射频消融后残留复发肝癌生长的生物学特征及机制研究

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.

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。

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。本研究完成射频消融（RFA）后肿瘤微血管相关标记物VEGF及CD34，肝细胞生长因子受体C-MET等表达与复发生长的关系探讨，比较不同加热微环境的影响。发现从不同加热方法后H22肿瘤的生长曲线比较可见，直接加热及间接加热后肿瘤生长的速度不同，提示加热后肿瘤微环境差异，导致对肿瘤增殖生长的影响。根据病理检测，VEGF-CD34通路在加热后上调，其中直接加热组明显高于间接加热组，提示直接加热对肿瘤微血管生长的促进作用。间接加热也高于对照组，提示即使不作用于肿瘤消融本身，通过加热产生的细胞因子会促进肿瘤新生血管的生长。间接RFA组缺氧标记物HIF-1α表达在72小时达峰值，明显高于直接RFA组。RFA组c-met表达在6小时增高，明显高于未RFA组。临床病例随访显示HCC局部复发癌行RFA的灭活率、局部复发率及长期生存期与是否行超声造影或射频针型相关。提示重视残留复发癌治疗策略，有助解决复发癌RFA治疗难题。建立基于iRGD靶向载药阿霉素热敏脂质体联合RFA的抗肿瘤治疗策略，借助iRGD的作用将阿霉素热敏脂质体主动靶向并渗透到肿瘤组织内部，利用射频引起的高温促进热敏脂质体迅速释放其中包含的药物，协同发挥药物和热消融的抗肿瘤作用。根据长期疗效观察，iRGD靶向热敏脂质体+RFA组获得最佳动物终点生存率。5个治疗组之间的动物体重曲线未见明显差异，提示靶向热敏脂质体的形式可改善长期疗效，同时未明显增加毒性，具有一定的临床应用前景。研究成果在核心期刊论文发表11篇，SCI论文发表11 篇，国内学术会议论文发表 4次，国际学术会议论文发表 6次并获奖3次。研究成果获得国家级专利授权1项，参加学习班（国家级继续教育项目）及进修班8次，并到各省市讲学推广，具有较好的社会效益。

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