伊马替尼通过PDGF/PDGFR通路对A549非小细胞肺癌裸鼠移植瘤的抑制作用及机制研究

Inhibition and Mechanism of Imatinib on A549 Xenograft Tumor in Nude Mice via PDGF/PDGFR Pathway

目的探讨伊马替尼对A549非小细胞肺癌裸鼠移植瘤生长及肿瘤组织和基质中PDGFB、PDGFRβ蛋白表达的影响,探究伊马替尼的抑瘤机制。方法建立裸鼠A549非小细胞肺癌移植瘤模型,随机分为对照组(0.9%NaCl)、低、中、高剂量伊马替尼组(50、100、200 mg/(kg·d))。连续灌胃给药28天,观察不同浓度伊马替尼对肿瘤生长的影响;HE染色观察肿瘤组织的病理变化;Western blot法检测移植瘤组织中PDGF/PDGFR通路相关蛋白的表达及AKT、ERK1/2蛋白磷酸化水平;双重免疫荧光染色检测PDGFB、PDGFRβ蛋白在肿瘤基质中的表达。结果伊马替尼组裸鼠A549非小细胞肺癌移植瘤的生长受到抑制,肿瘤组织中PDGFB的表达降低,PDGFRβ、AKT、ERK1/2的磷酸化水平降低。与对照组相比,给药组的肿瘤基质成纤维细胞中PDGFB、PDGFRβ表达显著减少。结论伊马替尼对裸鼠非小细胞肺癌A549移植瘤具有显著的抑制作用,其抑瘤机制可能是下调肿瘤基质成纤维细胞中PDGFB和PDGFRβ的表达。

Objective To investigate the effect of imatinib on the growth of A549 non-small cell lung cancer transplanted tumors and the expression of PDGFB and PDGFRβproteins in tumor tissues and stroma in nude mice and to explore the underlying tumor suppression mechanism.Methods A transplantation tumor model of A549 non-small cell lung cancer was established in nude mice.The mice were then randomly divided into four groups:control group(0.9%NaCl),low-dose imatinib group(50 mg/(kg·d)),medium-dose imatinib group(100 mg/(kg·d)),and high-dose imatinib group(200 mg/(kg·d)).The effect of different concentrations of imatinib administered by continuous gavage on tumor growth was observed for 28 days.HE staining was performed to observe the pathological changes of tumor tissues.The expression of PDGF/PDGFR pathwayrelated proteins and the phosphorylation levels of AKT and ERK1/2 proteins in tumor tissues were detected by Western blot analysis.Double immunofluorescence staining was used to detect the expression of PDGFB and PDGFRβproteins in the tumor stroma.Results Imatinib inhibited the growth of A549 non-small cell lung cancer cells in nude mice,suppressed the expression of PDGFB in tumor tissues,and decreased the phosphorylation levels of PDGFRβ,AKT,and ERK1/2.The expression of PDGFB and PDGFRβin tumor stromal fibroblasts of the administered group was significantly lower than that of the control group.Conclusion Imatinib exhibits a pronounced inhibitory effect on A549 xenografts of nude mice with non-small cell lung cancer,and its antitumor mechanism may involve the downregulation of PDGFB and PDGFRβexpression in tumor stromal fibroblasts.