2010 Fiscal Year Final Research Report
Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
| Project/Area Number |
21790768
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Kanazawa University |
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Principal Investigator |
WANG Wei Kanazawa University, がん研究所, 博士研究員 (80467117)
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| Project Period (FY) |
2009 – 2010
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| Keywords | 肺癌 / 分子標的治療 / 薬剤耐性 / 肝細胞増殖因子 / 線維芽細胞 / ゲフィチニブ |
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| Research Abstract |
Purpose : Lung cancers with EGFR activating mutations show good clinical response to gefitinib and erlotinib, selective TKIs to epidermal growth factor receptor (EGFR), but these tumors invariably develop drug resistance. Host stromal cells have been found to have a considerable effect on the behavior of cancer cells. Little is known, however, about the role of host cells on the sensitivity of cancer cells to receptor tyrosine kinase inhibitors (TKIs). We have therefore assessed the effect of crosstalk between stromal cells and lung cancer cells harboring EGFR mutations on susceptibility to EGFR-TKIs.
Experimental design : We evaluated the gefitinib sensitivity of lung cancer cells with EGFR activating muations, PC-9 and HCC827, when co-cultured with fibroblasts and co-injected into SCID mice. We also examined the effect of lung cancer cells to fibroblasts recruitment.
Results : Both human fibroblast cell lines and primary cultured fibroblasts produced various level of HGF. Lung cancer cells markedly recruited fibroblasts. The lung cancer cells became resistant to EGFR-TKIs when co-cultured in vitro with HGF-producing fibroblasts and co-injected into SCID mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4 successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Co-localization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens.
Conclusions : These findings indicate that crosstalk to stromal fibroblasts plays a critical role in lung cancer resistance to EGFR-TKIs and may be an ideal therapeutic target in lung cancer with EGFR activating mutations.
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[Journal Article] Crosstalk to stromal fibroblasts induces resistance of lung cancer to EGFR tyrosine kinase inhibitors.2009
Author(s)
Wang W, Li Q, Yamada T, Matsumoto K, Matsumoto I, Oda M, Watanabe G, Kayano Y, Nishioka Y, Sone S, Yano S.
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Journal Title
Clin Cancer Res. 15(21)
Pages: 6630-6638
Peer Reviewed
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