Biological role of CD280 in cancer metastasis-initiating cell

• Project/Area Number: 16H04697
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Aichi Gakuin University
• Principal Investigator: TAKEI YOSHIFUMI 愛知学院大学, 薬学部, 教授 (70362233)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥15,990,000 (Direct Cost: ¥12,300,000、Indirect Cost: ¥3,690,000); Fiscal Year 2018: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 癌転移 / スキルス胃癌 / 腹膜転移 / 分子標的 / 癌治療 / シングルセル解析 / 間質 / 細胞表面マーカー / 幹細胞性 / 診断マーカー / 分子標的治療 / 癌転移開始細胞 / バイオマーカー / 治療 / 胃癌 / 前立腺癌 / 結腸癌 / 膵臓癌 / 同所性移植

Outline of Final Research Achievements

The concept of metastasis-initiating cells (MICs) has been proposed. MICs originate in the primary tumors and are considered special cells to promote cancer metastasis. However, MICs have not been investigated in detail. We successfully isolated MICs from primary cancer tissues of a scirrhous gastric cancer patient, and then knocked out CD280 expression via genome editing methods. The CD280-deficient MICs showed the decreased proliferation, colony formation, and invasion activity compared with CD280 wild-type MICs. CD280 is a novel target to inhibit cancer metastasis.

Academic Significance and Societal Importance of the Research Achievements

癌転移研究は大変遅れている。その理由に、癌転移の良いモデルがない現状がある。我々は、癌転移でメインプレーヤーとなる癌転移開始細胞（MIC）を、スキルス胃癌患者から成功裡に単離した。その解析から、CD280がMICの機能維持に重要で、癌転移抑制に有用な新規標的であることが分かった。癌の死因の大半は癌転移による。故に癌患者の予後において、癌転移抑止医療が大切になる。本成果は、癌転移抑止医療の実現に繋がる社会的意義を有する。

