Crosstalk with cancer-associated fibroblasts induces resistance of non-small cell lung cancer cells to epidermal growth factor receptor tyrosine kinase inhibition

被引:59
作者
Choe, Chungyoul [1 ]
Shin, Yong-Sung [1 ]
Kim, Changhoon [2 ]
Choi, So-Jung [1 ]
Lee, Jinseon [1 ]
Kim, So Young [1 ]
Cho, Yong Beom [3 ]
Kim, Jhingook [1 ,4 ]
机构
[1] Sungkyunkwan Univ, Samsung Biomed Res Inst, Samsung Med Ctr, Sch Med, Seoul 135710, South Korea
[2] Hanyang Univ, Dept Biomed Sci, Grad Sch Biomed & Engn, Seoul 133791, South Korea
[3] Sungkyunkwan Univ, Dept Surg, Samsung Med Ctr, Sch Med, Seoul 135710, South Korea
[4] Sungkyunkwan Univ, Dept Thorac Surg, Samsung Med Ctr, Sch Med, Seoul 135710, South Korea
基金
新加坡国家研究基金会;
关键词
CAFs; lung cancer; NSCLC; direct coculture; hedgehog signaling; EMT; actin; EGFR TKIs; EPITHELIAL-MESENCHYMAL TRANSITION; TUMOR-STROMAL INTERACTIONS; DRUG-RESISTANCE; EGFR MUTATIONS; INCREASED SENSITIVITY; TARGETED THERAPY; HEDGEHOG PATHWAY; ENHANCE MOTILITY; GENE-EXPRESSION; COPY NUMBER;
D O I
10.2147/OTT.S89659
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Although lung cancers with activating mutations in the epidermal growth factor receptor (EGFR) are highly sensitive to selective EGFR tyrosine kinase inhibitors (TKIs), these tumors invariably develop acquired drug resistance. Host stromal cells have been found to have a considerable effect on the sensitivity of cancer cells to EGFR TKIs. Little is known, however, about the signaling mechanisms through which stromal cells contribute to the response to EGFR TKI in non-small cell lung cancer. This work examined the role of hedgehog signaling in cancer-associated fibroblast (CAF)-mediated resistance of lung cancer cells to the EGFR TKI erlotinib. PC9 cells, non-small cell lung cancer cells with EGFR-activating mutations, became resistant to the EGFR TKI erlotinib when cocultured in vitro with CAFs. Polymerase chain reaction and immunocytochemical assays showed that CAFs induced epithelial to mesenchymal transition phenotype in PC9 cells, with an associated change in the expression of epithelial to mesenchymal transition marker proteins including vimentin. Importantly, CAFs induce upregulation of the 7-transmembrane protein smoothened, the central signal transducer of hedgehog, suggesting that the hedgehog signaling pathway is active in CAF-mediated drug resistance. Indeed, downregulation of smoothened activity with the smoothened antagonist cyclopamine induces remodeling of the actin cytoskeleton independently of Gli-mediated transcriptional activity in PC9 cells. These findings indicate that crosstalk with CAFs plays a critical role in resistance of lung cancer to EGFR TKIs through induction of the epithelial to mesenchymal transition and may be an ideal therapeutic target in lung cancer.
引用
收藏
页码:3665 / 3678
页数:14
相关论文
共 77 条
[1]   Inhibition of Hedgehog signaling sensitizes NSCLC cells to standard therapies through modulation of EMT-regulating miRNAs [J].
Ahmad, Aamir ;
Maitah, Ma'in Y. ;
Ginnebaugh, Kevin R. ;
Li, Yiwei ;
Bao, Bin ;
Gadgeel, Shirish M. ;
Sarkar, Fazlul H. .
JOURNAL OF HEMATOLOGY & ONCOLOGY, 2013, 6
[2]   Unraveling the therapeutic potential of the Hedgehog pathway in cancer [J].
Amakye, Dereck ;
Jagani, Zainab ;
Dorsch, Marion .
NATURE MEDICINE, 2013, 19 (11) :1410-1422
[3]   Significance of cancer-associated fibroblasts in the regulation of gene expression in the leading cells of invasive lung cancer [J].
An, Jian ;
Enomoto, Atsushi ;
Weng, Liang ;
Kato, Takuya ;
Iwakoshi, Akari ;
Ushida, Kaori ;
Maeda, Keiko ;
Ishida-Takagishi, Maki ;
Ishii, Genichiro ;
Ming, Shuhong ;
Sun, Tieying ;
Takahashi, Masahide .
JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY, 2013, 139 (03) :379-388
[4]   Evaluating Smoothened as a G-protein-coupled receptor for Hedgehog signalling [J].
Ayers, Katie L. ;
Therond, Pascal P. .
TRENDS IN CELL BIOLOGY, 2010, 20 (05) :287-298
[5]   Sonic hedgehog induces transcription-independent cytoskeletal rearrangement and migration regulated by arachidonate metabolites [J].
Bijlsma, Maarten F. ;
Borensztajn, Keren S. ;
Roelink, Henk ;
Peppelenbosch, Maikel P. ;
Spek, C. Arnold .
CELLULAR SIGNALLING, 2007, 19 (12) :2596-2604
[6]   An Epithelial-Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance [J].
Byers, Lauren Averett ;
Diao, Lixia ;
Wang, Jing ;
Saintigny, Pierre ;
Girard, Luc ;
Peyton, Michael ;
Shen, Li ;
Fan, Youhong ;
Giri, Uma ;
Tumula, Praveen K. ;
Nilsson, Monique B. ;
Gudikote, Jayanthi ;
Tran, Hai ;
Cardnell, Robert J. G. ;
Bearss, David J. ;
Warner, Steven L. ;
Foulks, Jason M. ;
Kanner, Steven B. ;
Gandhi, Varsha ;
Krett, Nancy ;
Rosen, Steven T. ;
Kim, Edward S. ;
Herbst, Roy S. ;
Blumenschein, George R. ;
Lee, J. Jack ;
Lippman, Scott M. ;
Ang, K. Kian ;
Mills, Gordon B. ;
Hong, Waun K. ;
Weinstein, John N. ;
Wistuba, Ignacio I. ;
Coombes, Kevin R. ;
Minna, John D. ;
Heymach, John V. .
CLINICAL CANCER RESEARCH, 2013, 19 (01) :279-290
[7]   Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib [J].
Carey, Kendall D. ;
Garton, Andrew J. ;
Romero, Maria S. ;
Kahler, Jennifer ;
Thomson, Stuart ;
Ross, Sarajane ;
Park, Frances ;
Haley, John D. ;
Gibson, Neil ;
Sliwkowski, Mark X. .
CANCER RESEARCH, 2006, 66 (16) :8163-8171
[8]   Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened [J].
Chen, JK ;
Taipale, J ;
Cooper, MK ;
Beachy, PA .
GENES & DEVELOPMENT, 2002, 16 (21) :2743-2748
[9]  
Choe C, 2013, ANTICANCER RES, V33, P3715
[10]   Clinical and molecular evidences of epithelial to mesenchymal transition in acquired resistance to EGFR-TKIs [J].
Chung, Jin-Haeng ;
Rho, Jin Kyung ;
Xu, Xianhua ;
Lee, Jong Seok ;
Yoon, Ho Il ;
Lee, Choon Taek ;
Choi, Yun Jung ;
Kim, Hye-Ryoun ;
Kim, Cheol Hyeon ;
Lee, Jae Cheol .
LUNG CANCER, 2011, 73 (02) :176-182