Elucidation of regulatory mechanisms of intractable peritoneal metastasis treated with atmospheric pressure plasma for targeting the tumor microenvironment

• Project/Area Number: 20K09640
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Nagoya University
• Principal Investigator: Nakamura Kae 名古屋大学, 低温プラズマ科学研究センター, 特任講師 (10744047)
• Co-Investigator(Kenkyū-buntansha): 田中 宏昌 名古屋大学, 低温プラズマ科学研究センター, 教授 (00508129) ; 芳川 修久 名古屋大学, 医学部附属病院, 講師 (60804747)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 卵巣がん / 大気圧プラズマ / プラズマ活性液 / 腫瘍微小環境 / がん免疫 / T細胞 / がん微小環境 / 腫瘍浸潤リンパ球 / TIL / CAR-T細胞 / マクロファージ

Outline of Research at the Start

卵巣がんにおける腹膜播種は難治性・治療抵抗性の象徴的な病態として着目されており、がん細胞と腹膜微小環境に存在する腹膜中皮細胞やその他の免疫系細胞との細胞間相互作用が腹膜播種の形成・進展に重要な役割を担っていることが明らかになっている。本研究において、大気圧プラズマの抗腫瘍活性を液体化したプラズマ活性液が誘導する腹膜微小環境における腫瘍抑制機構を解明し、新規治療技術としての基礎的知見の集積を目指す。

Outline of Final Research Achievements

1It has been demonstrated that immune cells whose character was changed at the peritoneal metastasis microenvironment could contribute to cancer progression in gynecologic malignancy. In this study, we investigated the activation of anti-tumor immune response in tumor microenvironment treated with plasma-activated solution, liquified gaseous of an atmospheric pressure plasma, having an effect of anti-tumor and cell activation. The results showed 1) increased M1-type macrophage, having an anti-tumor activity, infiltration in the peritoneal metastasis, 2) cancellation of the immunosuppression of T cells induced by patient-derived cancerous ascites, and 3) activation of T cell immunosuppressed by TGF-β1.

Academic Significance and Societal Importance of the Research Achievements

婦人科悪性腫瘍に特徴的な腹膜播種は、難治性・治療抵抗性の象徴的な病態として着目されている。このような腫瘍微小環境では、恒常性維持に関わる細胞が変化し、難治性・治療抵抗性の基盤となっている。近年、注目されているがん免疫療法は、このような微小環境に対し本来の効果を十分発揮できないことが課題の1つとなっており、プラズマ活性液はこのような難治性となった腹膜播種に対し、複合がん免疫療法として既存の免疫療法のブレークスルーとなる可能性がある。

