Elucidation of alteration of tumor microenvironment for drug resistance in lung cancer

• Project/Area Number: 17K16606
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• Research Institution: Osaka University
• Principal Investigator: KANZAKI RYU 大阪大学, 医学系研究科, 助教 (10779060)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肺癌 / 化学療法 / 腫瘍微小環境 / 癌関連線維芽細胞 / PDGFR-β / 手術 / 癌関連間質細胞 / 外科 / 癌

Outline of Final Research Achievements

Relationships between stromal PDGFR-β expression and survival after operation were analyzed in patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy. Stromal PDGFR-β expression is negatively associated with worse outcomes in these patients. We assessed alterations of tumor microenvironment using cancer-associated fibroblast (CAF) cell line established from resected specimen and mouse model. We found that Gas6 expression by CAFs was upregulated following cisplatin treatment and Gas 6 derived from CAFs promote Axl-expressing lung cancer cells. In clinical samples, stromal Gas6 expression increased after chemotherapy and tumor Axl- and stromal Gas6-positive tumors were significantly worse than for the double negative group. Based on these findings, it is presumed that Gas6 derived from CAFs promotes migration of Axl-expressing lung cancer cells during chemotherapy and is involved in poor clinical outcome.

Academic Significance and Societal Importance of the Research Achievements

肺癌は我が国の死因の首位であり、その治療成績の改善はは喫緊の課題である。肺癌の主たる治療方法の一つに化学療法があるが、抗癌剤を使い続けると癌は薬剤耐性を示し転移能を獲得することが知られており、この現象に癌間質の関与が示唆されている。今回我々は、癌関連線維芽細胞が抗癌剤治療時に癌細胞の悪性化を促す可能性を示唆する機序の一つを解明した。この結果、癌細胞そのものではなく、腫瘍微小環境を構成する細胞が治療のターゲットとなりうる可能性が示唆された。今後腫瘍微小環境をターゲットとした新規治療法の開発が期待される。

Research Products

• [Journal Article] Stromal PDGFR-β Expression is Associated with Postoperative Survival of Non-Small Cell Lung Cancer Patients Receiving Preoperative Chemo- or Chemoradiotherapy Followed by Surgery (2018)
  • Author(s): Kanzaki Ryu、Ose Naoko、Kawamura Tomohiro、Funaki Soichiro、Shintani Yasushi、Minami Masato、Takakura Nobuyuki、Okumura Meinoshin
  • Journal Title: World Journal of Surgery Volume: 印刷中 Issue: 9 Pages: 2879-2886
  • DOI: 10.1007/s00268-018-4560-7
  • Peer Reviewed
• [Journal Article] Gas6 derived from cancer-associated fibroblasts promotes migration of Axl-expressing lung cancer cells during chemotherapy. (2017)
  • Author(s): Kanzaki R, Naito H, Kise K, Takara K, Eino D, Minami M, Shintani Y, Funaki S, Kawamura T, Kimura T, Okumura M, Takakura N.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 10613-10613
  • DOI: 10.1038/s41598-017-10873-2
  • Peer Reviewed / Open Access
• [Journal Article] Chemotherapy enhances programmed cell death 1/ligand 1 expression via TGF-β induced epithelial mesenchymal transition in non-small cell lung cancer. (2017)
  • Author(s): Funaki S, Shintani Y, Kawamura T, Kanzaki R, Minami M, Okumura M.
  • Journal Title: Oncology Report Volume: 38 Issue: 4 Pages: 2277-2284
  • DOI: 10.3892/or.2017.5894
  • Peer Reviewed
• [Presentation] cT3-4非小細胞肺癌に対する術前化学放射線療法後肺切除の検討 (2018)
  • Author(s): 神崎隆、大瀬尚子、川村知裕、舟木壮一郎、新谷康、南正人、奥村明之進
  • Organizer: 第71回日本胸部外科学会定期学術集会
• [Presentation] Stromal PDGFR-β expression influences postoperative survival of non-small cell lung cancer patients receiving preoperative chemo- or chemo-radiotherapy (2017)
  • Author(s): Kanzaki R, Naito H, Eino D, Kawamura T, Ose N, Funaki S, Shintani Y, Minami M,Okumura M, Takakura N.
  • Organizer: 18th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] 非小細胞性肺癌におけるPD-L1発現制御について (2017)
  • Author(s): 舟木壮一郎、福井絵里子、川村知裕、神崎 隆、新谷 康、南 正人、奥村明之進
  • Organizer: 第117回日本外科学会定期学術集会
• [Presentation] 免疫チェックポイント経路PD-1/PD-L1の発現制御による肺癌治療法の確立 (2017)
  • Author(s): 舟木壮一郎、福井絵里子、川村知裕、神崎 隆、新谷 康、南 正人、奥村明之進
  • Organizer: 第34回日本呼吸器外科学会総会
• [Presentation] Prognostic impact of Programmed cell death-1 (PD-1) tumor-infiltrating lymphocytes and Programmed cell death-1 -ligand 1 (PD-L1) expression in thymic cancer (2017)
  • Author(s): Funaki S, Shintani Y, Ose N, T. Kawamura T, Kanzaki R, Minami M, Okumura M
  • Organizer: 18th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Effects of pirfenidone targeting EMT and tumor-stroma interaction as novel treatment for non-small cell lung cancer (2017)
  • Author(s): Fujiwara A、Shinatni Y、Funaki S、Kawamura T、Kanzaki R、Fukui E、Minami M、Okumura M
  • Organizer: Effects of pirfenidone targeting EMT and tumor-stroma interaction as novel treatment for non-small cell lung cancer
  • Int'l Joint Research