Authors' Affiliations: Cancer Research Program, Epithelial to Mesenchymal Transition Laboratory, Cancer Research Program, IMIM; Consulting Service on Methodology for Biomedical Research; Departments of Oncology and Pathology, Hospital del Mar; Universitat Pompeu Fabra, Barcelona; Departments of Pathology and Oncology, IIS-Fundación Jiménez Díaz, Madrid, Spain.
Clin Cancer Res. 2014 Feb 15;20(4):938-50. doi: 10.1158/1078-0432.CCR-13-1330. Epub 2013 Nov 27.
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.
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.
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.
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.
Met 受体磷酸化与人类小细胞肺癌（SCLC）的预后不良有关。我们的工作旨在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/化疗耐药 SCLC 模型中的作用。
在体外和体内（BALB/c 裸鼠皮下异种移植）评估 HGF 诱导的 EMT 的 SCLC 模型，以评估化疗敏感性和对 Met 抑制的反应，使用 PF-2341066（克唑替尼）。通过免疫组化和免疫荧光法评估 87 例 SCLC 初诊（N=87）和 5 例复发（N=5）患者的 EMT 标志物和 Met 状态，并与患者的预后进行相关性分析。
我们发现，通过 HGF 激活 Met 受体诱导了间充质标志物的表达，形成侵袭性表型和化疗耐药性。用 Met 抑制剂阻断这一过程可使细胞在体外和体内对化疗重新敏感。此外，人类 SCLC 标本中的间充质标志物与 Met 激活相关，预示着更差的生存预后，并且在化疗耐药性疾病中上调。
这些结果为 Met 依赖性 EMT 在 SCLC 的不良临床行为中的重要作用提供了新的证据，并支持在这种致命疾病中进行 Met 抑制剂和化疗的临床试验。
