Why cancer cells metastasize to lymphatics from the early stage ?

• Project/Area Number: 19K07676
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Kawasaki Medical School
• Principal Investigator: Yamauchi Akira 川崎医科大学, 医学部, 教授 (80372431)
• Co-Investigator(Kenkyū-buntansha): 岡本 秀一郎 川崎医科大学, 医学部, 講師 (10529035) ; 山村 真弘 川崎医科大学, 医学部, 講師 (70299204) ; 片瀬 直樹 長崎大学, 医歯薬学総合研究科(歯学系), 助教 (30566071) ; 阪口 政清 岡山大学, 医歯薬学総合研究科, 教授 (70379840) ; 栗林 太 川崎医科大学, 医学部, 教授 (60251443)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 癌転移 / リンパ内皮細胞 / S100 protein / 走化性 / 細胞動態 / マイクロアレイ / リンパ向性転移 / 活性酸素 / S100タンパク質 / リンパ組織 / 膵癌

Outline of Research at the Start

癌では初期からリンパ節転移が観られステージ分類や治療方針に影響しているが、リンパ組織に侵入する機序は詳しく分かっていない。本研究の目的は、癌細胞がリンパ向性転移する際に作用する分子を探索・同定することにより癌細胞のリンパ管起始部に侵入する機序を解明することである。リンパ向性転移因子が明らかになれば、癌転移を制御することにより癌治療に貢献できる。
我々は独自に開発してきた細胞解析法を用いて癌の動態を解析してきた。最近、炎症に関わるS100タンパク質が癌細胞の遊走を活性化する姿を捉えることに成功した。これは何らかの“リンパ向性転移因子”が存在することを示しており、これを明らかにしたいと考えている。

Outline of Final Research Achievements

Lymphotropic metastasis of cancer closely relates to the prognosis, however, little is known about the mechanism how cancer cells invade into lymphatics. S100 proteins are known to be produced in inflammatory tissues and has been pointed out to be related to cancer metastasis. In this study, we analyzed the interaction of cancer cells and lymphatic endothelial cells using our own technology to clarify the mechanism. The cell dynamics assay showed that S100A8-stimulated human lymphatic endothelial cells enhanced the migration of human pancreatic cancer cells. The DNA microarray using the samples from S100A8-stimulated human lymphatic endothelial cells showed that various DNA-binding proteins and transcriptional factors were up- or down-regulated. Also EMT, CAF, chemokine productions were shown to be correlated to the cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

本研究から得られる成果は、癌転移の機序解明に貢献すると共に、新規治療ターゲットおよび新規バイオマーカーとして将来の癌診療に応用できることが期待される。リンパ向性転移を抑制できれば転移克服に大きく近づき、生命予後を大幅に改善できることが予想される。

