肿瘤相关成纤维细胞在非小细胞肺癌EGFR-TKI耐药中作用与机制研究

Mutational activation of epidermal growth factor receptor(EGFR) is the most common genetic alterations in non-small cell lung cancer (NSCLC) in East Asian population. Moreover, the marked tumor regression of advanced lung cancer patients with EGFR mutations in response to treatment with EGFR tyrosine kinase inhibitors(EGFR TKI) showed the essential role of EGFR in lung cancers. However,resistance to EGFR TKI treatment invariably occurs. Recent studies have identified the critical role of tumor associated fibroblast in the development of chemotherapeutic agents or targeted therapy resistance. We previously identified the major mechanisms associated with EGFR-TKI resistance by large scale library screening, which still could not address all the reasons that confer EGFR-TKI resistance.Complex interactions between tumor-infiltrating stromal cells and tumor cells play an important role in the development of tumors and drug resistance.Tumor-associated fibroblast (TAF) are the most abundant cancer stromal cells. It remains largely unknown whether tumor-associated fibroblast are involved in EGFR-TKI resistance. The aim of our study was to obtain an accurate overview of the broad range of changes occurring in fibroblast that could confer EGFR-TKI resistance in non-small cell lung cancer.

肿瘤是由肿瘤细胞和间质细胞组成的异质性组织，以往针对EGFR-TKI耐药研究大都把重点放在研究肿瘤细胞上，肿瘤中广泛存在的间质细胞在EGFR-TKI治疗耐受中作用和机制目前尚无全面系统性研究。肿瘤相关成纤维细胞是肿瘤间质组织最重要的细胞之一，其可分泌多种细胞因子。以往研究证实成纤维细胞分泌的部分细胞因子在介导靶向药物治疗耐受中发挥了关键作用。本研究以肿瘤相关成纤维细胞为切入点，分析能诱导EGFR-TKI耐药的肿瘤相关成纤维细胞有何特点，是否能用于解释临床上患者EGFR-TKI治疗后部分缓解肿瘤内原发耐药发生的原因。以此出发，本研究在原代分离肿瘤相关成纤维细胞并鉴定其表型基础上，与EGFR突变细胞株共培养，系统全面研究成纤维细胞分泌的细胞因子在EGFR-TKI治疗耐受中的作用及机制。

大多数接受EGFR-TKI治疗的患者治疗有效后体内残存相当大比例原发性耐药肿瘤，其瘤内肿瘤间质细胞，尤其是成纤维细胞，是肿瘤内的主要细胞成分之一，发挥了什么作用目前了解还十分有限。我们在原代分离培养成纤维细胞的基础上，通过直接共培养，研究肿瘤组织来源的肿瘤相关成纤维细胞在EGFR-TKI耐药中的作用和机制。研究发现原代培养的肿瘤相关成纤维细胞可分泌EGF, FGF, NRG1等细胞因子，其可诱导肺癌细胞株对EGFR-TKI治疗耐受，不同患者体内成纤维细胞诱导耐药机制存在较大异质性。这为进一步开发针对性治疗和相关临床试验的开展提供依据。