Research Products

• [Journal Article] Novel therapeutic strategies targeting UCP2 in uterine leiomyosarcoma (2023)
  • Author(s): Nagao Yukari、Yokoi Akira、Yoshida Kosuke、Sugiyama Mai、Watanabe Eri、Nakamura Kae、Kitagawa Masami、Asano-Inami Eri、Koya Yoshihiro、Yoshihara Masato、Tamauchi Satoshi、Shimizu Yusuke、Ikeda Yoshiki、Yoshikawa Nobuhisa、Kato Tomoyasu、Yamamoto Yusuke、Kajiyama Hiroaki
  • Journal Title: Pharmacological Research Volume: 189 Pages: 106693-106693
  • DOI: 10.1016/j.phrs.2023.106693
  • Peer Reviewed / Open Access
• [Journal Article] Low-temperature plasma as magic wand to differentiate between the good and the evil. (2023)
  • Author(s): Toyokuni S, Zheng H, Kong Y, Sato K, Nakamura K, Tanaka H, Okazaki Y.
  • Journal Title: Free Radic Res. Volume: 57 Issue: 1 Pages: 38-46
  • DOI: 10.1080/10715762.2023.2190860
  • Peer Reviewed
• [Journal Article] Organic decomposition and synthesis reactions in lactated solution exposed to nonequilibrium atmospheric pressure plasma (2023)
  • Author(s): Liu Yang、Ishikawa Kenji、Tanaka Hiromasa、Miron Camelia、Kondo Takashi、Nakamura Kae、Mizuno Masaaki、Kajiyama Hiroaki、Toyokuni Shinya、Hori Masaru
  • Journal Title: Plasma Processes and Polymers Volume: 20 Issue: 5 Pages: 2200193-2200193
  • DOI: 10.1002/ppap.202200193
  • Peer Reviewed / Open Access
• [Journal Article] Plasma activated Ringer’s lactate solution (2023)
  • Author(s): Tanaka Hiromasa、Mizuno Masaaki、Ishikawa Kenji、Miron Camelia、Okazaki Yasumasa、Toyokuni Shinya、Nakamura Kae、Kajiyama Hiroaki、Hori Masaru
  • Journal Title: Free Radical Research Volume: 57 Issue: 1 Pages: 14-20
  • DOI: 10.1080/10715762.2023.2182663
  • Peer Reviewed
• [Journal Article] Current understanding of plasma-activated solutions for potential cancer therapy. (2023)
  • Author(s): Yoshikawa N, Nakamura K, Kajiyama H.
  • Journal Title: Free Radic Res. Volume: - Issue: 2 Pages: 69-80
  • DOI: 10.1080/10715762.2023.2193308
  • Peer Reviewed
• [Journal Article] プラズマ活性化溶液を用いた難治性腹膜播種に対する新規治療 (2022)
  • Author(s): 芳川 修久, 中村 香江, 梶山 広明
  • Journal Title: 日本婦人科腫瘍学会雑誌 Volume: 40 Pages: 151-158
  • Peer Reviewed
• [Journal Article] Lysosomal nitric oxide determines transition from autophagy to ferroptosis after exposure to plasma-activated Ringer's lactate (2021)
  • Author(s): Jiang Li、Zheng Hao、Lyu Qinying、Hayashi Shotaro、Sato Kotaro、Sekido Yoshitaka、Nakamura Kae、Tanaka Hiromasa、Ishikawa Kenji、Kajiyama Hiroaki、Mizuno Masaaki、Hori Masaru、Toyokuni Shinya
  • Journal Title: Redox Biology Volume: 43 Pages: 101989-101989
  • DOI: 10.1016/j.redox.2021.101989
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low temperature plasma irradiation products of sodium lactate solution that induce cell death on U251SP glioblastoma cells were identified (2021)
  • Author(s): Tanaka Hiromasa、Hosoi Yugo、Ishikawa Kenji、Yoshitake Jun、Shibata Takahiro、Uchida Koji、Hashizume Hiroshi、Mizuno Masaaki、Okazaki Yasumasa、Toyokuni Shinya、Nakamura Kae、Kajiyama Hiroaki、Kikkawa Fumitaka、Hori Masaru