Research Products

• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] University of Oxford(英国)
• [Int'l Joint Research] University of Oxford(英国)
• [Journal Article] Fine definition of the epitopes on the human gp91 phox/NOX2 for the monoclonal antibodies CL-5 and 48 (2022)
  • Author(s): Kawai C, Miyano K, Okamoto S, Yamauchi A, Kuribayashi F.
  • Journal Title: Journal of Immunological Methods Volume: 501 Pages: 113213-113213
  • DOI: 10.1016/j.jim.2021.113213
  • Peer Reviewed / Open Access
• [Journal Article] The downregulation of NADPH oxidase Nox4 during hypoxia in hemangioendothelioma cells: a possible role of p22 phox on Nox4 protein stability (2021)
  • Author(s): Miyano K, Okamoto S, Yamauchi A, Kawai C, Kajikawa M, Kiyohara T, Itsumi M, Taura M, Kuribayashi F.
  • Journal Title: Free Radical Research Volume: 55 Issue: 9-10 Pages: 996-1004
  • DOI: 10.1080/10715762.2021.2009116
  • Peer Reviewed
• [Journal Article] Nanoparticle-Mediated Delivery of 2-Deoxy-D-Glucose Induces Antitumor Immunity and Cytotoxicity in Liver Tumors in Mice (2021)
  • Author(s): Sasaki Kyo、Nishina Sohji、Yamauchi Akira、Fukuda Kotaro、Hara Yuichi、Yamamura Masahiro、Egashira Kensuke、Hino Keisuke
  • Journal Title: Cellular and Molecular Gastroenterology and Hepatology Volume: 11 Issue: 3 Pages: 739-762
  • DOI: 10.1016/j.jcmgh.2020.10.010
  • Peer Reviewed / Open Access
• [Journal Article] The rRNA synthesis inhibitor CX-5461 may induce autophagy that inhibits anticancer drug-induced cell damage to leukemia cells (2020)
  • Author(s): Okamoto Shuichiro、Miyano Kei、Kajikawa Mizuho、Yamauchi Akira、Kuribayashi Futoshi
  • Journal Title: Bioscience, Biotechnology, and Biochemistry Volume: 84 Issue: 11 Pages: 2319-2326
  • DOI: 10.1080/09168451.2020.1801378
  • Peer Reviewed
• [Journal Article] Constitutive activity of NADPH oxidase 1 (Nox1) that promotes its own activity suppresses the colon epithelial cell migration (2020)
  • Author(s): Miyano Kei、Okamoto Shuichiro、Yamauchi Akira、Kajikawa Mizuho、Kiyohara Takuya、Taura Masahiko、Kawai Chikage、Kuribayashi Futoshi
  • Journal Title: Free Radical Research Volume: 54 Issue: 8-9 Pages: 640-648
  • DOI: 10.1080/10715762.2020.1823383
  • Peer Reviewed
• [Journal Article] Inhibitory Effect of Eicosapentaenoic Acid on the Migration of the Esophageal Squamous Cell Carcinoma Cell Line TE-1 (2020)
  • Author(s): KUBOTA HISAKO、HIRAI TOSHIHIRO、YAMAUCHI AKIRA、OGO AYAKO、MATSUMOTO HIDEO、UENO TOMIO
  • Journal Title: Anticancer Research Volume: 40 Issue: 9 Pages: 5043-5048
  • DOI: 10.21873/anticanres.14507
  • Peer Reviewed
• [Journal Article] The NADPH oxidase NOX4 promotes the directed migration of endothelial cells by stabilizing vascular endothelial growth factor receptor 2 protein (2020)
  • Author(s): Miyano Kei、Okamoto Shuichiro、Yamauchi Akira、Kawai Chikage、Kajikawa Mizuho、Kiyohara Takuya、Tamura Minoru、Taura Masahiko、Kuribayashi Futoshi
  • Journal Title: Journal of Biological Chemistry Volume: 295 Issue: 33 Pages: 11877-11890
  • DOI: 10.1074/jbc.ra120.014723
  • Peer Reviewed / Open Access
• [Journal Article] Neuroplastinβ-mediated upregulation of solute carrier family 22 member 18 antisense (SLC22A18AS) plays a crucial role in the epithelial-mesenchymal transition, leading to lung cancer cells' enhanced motility (2020)
  • Author(s): Bajkowska Karolina、Sumardika I. Wayan、Tomonobu Nahoko、Chen Youyi、Yamamoto Ken-ichi、Kinoshita Rie、Murata Hitoshi、Gede Yoni Komalasari Ni Luh、Jiang Fan、Yamauchi Akira、Winarsa Ruma I. Made、Kasano-Camones Carlos Ichiro、Inoue Yusuke、Sakaguchi Masakiyo
  • Journal Title: Biochemistry and Biophysics Reports Volume: 22 Pages: 100768-100768
  • DOI: 10.1016/j.bbrep.2020.100768
  • NAID: 120006890008
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts (2019)
