Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer

被引:117
作者
Canadas, Israel [1 ,4 ]
Rojo, Federico [1 ,7 ]
Taus, Alvaro [4 ]
Arpi, Oriol [1 ,4 ]
Arumi-Uria, Montserrat [5 ,6 ]
Pijuan, Lara [5 ]
Menendez, Silvia [1 ,4 ]
Zazo, Sandra [7 ]
Domine, Manuel [8 ]
Salido, Marta [5 ]
Mojal, Sergi [3 ]
Garcia de Herreros, Antonio [2 ,6 ]
Rovira, Ana [1 ,4 ]
Albanell, Joan [1 ,4 ,6 ]
Arriola, Edurne [1 ,4 ]
机构
[1] IMIM, Canc Res Program, Madrid, Spain
[2] IMIM, Epithelial Mesenchymal Transit Lab, Canc Res Program, Madrid, Spain
[3] Consulting Serv Methodol Biomed Res, Madrid, Spain
[4] Hosp del Mar, Dept Oncol, Barcelona 08003, Spain
[5] Hosp del Mar, Dept Pathol, Barcelona 08003, Spain
[6] Univ Pompeu Fabra, Barcelona, Spain
[7] Fdn Jimenez Diaz, IIS, Dept Pathol, E-28040 Madrid, Spain
[8] Fdn Jimenez Diaz, IIS, Dept Oncol, E-28040 Madrid, Spain
关键词
HEPATOCYTE GROWTH-FACTOR; AUTOCRINE ACTIVATION; UP-REGULATION; PROMOTES; KINASE; ANGIOGENESIS; ONCOGENE; INVASION; MARKER;
D O I
10.1158/1078-0432.CCR-13-1330
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: Met receptor phosphorylation is associated with poor prognosis in human small cell lung cancer (SCLC). The aim of our work was to investigate the effects of hepatocyte growth factor (HGF)/Met-mediated epithelial-to-mesenchymal transition (EMT) in SCLC and to evaluate the role of Met inhibition in mesenchymal/chemorefractory SCLC models. Experimental Design: SCLC models of HGF-induced EMT were evaluated in vitro and in vivo (subcutaneous xenografts in BALB/c nude mice) for chemosensitivity and response to Met inhibition with PF-2341066 (crizotinib). Human SCLC samples at diagnosis (N = 87) and relapse (N = 5) were evaluated by immunohistochemistry and immunofluorescence for EMT markers and Met status and these were correlated with patient outcome. Results: We identified that the activation of the Met receptor through HGF induced expression of mesenchymal markers, an aggressive phenotype, and chemoresistance. Blockade of this process with the Met inhibitor resensitized cells to chemotherapy in vitro and in vivo. Moreover, mesenchymal markers in human SCLC specimens were associated with Met activation, predicted worse survival, and were upregulated in chemorefractory disease. Conclusion: These results provide novel evidence on an important role of Met-dependent EMT in the adverse clinical behavior of SCLC and support clinical trials of Met inhibitors and chemotherapy in this fatal disease. (C)2013 AACR.
引用
收藏
页码:938 / 950
页数:13
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