Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma
Tumor-associated macrophages modulate resistance to oxaliplatin via inducing autophagy in hepatocellular carcinoma
复制标题
肿瘤相关巨噬细胞通过诱导肝细胞癌自噬来调节对奥沙利铂的耐药性。
DOI：
10.1186/s12935-019-0771-8
复制
发表时间：
2019-03-25
影响因子：
5.8
通讯作者：
Fan, Jia
中科院分区：
文献类型：
--
作者：
Fu, Xiu-Tao;Song, Kang;Fan, Jia
研究背景以奥沙利铂为基础的化疗广泛应用于肝细胞癌（HCC）的治疗。近年来的研究表明，肿瘤微环境（TME）影响肿瘤的耐药性。肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）作为TME的主要成分，在肝癌耐药中的作用尚不清楚。免疫组化法检测组织中TAM的密度。SMMC-7721和Huh-7细胞系用于与THP-1衍生的巨噬细胞共培养。在奥沙利铂处理下，使用MTT和膜联蛋白V/碘化丙啶测定来测量细胞死亡。通过SMMC-7721和Huh-7中的GFP-LC 3再分布和LC 3转化评价自噬活化。应用针对ATG 5基因的短干扰RNA抑制自噬。在体内验证中进行Huh-7与或不使用巨噬细胞在裸鼠中的肝癌异种移植模型奥沙利铂administration.ResultsWe发现，肝癌样品中的TAM的密度与TACE的疗效。巨噬细胞抑制肝癌细胞中奥沙利铂诱导的细胞死亡。肝癌细胞与巨噬细胞共培养后，自噬功能被激活。在HCC细胞中使用ATG 5的RNA干扰抑制自噬促进了共培养系统中奥沙利铂的细胞毒性。至关重要的是，共同植入与巨噬细胞在肝癌异种移植削弱奥沙利铂的细胞毒性作用，通过诱导自噬，以避免apoptosis.ConclusionsOur结果表明，TAM诱导自噬在肝癌细胞，这可能有助于奥沙利铂耐药。靶向TAMs是一种有前途的治疗策略，可增强HCC患者化疗奥沙利铂的效果。
BackgroundOxaliplatin-based chemotherapy is widely used to treat hepatocellular carcinoma (HCC). Recent studies suggested that therapeutic resistance of tumors was affected by tumor microenvironment (TME). As a major component of TME, the role of tumor-associated macrophages (TAMs) on drug resistance in HCC is largely unknown.Methods26 HCC samples were obtained from patients who had underwent transarterial chemoembolization (TACE) within 3months before receiving curative resections. Immunohistochemistry was applied to detect the density of TAMs in these tissues. SMMC-7721 and Huh-7 cell lines were used to co-culture with THP-1 derived macrophages. Under oxaliplatin treatment, cell death was measured using MTT and annexin V/propidium iodide assays. Autophagy activation was evaluated by GFP-LC3 redistribution and LC3 conversion in SMMC-7721 and Huh-7. Short-interfering RNA against ATG5 gene was applied to inhibit autophagy. In vivo validation was conducted in Huh-7 with or without macrophages using an HCC xenograft model in nude mice after oxaliplatin administration.ResultsWe found that the density of TAMs in HCC samples was associated with the efficacy of TACE. Macrophages inhibited cell death induced by oxaliplatin in HCC cells. Autophagy was functionally activated in HCC cells after co-culturing with macrophages. Suppression of autophagy using RNA interference of ATG5 in HCC cells promoted the oxaliplatin cytotoxicity in the co-culture system. Critically, co-implantation with macrophages in HCC xenografts weakens cytotoxic effect of oxaliplatin through inducing autophagy to avoid apoptosis.ConclusionsOur results suggest that TAMs induce autophagy in HCC cells which might contribute to oxaliplatin resistance. Targeting TAMs is a promising therapeutic strategy to enhance the effects of chemotherapy oxaliplatin in HCC patients.