Malignant potential of PD-L1-positive pancreatic cancer cells. Analysis of the stemness and epithelial to mesenchymal transition.

• Project/Area Number: 17K08706
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Nagoya City University (2019-2020); Aichi Medical University (2017-2018)
• Principal Investigator: Inaguma Shingo 名古屋市立大学, 医薬学総合研究院(医学), 実験病態病理学教授 (80410786)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: CD274 / 膵臓癌 / 大腸癌 / CD70 / 癌間質 / 浸潤 / 細胞増殖 / PD-L1 / 悪性形質 / ヘッジホッグ

Outline of Final Research Achievements

This study identified that PD-L1-high fraction of pancreatic and colorectal cancer cells harbor higher potentials for migration, invasion, and cellular proliferation than PD-L1-low fraction. Gene expression microarray analyses identified specifically expressed genes in PD-L1-high fraction. Among them, we have selected several genes those might be responsible for tumor stemness and epithelial-mesenchymal transition (EMT). We are now analyzing the malignant potentials of pancreatic and colorectal cancer cells those gene expressions were modulated by lentiviral vectors.
This study also identified the clinicopathological characteristics of PD-L1-positive colorectal cancer from tissue microarray analyses. Furthermore, prognostic significance of CD47, PHH3, and PBK expressions in colorectal cancer cells were identified. Also, CD70 expression in tumor-associated fibroblasts was identified as a worse prognostic factor in colorectal cancer patients.

Academic Significance and Societal Importance of the Research Achievements

現在、様々な固形腫瘍において、PD-1/PD-L1シグナルを標的とした分子標的治療薬が用いられているものの、単剤では腫瘍の治癒には至っておらず、他の分子標的治療薬との併用療法の重要性が示唆されている。本研究において、膵臓癌、および大腸癌におけるPD-L1高発現分画が高い悪性度を有していること、また、その分画において特異的に発現する遺伝子群を同定したことで、それらの遺伝子が新規併用療法の標的となる可能性を有していると考えられた。
また、腫瘍組織アレイを用いた発現解析より同定された予後因子群に関しても、今後、それらの分子メカニズムを解析することで、新たな治療標的となりうると考えている。

