Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer
Targeting Epithelial-to-Mesenchymal Transition with Met Inhibitors Reverts Chemoresistance in Small Cell Lung Cancer
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DOI：
10.1158/1078-0432.ccr-13-1330
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发表时间：
2014-02-15
影响因子：
11.5
通讯作者：
Arriola, Edurne
中科院分区：
文献类型：
--
作者：
Canadas, Israel;Rojo, Federico;Arriola, Edurne
目的：Met受体磷酸化与小细胞肺癌（SCLC）预后不良相关。我们工作的目的是研究肝细胞生长因子（HGF）/Met介导的上皮-间充质转化（EMT）在SCLC中的作用，并评估Met抑制在间充质/化学难治性SCLC模型中的作用。在体外和体内评价HGF诱导EMT的SCLC模型（Balb/c裸小鼠皮下异种移植物）对PF-2341066（克唑替尼）抑制Met的化学敏感性和反应。在诊断（N = 87）和复发（N = 5）的人小细胞肺癌样本进行了评价，免疫组化和免疫荧光EMT标志物和Met状态，这些都与患者outcome.Results：我们确定了激活的Met受体通过HGF诱导间充质标志物的表达，积极的表型，和耐药性。用Met抑制剂阻断这一过程使细胞在体外和体内对化疗再敏感。此外，在人类小细胞肺癌标本间充质标志物与Met激活，预测生存较差，并上调chemorefractory diseases.Conclusion：这些结果提供了新的证据，在小细胞肺癌的不良临床行为的重要作用，Met依赖的EMT和支持在这个致命的疾病的Met抑制剂和化疗的临床试验。（C）2013年AACR。
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.