  • Author(s): Mitsui Yosuke、Tomonobu Nahoko、Watanabe Masami、Kinoshita Rie、Sumardika I Wayan、Youyi Chen、Murata Hitoshi et al.
  • Journal Title: Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics Volume: 27 Issue: 8 Pages: 945-956
  • DOI: 10.3727/096504019x15555408784978
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Convenient methodology for extraction and subsequent selective propagation of mouse melanocytes in culture from adult mouse skin tissue. (2019)
  • Author(s): Tomonobu N, Kinoshita R, Sumardika IW, Chen Y, Inoue Y, Yamauchi A, Yamamoto KI, Murata H, Sakaguchi M
  • Journal Title: Biochem Biophys Rep. Volume: - Pages: 100619-100619
  • DOI: 10.1016/j.bbrep.2019.100619
  • NAID: 120006948964
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Critical role of the MCAM-ETV4 axis triggered by extracellular S100A8/A9 in breast cancer aggressiveness. (2019)
  • Author(s): Chen Y, Sumardika IW, Tomonobu N, Kinoshita R, Inoue Y, Iioka H, Mitsui Y, Saito K, Ruma IMW, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Kubo M, Putranto EW, Murakami T, Liu M, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Neoplasia. Volume: 21(7) Issue: 7 Pages: 627-640
  • DOI: 10.1016/j.neo.2019.04.006
  • NAID: 120006948963
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Melanoma cell adhesion molecule is the driving force behind the dissemination of melanoma upon S100A8/A9 binding in the original skin lesion. (2019)
  • Author(s): Chen Y, Sumardika IW, Tomonobu N, Winarsa Ruma IM, Kinoshita R, Kondo E, Inoue Y, Sato H, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Liu M, Futami J, Sasai K, Katayama H, Kubo M, Putranto EW, Hibino T, Sun B, Nishibori M, Toyooka S, Sakaguchi M
  • Journal Title: Cancer Lett. Volume: - Pages: 178-190
  • DOI: 10.1016/j.canlet.2019.03.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis. (2018)
  • Author(s): Kinoshita R, Sato H, Yamauchi A, Takahashi Y, Inoue Y, Sumardika IW, Chen Y, Tomonobu N, Araki K, Shien K, Tomida S, Torigoe H, Namba K, Kurihara E, Ogoshi Y, Murata H, Yamamoto KI, Futami J, Putranto EW, Ruma IMW, Yamamoto H, Soh J, Hibino T, Nishibori M, Kondo E, Toyooka S, Sakaguchi M.
  • Journal Title: Int J Cancer. Volume: 印刷中 Issue: 2 Pages: 569-575
  • DOI: 10.1002/ijc.31982
  • Peer Reviewed / Int'l Joint Research
• [Presentation] NOX4 on lymphatic endothelial cells (LEC) plays an important role on the migration of pancreatic cancer cells. (2020)
  • Author(s): Akira Yamauchi, Masahiro Yamamura, Naoki Katase, Nahoko Tomonobu, Rie Kinoshita, Masakiyo Sakaguchi, and Shuichiro Okamoto
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Nox1は、消化管粘膜損傷の回復に必須の上皮細胞遊走を調節する (2020)
  • Author(s): 宮野 佳、岡本 秀一郎、山内 明、 梶川 瑞穂、川井 千景、栗林 太
  • Organizer: 第31回日本生体防御学会学術総会
• [Presentation] HSP90 inhibitor inhibit the activation of multiple kinase pathways and migration of pancreatic cancer cells (2019)
  • Author(s): Yamamura M, Yamauchi A, Katase N, Yamaguchi Y.
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] ヒト末梢血由来制御性T細胞の走化性はLEMによって抑制される (2019)
  • Author(s): Yamauchi A, Kajiyama S.
  • Organizer: 第48回日本免疫学会学術集会
• [Presentation] Novel therapeutic approach based on S100A8/A9-mediated organ tropic cancer metastasis. (2019)
  • Author(s): Kinoshita R, Tomonobu N, Yamauchi A, Shien K, Tomida S, Murata H, Futami J, Kondo E, Toyooka S, Sakaguchi M.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Melanoma cell adhesion malecule (MCAM) induces dissemination of melanoma upon S100A8/S9 binding. (2019)
  • Author(s): Tomonobu N, Kinoshita R, Kondo E, Yamauchi A, Futami J, Toyooka S, Sakaguchi M.
  • Organizer: 第78回日本癌学会学術総会
• [Remarks] 川崎医科大学 生化学教室
  • URL: https://m.kawasaki-m.ac.jp/classroom/course.php?id=203
• [Remarks] Reasearchmap
  • URL: https://researchmap.jp/akiranik