疫学会学術集会
• [Presentation] C3a受容体アンタゴニストはヒストンにより惹起された急性肺障害を改善した (2019)
  • Author(s): 石橋和晃、水野智博、長野文彦、今井優樹、丸山彰一、永松 正、水野 正司
  • Organizer: 第56回日本補体学会
• [Presentation] 頭頸部癌における制御性T細胞の新たな特徴。 (2019)
  • Author(s): 的場拓磨、今井優樹、大倉永也、川北大介、伊地知圭、遠山竜也、森田明理、村上信五、坂口志文、山崎小百合
  • Organizer: 第37回日本耳鼻咽喉科免疫アレルギー学会
• [Presentation] Extracellular histones decrease the expression of membrane complement regulators. (2018)
  • Author(s): Mizuno T, Nagano F, Mizuno M, Iwata A, Takahashi K, Tsuboi N, Maruyama S, Nagamatsu T, Imai M.
  • Organizer: 27th International Complement Workshop
  • Int'l Joint Research
• [Presentation] Foxp3+ regulatory T cells are expanded by ultraviolet B-exposed PD-L1+ skin dendritic cell expressing a unique set of genes in a CSF1-independent manner. (2018)
  • Author(s): Yamazaki S, Odanaka M, Nishioka A, Kasuya S, Shime H, Hemmi H, Imai M, Riethmacher D, Kaisho T, Ohkura N, Sakaguchi S, Morita A
  • Organizer: International Investigative Dermatology 2018
  • Int'l Joint Research
• [Presentation] Dendritic cells expressing a unique set of genes associated with immunological tolerance are specialized to expand thymus-derived Foxp3+ regulatory T cells in the ultraviolet B-exposed skin. (2018)
  • Author(s): Yamazaki S, Odanaka S, Shime H, Imai M, Nishioka A, Hemmi H, Kaisho T, Ohkura N, Sakaguchi S, Morita M
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] Hyperglycemia is associated with psoriatic inflammation in both humans and mice. (2018)
  • Author(s): Odanaka M, Ikumi K, Shime H, Imai M, Taguchi O, Hemmi H, Kaisho T, Morita A, Yamazaki S
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] A New Feature of Regulatory T Cells in Human Head and Neck Cancer. (2018)
  • Author(s): Matoba T, Imai M, Ohkura N, Kawakita D, Ijichi K, Toyama T, Morita A, Murakami S, Sakaguchi S, Yamazaki S
  • Organizer: 第47回日本免疫学会総会・学術集会
• [Presentation] 致死性血栓症モデルにおける膜補体制御因子の発現解析。 (2018)
  • Author(s): 水野智博、長野文彦、水野正司、岩田歩実、高橋和男、坪井直毅、丸山彰一、今井優樹、永松 正
  • Organizer: 日本病院薬剤師会東海ブロック日本薬学会東海支部 合同学術大会2018
• [Presentation] 補体制御によるがん免疫療法の開発。 (2018)
  • Author(s): 今井優樹
  • Organizer: 第55回日本補体学会
  • Invited
• [Presentation] 細胞外ヒストンは細胞表面のCrryおよびCD59a発現を低下させる。 (2018)
  • Author(s): 水野智博、長野文彦、水野正司、岩田歩実、高橋和男、坪井直毅、 丸山彰一、永松 正、今井優樹
  • Organizer: 第55回日本補体学会
• [Presentation] ミエロイド系細胞における補体アナフィラトキシン受容体の発現解析。 (2018)
  • Author(s): 今井 優樹、辻村 幸平、太田 里永子、山崎 小百合
  • Organizer: 第28回日本樹状細胞研究会
• [Presentation] 細胞外ヒストンは細胞表面の膜補体制御因子（CD59a）発現を低下させる。 (2018)
  • Author(s): 岩田歩実、水野智博、長野文彦、高橋和男、坪井直毅、丸山彰一、今井優樹、水野正司、永松 正
  • Organizer: 医療薬学フォーラム2018
• [Presentation] 細胞外ヒストンは血小板凝集を介して、補体を活性化させる (2018)
  • Author(s): 近藤亜美、水野智博、長野文彦、岩田歩実、余吾菜摘、高橋和男、坪井直毅、丸山彰一、水野正司、永松 正、今井優樹
  • Organizer: 医療薬学フォーラム2018
• [Presentation] 補体活性化による腫瘍の分子標的治療薬の開発 (2017)
  • Author(s): 太田 里永子、葛島 清隆、藤田 禎三、岡田 秀親、今井 優樹
  • Organizer: 第53回日本補体学会
• [Presentation] C5、C5aは細胞外ヒストンにより誘発された致死性血栓症を増悪する (2017)
  • Author(s): 水野 智博、吉岡 憲吾、水野 正司、清水 美衣、長野 文彦、 奥田 知将、坪井 直毅、丸山 彰一、永松 正、今井 優樹
  • Organizer: 第53回日本補体学会
• [Presentation] 福井聡介、多和田光洋、鈴木康弘、松川宜久、今井優樹、丸山彰一、水野正司 (2017)
  • Author(s): 真菌性腹膜炎を発症した PD 患者腹膜組織における補体制御因子の発現分布
  • Organizer: 第53回日本補体学会