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41598-021-98020-w
  • Peer Reviewed / Open Access
• [Journal Article] Plasma‐activated Ringer's lactate solution inhibits the cellular respiratory system in HeLa cells (2021)
  • Author(s): Tanaka Hiromasa、Maeda Shogo、Nakamura Kae、Hashizume Hiroshi、Ishikawa Kenji、Ito Mikako、Ohno Kinji、Mizuno Masaaki、Motooka Yashiro、Okazaki Yasumasa、Toyokuni Shinya、Kajiyama Hiroaki、Kikkawa Fumitaka、Hori Masaru
  • Journal Title: Plasma Processes and Polymers Volume: 18 Issue: 10 Pages: 2100056-2100056
  • DOI: 10.1002/ppap.202100056
  • Peer Reviewed / Open Access
• [Journal Article] Pro‐tumoral behavior of omental adipocyte‐derived fibroblasts in tumor microenvironment at the metastatic site of ovarian cancer (2021)
  • Author(s): Iyoshi Shohei、Yoshihara Masato、Nakamura Kae、Sugiyama Mai、Koya Yoshihiro、Kitami Kazuhisa、Uno Kaname、Mogi Kazumasa、Tano Sho、Tomita Hiroyuki、Kajiwara Keiji、Taki Masayasu、Yamaguchi Shigehiro、Nawa Akihiro、Kajiyama Hiroaki
  • Journal Title: International Journal of Cancer Volume: 149 Issue: 11 Pages: 1961-1972
  • DOI: 10.1002/ijc.33770
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Enhancement of ethanol production and cell growth in budding yeast by direct irradiation of low-temperature plasma (2021)
  • Author(s): Tanaka Hiromasa、Matsumura Shogo、Ishikawa Kenji、Hashizume Hiroshi、Ito Masafumi、Nakamura Kae、Kajiyama Hiroaki、Kikkawa Fumitaka、Ito Mikako、Ohno Kinji、Okazaki Yasumasa、Toyokuni Shinya、Mizuno Masaaki、Hori Masaru
  • Journal Title: Japanese Journal of Applied Physics Volume: 61 Issue: SA Pages: SA1007-SA1007
  • DOI: 10.35848/1347-4065/ac2037
  • Peer Reviewed / Open Access
• [Journal Article] Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy (2021)
  • Author(s): Nakamura Kae、Yoshikawa Nobuhisa、Mizuno Yuko、Ito Miwa、Tanaka Hiromasa、Mizuno Masaaki、Toyokuni Shinya、Hori Masaru、Kikkawa Fumitaka、Kajiyama Hiroaki
  • Journal Title: Cancers Volume: 13 Issue: 5 Pages: 1141-1141
  • DOI: 10.3390/cancers13051141
  • Peer Reviewed / Open Access
• [Journal Article] Non-thermal plasma?activated lactate solution kills U251SP glioblastoma cells in an innate reductive manner with altered metabolism (2020)
  • Author(s): Ishikawa Kenji、Hosoi Yugo、Tanaka Hiromasa、Jiang Li、Toyokuni Shinya、Nakamura Kae、Kajiyama Hiroaki、Kikkawa Fumitaka、Mizuno Masaaki、Hori Masaru
  • Journal Title: Archives of Biochemistry and Biophysics Volume: 688 Pages: 108414-108414
  • DOI: 10.1016/j.abb.2020.108414
  • Peer Reviewed
• [Journal Article] Adjusted multiple gases in the plasma flow induce differential antitumor potentials of plasma‐activated solutions (2020)
  • Author(s): Nakamura Kae、Yoshikawa Nobuhisa、Yoshihara Masato、Ikeda Yoshiki、Higashida Akihiro、Niwa Akihiro、Jindo Takahiro、Tanaka Hiromasa、Ishikawa Kenji、Mizuno Masaaki、Toyokuni Shinya、Hori Masaru、Kikkawa Fumitaka、Kajiyama Hiroaki
  • Journal Title: Plasma Processes and Polymers Volume: 17 Issue: 10 Pages: 1900259-1900259
  • DOI: 10.1002/ppap.201900259
  • Peer Reviewed / Open Access
