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

2018 Fiscal Year Final Research Report

• 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
• Keywords: 肺癌 / 化学療法 / 腫瘍微小環境

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.

Free Research Field

呼吸器外科学

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。