Research Products

• [Journal Article] TGF-β1-VEGF-A pathway induces neoaniogenesis with peritoneal fibrosis in patients undergoing pertoneal dialysis. (2018)
  • Author(s): Kariya T., Nishimura H., Mizuno M., Suzuki Y, Matsukawa Y., Sakata F., Maruyama S., Takei Y., Ito Y.
  • Journal Title: Am J Physiol Renal Physiol. Volume: 314 Issue: 2 Pages: F167-F180
  • DOI: 10.1152/ajprenal.00052.2017
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNAs Associated with Epithelial-Mesenchymal Transition Can Be Targeted to Inhibit Peritoneal Dissemination of Human Scirrhous Gastric Cancers (2018)
  • Author(s): Takei Y, Shen G, Morita-Kondo A, Hara T, Mihara K, Yanagihara K
  • Journal Title: Pathobiology Volume: 85 Issue: 4 Pages: 232-246
  • DOI: 10.1159/000488801
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Combined anti-metastasis therapy of an siRNA-based medicine and ABT-263 in orthotopically xenografted prostate cancer model mice. (2018)
  • Author(s): Takei Y*, Yuan Y, Suzuki A, Mihara K.
  • Journal Title: Medical Research Archives Volume: 6 Pages: 1-10
  • Peer Reviewed / Open Access
• [Journal Article] Roles of the TGFb-VEGF-C pathway in fibrosis-related lymphangiogenesis. (2018)
  • Author(s): Kinashi H, Ito Y, Sun T, Katsuno T, Takei Y.
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 9 Pages: 2487-2487
  • DOI: 10.3390/ijms19092487
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sodium chloride promotes tissue inflammation via osmotic stimuli in sub-total-nephrectomized mice. (2017)
  • Author(s): Sakata F., Ito Y., Mizuno M, Sawai A, Suzuki Y, Tomita T, Tawada M, Tanaka A, Hirayama A, Sagara A, Wada T, Maruyama S, Soga T, Matsuo S, Imai E, Takei Y.
  • Journal Title: Lab Invest Volume: 97(4) Issue: 4 Pages: 432-446
  • DOI: 10.1038/labinvest.2017.4
  • Peer Reviewed / Open Access
• [Journal Article] T cells bearing anti-CD19 and/or anti-CD38 chimeric antigen receptors effectively abrogate primary double-hit lymphoma cells (2017)
  • Author(s): Mihara K, Yoshida T, Takei Y, Sasaki N, Takihara Y, Kuroda J, Ichinohe T.
  • Journal Title: J Hematol Oncol Volume: 10 Issue: 1 Pages: 116-116
  • DOI: 10.1186/s13045-017-0488-x
  • Peer Reviewed
• [Journal Article] Apoptosis inhibitor of macrophage ameliorates fungus-induced peritoneal injury model in mice (2017)
  • Author(s): Tomita T, Arai S, Kitada K, Mizuno M, Suzuki Y, Sakata F, Nakano D, Hiramoto E, Takei Y, Maruyama S, Nishiyama A, Matsuo S, Miyazaki T, Ito Y.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 6450-6450
  • DOI: 10.1038/s41598-017-06824-6
  • Peer Reviewed / Open Access
• [Journal Article] The microRNA miR-516a-3p regulates the Wnt pathway by targeting extracellular sulfatase 1 in human scirrhous gastric cancers: Anti-metastatic therapy via miRNA-based medicine (2017)
  • Author(s): Takei Y, Suzuki A, Mihara K, Yanagihara K.
  • Journal Title: Med Res Arch Volume: 5 Pages: 1-19
  • Peer Reviewed / Open Access
• [Journal Article] Vascular endothelial cell injury is an important factor in the development of encapsulating peritoneal sclerosis in long-term peritoneal dialysis patients. (2016)
  • Author(s): Tawada M, Ito Y, Hamada C, Honda K, Mizuno M, Suzuki Y, Sakata F, Terabayashi T, Matsukawa Y, Maruyama S, Imai E, Matsuo S, Takei Y.
  • Journal Title: PLoS One Volume: 11 Issue: 4 Pages: e0154644-e0154644
  • DOI: 10.1371/journal.pone.0154644
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A therapeutic trail of human melanoma with combined small interfering RNAs targeting adaptor molecules p130Cas and paxillin activated under expression of ganglioside GD3. (2016)
  • Author(s): Makino Y, Hamamura K, Takei Y, Bhuiyan RH, Ohkawa Y, Ohmi Y, Nakashima H, Furukawa K, Furukawa K.
  • Journal Title: Biochimica et Biophysica Acta Volume: in press Issue: 8 Pages: 1753-1763
  • DOI: 10.1016/j.bbagen.2016.04.005
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] All-trans retinoic acid and interferon-α increase CD38 expression on adult T-cell leukemia cells and sensitize them to T cells bearing anti-CD38 chimeric antigen receptors. (2016)
  • Author(s): Mihara K, Yoshida T, Ishida S, Takei Y, Kitanaka A, Shimoda K, Morishita K, Takihara Y, Ichinohe T.
  • Journal Title: Blood Cancer J Volume: 6 Issue: 5 Pages: e421-e421
  • DOI: 10.1038/bcj.2016.30
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] All-trans retinoic acid enhances cytotoxic effect of T cells with an anti-CD38 chimeric antigen receptor in acute myeloid leukemia. (2016)
  • Author(s): Yoshida T, Mihara K, Takei Y, Yanagihara K, Kubo T, Bhattacharyya J, Imai C, Mino T, Takihara Y, Ichinohe T.
  • Journal Title: Clin Trans Immunol Volume: 5 Issue: 12
  • DOI: 10.1038/cti.2016.73
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] スキルス胃癌の腹膜転移制御におけるlong non-coding RNA(lncRNA)の機能解析 (2018)
  • Author(s): 山口優紀、原敏文、森田あや美、武井佳史
  • Organizer: 第64回日本薬学会東海支部 総会・大会
• [Presentation] スキルス胃癌の転移を標的とした化合物スクリーニング方法の確立と一次スクリーニングの結果 (2018)
  • Author(s): 野村有紀、原敏文、森田あや美、小幡徹、田中基裕、武井佳史
  • Organizer: 第64回日本薬学会東海支部 総会・大会
• [Presentation] スキルス胃癌の腹膜転移制御におけるGalectin 4の役割 (2018)
  • Author(s): 森田あや美、吉見一志、原敏文、武井佳史
  • Organizer: 日本薬学会第138年会
• [Presentation] スキルス胃癌の腹膜転移機構の解明に関する研究 (2018)
  • Author(s): 服部真晃、原敏文、森田あや美、武井佳史
  • Organizer: 日本薬学会第138年会
• [Presentation] スキルス胃癌の腹膜転移に関わる遺伝子の機能解析 (2018)
  • Author(s): 花井檀、原敏文、森田あや美、武井佳史
  • Organizer: 日本薬学会第138年会
• [Presentation] スキルス胃癌の転移に伴い発現変動する遺伝子シグネチャーの同定とそれら遺伝子の機能解析 (2018)
  • Author(s): 原敏文、服部真晃、花井檀、森田あや美、武井佳史
  • Organizer: 第82回日本生化学会中部支部例会・シンポジウム
• [Presentation] スキルス胃がんの腹膜転移に伴い発現変動するlncRNAの同定とその機能解析 (2018)
  • Author(s): 原敏文、柳原五吉、武井佳史
  • Organizer: 第20回日本RNA学会年会
• [Presentation] ヒトスキルス胃がんの腹膜転移に関わる長鎖非コードRNAシグネチャーの解析 (2018)
  • Author(s): 原敏文、柳原五吉、武井佳史
  • Organizer: 第７７回 日本癌学会学術総会
• [Presentation] スキルス胃癌患者由来のリンパ行性転移細胞株の樹立とその抗転移療法への応用 (2017)
  • Author(s): 武井佳史、原敏文、落谷孝広、柳原五吉
  • Organizer: 第７６回 日本癌学会学術総会
• [Presentation] ヒトスキルス胃がんの網羅的転写解析による新たな転移シグネチャーの抽出 (2017)
  • Author(s): 原敏文、柳原五吉、武井佳史
  • Organizer: 第７６回 日本癌学会学術総会
• [Presentation] スキルス胃癌の腹膜転移を制御する代謝酵素の解析 (2016)
  • Author(s): 鈴木亜希子、三原圭一朗、柳原五吉、武井佳史
  • Organizer: 第８９回日本生化学会大会
  • Place of Presentation: 仙台国際センター（宮城県仙台市）
  • Year and Date: 2016-09-25