• [Journal Article] Increased dipeptidyl peptidase-4 accelerates chronic stress-related thrombosis in a mouse carotid artery model (2020)
  • Author(s): Jin Xianglan、Jin Chunzi、Nakamura Kae、Jin Tiefeng、Xin Minglong、Wan Ying、Yue Xueling、Jin Shengyu、Wang Hailong、Inoue Aiko、Nan Yongshan、Lin Zhenhua、Kuzuya Masafumi、Cheng Xian Wu
  • Journal Title: Journal of Hypertension Volume: 38 Issue: 8 Pages: 1504-1513
  • DOI: 10.1097/hjh.0000000000002418
  • Peer Reviewed / Open Access
• [Journal Article] Deficiency of cysteinyl cathepsin K suppresses the development of experimental intimal hyperplasia in response to chronic stress. (2020)
  • Author(s): Meng X, Piao L, Wang H, Inoue A, Huang Z, Jiang H, Nakamura K, Sasaki T, Li X, Xu W, Yu C, Hu L, Wu H, Murohara T, Shi GP, Kuzuya M, Cheng XW.
  • Journal Title: Journal of Hypertension Volume: in press Issue: 8 Pages: 1514-1524
  • DOI: 10.1097/hjh.0000000000002424
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Gene Expression Analysis of Plasma Activated Ringer’s Lactate Solution Treated Cells. (2022)
  • Author(s): H. Tanaka, M. Mizuno, K. Ishikawa, H. Hashizume, K. Nakamura, H. Kajiyama, F. Kikkawa, Y. Okazaki, S. Toyokuni, M. Hori
  • Organizer: MRS Spring Meetings & Exhibits
  • Int'l Joint Research
• [Presentation] The aqueous plasma therapy for ovarian cancer ~Aiming for controlling disseminated peritoneal metastasis~ (2022)
  • Author(s): H. Kajiyama, K. Nakamura, H. Tanaka, M. Mizuno, K. Ishikawa, S. Toyokuni, M. Hori
  • Organizer: 9th International Conference on Plasma Medicine (ICPM9)
  • Int'l Joint Research / Invited
• [Presentation] Immunostimulatory Effect of Plasma-Activated Solutions in the Intraperitoneal Environment of Ovarian Cancer. (2022)
  • Author(s): K. Nakamura, K. Sugiyama, N. Yoshikawa, M. Yoshihara, T. Matsukawa, H. Tanaka, M. Mizuno, S. Toyokuni, M. Hori and H. Kajiyama.
  • Organizer: 9th International Conference on Plasma Medicine (ICPM9)
  • Int'l Joint Research
• [Presentation] Comprehensive analysis of gene expression in PAL-treated glioblastoma cells. (2022)
  • Author(s): H. Tanaka, M. Mizuno, A. Tanaka, Y. Shibata, K. Ishikawa, H. Kondo, H. Hashizume, C. Miron, Y. Okazaki, S. Toyokuni, K. Nakamura, H. Kajiyama, F. Kikkawa, M. Hori
  • Organizer: 11th International Conference on Reactive Plasmas/2022 Gaseous Electronics Conference (ICRP-11/GEC2022)
  • Int'l Joint Research
• [Presentation] Cooperation of Poly(rC)-binding Proteins 1/2 and Glutathione in Ferroptosis Induced by Plasma-activated Ringer’s Lactate (2022)
  • Author(s): H. Zheng, L. Jiang, Q. Lyu, S. Akatsuka, Y. Motooka, Y. Sekido, K. Nakamura, H. Tanaka, K. Ishikawa, H. Kajiyama, M. Mizuno, M. Hori, S. Toyokuni.
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Impact of obesity and the role of dedifferentiated adipocytes upon peritoneal metastasis of ovarian cancer. (2022)
  • Author(s): S. Iyoshi, M. Yoshihara, K. Nakamura, A. Sumi, M. Sugiyama, Y. Koya, E. Miyamoto, H. Fujimoto, K. Mogi, K. Uno, K. Kitami, R. Emoto, S. Matsui, A. Nawa, H. Kajiyama.
