吡非尼酮靶向调控肿瘤微环境联合肝动脉灌注化疗栓塞术治疗原发性肝癌的作用及机制研究

Transarterial chemoembolization (TACE) is the preferred treatment for intermediated or advanced hepatocellular carcinoma (HCC), but TACE causes increased hypoxia leading to the activation of hepatic stellate cells(HSC) , the activated HSC produce numerous vascular endothelial growth factor(VEGF) which promotes tumor vascularization and the development of metastasis after TACE. So the combination of TACE with drugs which inhibit the expression of VEGF and the activation of HSC might constitute an effective strategy to improve outcomes in patients with intermediated or advanced HCC. We found that pirfenidone (PFD) could effectively suppress the activity of HSC ,the expression of collagen I and the heat shock protein47(HSP47).To demonstrate the possible mechanism of PFD in suppressing the activity of HSC and the invasion ability of tumor cells, we study the effect of PFD on the proliferation and apoptosis of human hepatocytes ,HSC，human cancer cells,analysis the changes of cytokines. Futher more,we combine TACE with PFD in a HCC model on rabbits, and examine the activity of HSC,the invasion and metastasis of tumor . So this project is important to improve the efficacy of TACE and increase the survival time of patients with HCC.

肝动脉灌注化疗栓塞术(TACE)是中晚期原发性肝癌（HCC）的首选治疗方法，研究表明TACE术后所致的缺氧会引起肿瘤微环境中肝星形细胞（HSC）活化，分泌血管内皮生长因子（VEGF）促进肿瘤血管生成，导致TACE术后HCC的复发以及转移。因此TACE联合抑制VEGF生成、逆转HSC活性的药物将能提高治疗中晚期HCC的疗效。我们研究发现吡非尼酮（PFD）能有效抑制HSC的活性，降低胶原伴侣分子-热休克蛋白47（HSP-47）及胶原I的表达。本研究采用PFD处理人正常肝细胞、HSC、肝癌细胞，通过研究细胞增殖与凋亡、检测相关细胞因子的分泌等，阐述PFD逆转HSC活性、抑制肝癌细胞侵袭的机制，并在肝癌动物模型中联合TACE治疗，研究PFD对HSC活性、肿瘤侵袭转移的影响及机制。本项目的开展对于提高HCC患者TACE疗效及生存期具有重要临床意义。

经肝动脉灌注化疗栓塞术(TACE)是中晚期原发性肝癌（HCC）的首选治疗方法，但远期生存率并不理想，研究表明TACE术后所致的缺氧环境会引起肝星形细胞（HSC）活化，导致TACE术后HCC的复发以及转移。因此TACE联合逆转HSC活性的药物将能提高治疗中晚期HCC的疗效。本研究表明抗纤维化药物吡非尼酮可以抑制肝癌细胞的增殖、迁移、细胞周期，并协同增强阿霉素的抗肿瘤效果，利用B超构建兔肝癌模型，并辅助X线行TACE手术，同时进一步研究了肝癌的发生机制，为肝癌患者提供新的、有效的综合治疗手段，有良好的经济效益和社会效益。