Research Products

• [Int'l Joint Research] National Cancer Institute/NIH(米国)
• [Int'l Joint Research] National Cancer Institute(米国)
• [Int'l Joint Research] Medical University of Gdansk/Nat. Tuber. and Lung Dis. Res. Inst./Maria Sklodowska-Curie Memorial Inst.(ポーランド)
• [Int'l Joint Research] Otto-von-Guericke University Magdeburg(ドイツ)
• [Int'l Joint Research] National Institutes of Health/National Cancer Institute/Laboratory of Pathology(米国)
• [Int'l Joint Research] National Institutes of Health/National Cancer Institute/Laboratory of Pathology(米国)
• [Int'l Joint Research]
• [Journal Article] High phospho-histone H3 expression uniquely predicts favorable survival among four markers of cellular proliferation in colorectal cancer. (2021)
  • Author(s): Koshino A, Inoue S, Sugimura-Nagata A, Nishiyama T, Murakami H, Ito H, Riku M, Inoko A, Ebi M, Ogasawara N, Tsuzuki T, Kasugai K, Kasai K, Inaguma S.
  • Journal Title: Pathol Int. Volume: - Issue: 5 Pages: 2690-2690
  • DOI: 10.1111/pin.13084
  • Peer Reviewed / Open Access
• [Journal Article] PBK expression predicts favorable survival in colorectal cancer patients (2021)
  • Author(s): Nagano-Matsuo A, Inoue S, Koshino A, Ota A, Nakao K, Komura M, Kato H, Naiki-Ito A, Watanabe K, Nagayasu Y, Hosokawa Y, Takiguchi S, Kasugai K, Kasai K, Inaguma S, Takahashi S
  • Journal Title: Virchows Archiv Volume: - Issue: 2 Pages: 277-284
  • DOI: 10.1007/s00428-021-03062-0
  • Peer Reviewed / Open Access
• [Journal Article] Expression and Prognostic Significance of CD47-SIRPA Macrophage Checkpoint Molecules in Colorectal Cancer (2021)
  • Author(s): Sugimura-Nagata A, Koshino A, Inoue S, Matsuo-Nagano A, Komura M, Riku M, Ito H, Inoko A, Murakami H, Ebi M, Ogasawara N, Tsuzuki T, Takahashi S, Kasugai K, Kasai K, Inaguma S
  • Journal Title: International Journal of Molecular Science Volume: 22 Issue: 5 Pages: 2690-2690
  • DOI: 10.3390/ijms22052690
  • Peer Reviewed / Open Access
• [Journal Article] Colorectal Adenocarcinomas Harboring ALK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 12 Cases and Review of the Literature. (2021)
  • Author(s): Lasota J, Inaguma S, Izycka-Swieszewska E, Kaczorowski M, Kolos M, Kopczynski J, Michal M, Milione M, Okon K, Peksa R, Pyzlak M, Rys J, Waloszczyk P, Wejman J, Miettinen M.
  • Journal Title: Am J Surg Pathol. Volume: 44(9) Issue: 9 Pages: 1224-1234
  • DOI: 10.1097/pas.0000000000001512
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Diffuse mesothelin expression leads to worse prognosis through enhanced cellular proliferation in colorectal cancer. (2020)
  • Author(s): Inoue S, Tsunoda T, Riku M, Ito H, Inoko A, Murakami H, Ebi M, Ogasawara N, Pastan I, Kasugai K, Kasai K, Ikeda H, Inaguma S.
  • Journal Title: Oncol Lett. Volume: 19(3) Pages: 1741-1750
  • DOI: 10.3892/ol.2020.11290
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness. (2020)
  • Author(s): Inaguma S, Lasota J, Czapiewski P, Langfort R, Rys J, Szpor J, Waloszczyk P, Okon; K, Biernat W, Schrump DS, Hassan R, Kasai K, Miettinen M, Ikeda H.
  • Journal Title: J Pathol. Volume: 250(2) Issue: 2 Pages: 205-216
  • DOI: 10.1002/path.5361
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Colonic Adenocarcinomas Harboring NTRK Fusion Genes: A Clinicopathologic and Molecular Genetic Study of 16 Cases and Review of the Literature. (2020)
  • Author(s): Lasota J, Chlopek M, Lamoureux J, Christiansen J, Kowalik A, Wasag B, Felisiak-Golabek A, Agaimy A, Biernat W, Canzonieri V, Centonze G, Chmielik E, Daum O, Dubova M, Dziuba I, Goertz S, Gozdz S, Guttmejer-Nasierowska A, Haglund C, Halon A, Hartmann A, Inaguma S, Miettinen M et. al.
  • Journal Title: Am J Surg Pathol. Volume: 44(2) Issue: 2 Pages: 162-173
  • DOI: 10.1097/pas.0000000000001377
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD70 expression in tumor-associated fibroblasts predicts worse survival in colorectal cancer patients (2019)
  • Author(s): Inoue Satoshi、Ito Hideaki、Tsunoda Takumi、Murakami Hideki、Ebi Masahide、Ogasawara Naotaka、Kasugai Kunio、Kasai Kenji、Ikeda Hiroshi、Inaguma Shingo
  • Journal Title: Virchows Archiv Volume: 000 Issue: 4 Pages: 000-000
  • DOI: 10.1007/s00428-019-02565-1
  • Peer Reviewed / Open Access
• [Journal Article] Histopathological and genotypic characterization of metastatic colorectal carcinoma with PD-L1 (CD274)-expression: Possible roles of tumour micro environmental factors for CD274 expression. (2017)
  • Author(s): Inaguma S., Lasota J., Felisiak-Golabek A., Kowalik A., Wang Z., Zieba S., Kalisz J., Ikeda H., Miettinen M.
  • Journal Title: J Pathol Clin Res. Volume: 3(4) Issue: 4 Pages: 268-278
  • DOI: 10.1002/cjp2.81
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CD70分子はMET-ERK経路の活性化、腫瘍細胞の免疫逃避亢進により悪性胸膜中皮腫患者の予後を悪化させる (2020)
  • Author(s): 稲熊真悟、Jerzy Lasota, 池田 洋、笠井謙次、Markku Miettinen、高橋 智
  • Organizer: 日本病理学会
• [Presentation] Inaguma S., Inoue S., Ito H., Tsunoda T., Murakami H., Kasugai K., Kasai K., Ikeda H. (2019)
  • Author(s): Expression analysis of CD70, CD27 and FOXP3 with an evaluation of their prognostic values in colorectal cancer.
  • Organizer: United States and Canadian Academy of Pathology
  • Int'l Joint Research
• [Presentation] CD70 upregulates migration and invasion of malignant pleural mesothelioma cells through ERK pathway. (2019)
  • Author(s): Inaguma S., Lasota J., Tsunoda T., Ito H., Murakami H., Kasai K., Miettinen M., Ikeda H.
  • Organizer: 日本病理学会
• [Presentation] CD70 expression in tumor-associated fibroblasts predicts worse survival in colorectal cancer patients. (2019)
  • Author(s): Inoue S., Ito H., Tsunoda T., Murakami H., Ebi M., Ogasawara N., Kasugai K., Kasai K., Ikeda H., Inaguma S.
  • Organizer: 日本病理学会