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Notch signaling can be a new therapeutic target for advanced ovarian cancer (2022)
  • Author(s): M. Sugiyama, M. Yoshihara, Y. Koya, K. Kitami, K. Uno, S. Iyoshi, K. Mogi, A. Yokoi, K. Nakamura, A. Nawa, H. Kajiyama.
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] プラズマ活性乳酸リンゲル液によるマクロファージの形質発現誘導 (2022)
  • Author(s): 出野 雄大, 柏倉 慧史, 田中 宏昌, 石川 健治, 橋爪 博司, 中村 香江, 豊國 伸哉, 水野 正明, 梶山 広明, 堀 勝
  • Organizer: 第83回 応用物理学会 秋季学術講演
• [Presentation] Evaluation of Selective Anti-Cancer Effect in Plasma-Activated Ringer's Lactate Solution Produced by Regulated Surrounding Atmosphere. (2022)
  • Author(s): Ito D, Iwata N, Ishikawa K, Hashizume H, Nakamura K, Miron C, Tanaka H, Kajiyama H, Toyokuni S, Mizuno M, Hori M.
  • Organizer: ISPlasma2022/IC-PLANTS2022
• [Presentation] プラズマ照射乳酸リンゲル液の抗腫瘍成分の評価 (2022)
  • Author(s): 伊藤大貴,岩田直幸,石川健治,橋爪博司,中村香江,ミロン カメリア,田中宏昌,梶山広明,豊國伸哉,水野正明,堀 勝
  • Organizer: 第69回応用物理学会春季学術講演会
• [Presentation] Cell Death Mechanisms by Plasma Activated Medium and Plasma Activated Ringer’s Lactate Solution. (2021)
  • Author(s): Hori M, Tanaka H, Mizuno M, Ishikawa K, Nakamura K, Kajiyama H, Okazaki Y, Toyokuni S, Kikkawa F.
  • Organizer: 8th International Conference on Plasma Medicine
  • Int'l Joint Research / Invited
• [Presentation] Analysis of Cellular Respiration in Plasma-activated Solutions-treated Cancer Cells. (2021)
  • Author(s): Tanaka H, Maeda S, Mizuno M, Ishikawa K, Nakamura K, Kajiyama H, Okazaki Y, Toyokuni S, Ito M, Ohno K, Kikkawa F, Hori M.
  • Organizer: 8th International Conference on Plasma Medicine
  • Int'l Joint Research / Invited
• [Presentation] Plasma-activated Solution Promotes Wound Healing in Diabetic Mouse via Keratinocytes Activation. (2021)
  • Author(s): Nakamura K, Mizuno M, Yoshikawa N, Tanaka H, Ebisawa K, Kamei Y, Toyokuni S, Niwa A, Jindo T, Hori M, Kikkawa F, Kajiyama H.
  • Organizer: 8th International Conference on Plasma Medicine.
  • Int'l Joint Research
• [Presentation] プラズマ活性溶液及びプラズマ照射が細胞呼吸に与える影響 (2021)
  • Author(s): 田中宏昌,前田昌吾,松村 翔伍,水野正明,石川健治,伊藤昌文,橋爪博司,伊藤美佳子,大野欽司,中村香江,梶山広明,吉川史隆,岡崎泰昌,豊國伸哉,堀 勝
  • Organizer: 第82回応用物理学会秋季学術講演会
• [Presentation] Production of plasma activated Ringer s l actate solution with regulated surrounding atmosphere. (2021)
  • Author(s): Ito D, Iwata N, Ishikawa K, Hashizume H, Nakamura K, Miron C, Tanaka H, Kajiyama H, Toyokuni S, Mizuno M, Hori M
  • Organizer: 第31回 日本MRS年次大会
• [Presentation] Anti-tumor effect of plasma-activated solution produced by the flowing system. (2021)
  • Author(s): Kashiwagura S, Iwata N, Ishikawa K, Hashizume H, Miron C, Nakamura K, Tanaka H, Kajiyama H, Toyokuni S, Mizuno M, Hori M.
  • Organizer: 第31回 日本MRS年次大会
• [Remarks]
  • URL: https://profs.provost.nagoya-u.ac.jp/html/100010708_ja.html
• [Remarks] 名古屋大学 低温プラズマ科学研究センター
  • URL: https://www.plasma.nagoya-u.ac.jp/
• [Remarks] 微小な腹膜播種に対するプラズマ活性溶液の有効性を前臨床試験にて実証！
  • URL: https://www.plasma.nagoya-u.ac.jp/news/post-47.html#000091