基于PDTX模型研究原发性肺癌顺铂耐药与ERCC1 IGFBP5表达水平的关系

Relationship between cisplatin resistance of primary lung cancer and expression levels of ERCC1 and IGFBP5 in patient-derived tumor xenograft models

目的:构建PDTX(patient-derived tumor xenografts)肺癌模型,探索ERCC1、IGFBP5的表达水平与原发性肺癌顺铂耐药的关系。方法:取新鲜切除的84例肺癌组织移植于裸鼠(BALB/c)的皮下,构建PDTX模型,分析一代成瘤率与临床病理参数关系。三代移植瘤接受顺铂化疗,采用免疫组织化学方法检测敏感组和耐药组ERCC1、IGFBP5的表达情况。结果:移植瘤一代成瘤率32.14%(27/84),二代成瘤率88.89%(24/27),三代成瘤率95.83%(23/24),能否一代成瘤与肿瘤的大小、分化、分级、病理类型相关;此模型移植瘤在传代中能够保持亲代肿瘤的结构特征。ERCC1在耐药组表达高于敏感组,而IGFBP5在耐药组表达低于敏感组。结论:构建了肺癌组织块移植瘤模型,其能够保持亲代癌种的结构特征,是研究肺癌发生和探索肿瘤耐药机制的理想模型。原发性肺癌顺铂耐药性与ERCC1、IGFBP5的表达水平相关。

Objective： To establish a lung cancer model of patient-derived tumor xenografts （PDTX） and to explore the relation- ship between primary cisplatin resistance and ERCC1 and IGFBP5 expression levels. Methods： Lung cancer tissues from 84 patients who underwent surgery were collected and implanted into nude mice. Patient characteristics for the first generation xenografis that were and were not engrafted were compared. Passage 3 xenografts were treated with cisplatin. The expression levels of ERCC 1 and IGFBP5 in cisplatin-resistant and cisplatin-sensitive groups were detected using immunohistochemistry assay. Results： The model success rates were 32.14% （27/84） in first-generation xenografts, 88.89% （24/27） in second-generation xenografts, and 95.83% （23/24） in third-gener- ation xenografts. The tumorigenicity of first-generation xenografts was correlated with size, differentiation, clinical stage, and histologi- cal type. PDTX tumors maintain the histological type of parental tumors through serial passage in nude mice. ERCC 1 expression level was significantly higher in the cisplatin-resistant group than in the cisplatin-sensitive group, whereas the IGFBP5 expression level was lower in the cisplatin-resistant group than in the cisplatin-sensitive group. Conclusion： Lung cancer PDTX models were successfully es- tablished, and histological characteristics of the primary cancers were retained. Therefore, the models may serve a function in preclini- cal research of lung tumor biology and for exploring the drug resistance mechanism of tumors. The cisplatin resistance of primary lung cancer may be correlated with the expression level of ERCC 1 and IGFBP5 in lung carcinoma.