射频消融后残留复发肝癌生长的生物学特征及机制研究

项目名称： 射频消融后残留复发肝癌生长的生物学特征及机制研究

项目编号： No.81471768

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 杨薇

作者单位： 北京大学

项目金额： 73万元

中文摘要： 影像引导射频消融与手术、肝移植列为肝癌的三大治疗手段之一，被临床应用。然而，残留复发率高成为影响疗效的难题，射频消融引起机体局部反应，尤其可能刺激残留肿瘤生长的机理尚未阐明，并缺乏有效的处理措施。据报道，肝癌组织热休克蛋白及缺氧诱导因子高表达与治疗预后相关。前期研究显示射频引起肿瘤HSP90，HIF-1α高表达，同时c-Met及VEGF明显上调，可能为加速肿瘤生长的重要机制。已通过动物实验证实，应用脂质体抑制剂可减弱消融后局部细胞因子或蛋白的过度表达，并抑制肿瘤生长。针对肿瘤消融引起的局部反应是多基因、多通路共同参与的科学问题；申请人已完成前期研究(国自然青年基金)基础上，本课题将进一步探讨消融后肿瘤复发生长的特征及关键机制：与HSP90/HIF-1α(消融产物)和VEGF/c-Met等通路的相关性；并应用纳米技术传递抑制剂，阻断消融后反应的关键靶点，探讨消融联合治疗的新模式，降低复发率。

中文关键词： 射频消融；肝癌；血管生成；肿瘤生长；脂质体

英文摘要： Imaging guided radiofrequency ablation (RFA) has widespread clinical use to treat a wide range of focal tumors，especially in the liver. Yet, poorly characterized and underappreciated regional effects of the procedure, including ablation-stimulated tumorigenesis, remain a significant barrier to clinical efficacy. Thus, treatment strategies to modulate regional effects of tumor ablation are urgently required to further improve outcomes. We and others have shown that expression levels of heat shock protein and hypoxia inducible factors were related to poor prognosis in HCC patients.Our previous studies showed post-ablation reactions in the mandatory to ablate surrounding tissues results in the generation of HSP90, HIF-1α, and also found VEGF and c-Met passway upregulation leading to increased tumorigenesis. Recently, we present compelling preliminary data demonstrating that the administration of adjuvant liposomal agent against heat shock protein with tumor RFA can successfully attenuate both HSP experession as well as secondary downstream effects on local tumor growth in animal models. Building upon our history of combining liposomal agents with tumor ablation to achieve concentrated drug delivery to tissues surrounding the ablation zone and our demonstrated ability to modulate responses to cytokines/transcription factors (NSFC grants), we hypothesize that the secondary effects of regional tumor progression caused by local ablation-induced cytokine and growth factors can be successfully modulated with adjuvant use of targeted liposomal agent to key mechanistic pathways (the HSP90 and HIF-1α production and VEGF / c-Met signaling pathway) ,induced by RFA in periablational tissues, and finally imporve the overall outcome of RFA of tumors.

英文关键词： Radiofrequency;Liver cancer;Angiogenesis;Tumor growth;Liposomal