肝癌介入栓塞后缺氧诱导上皮间质转化的分子机制及磁共振功能成像研究

Hepatocellular carcinoma (HCC) is the sixth most common malignancy worldwide and TACE is widely used as as a nonsurgical treatment for unresectable HCC and has shown encouraging results in terms of survival. However, the survival benefit is limited and the high mortality rate is still a problem to confront due to a high incidence of tumor recurrence and metastasis rate following any therapies, and the merits of TACE in treatment of HCC are disputable. The research was to verify if transarterial embolization (TAE) enhance the metastatic potential of the residual HCC, and investigate the mechanisms underlying the effects of embolization with Buffalo rat model orthotopic implanted with McA-RH7777 marked by GFP (Green Fluorescent Protein). We try to confirm the possibility that Hypoxia-induced epithelial-mesenchymal transition increases the metastatic potential of the tumor cells. In the study we also assess the value of fMRI in dynamically evaluating hypoxic state of residue tumor after TAE. We can obtain the theoretical evidence of recurrence and metastasis interacting with TACE, and lay the foundations for making scientific plan which is to augmenting the therapeutic effects of TACE.

TACE已成为不能手术切除的肝癌患者的主要治疗方法，但复发和转移仍是影响其疗效和临床亟需解决的难题，关于栓塞对转移的影响也是广泛争议的学术问题。本研究采用GFP标记McA-RH7777肝癌细胞，建立可用于介入栓塞研究的Buffalo大鼠肝癌模型，对栓塞后缺氧诱发的上皮间质转化影响残癌转移潜能的分子机制进行研究，探讨栓塞对肝癌转移和复发造成影响的机理，并通过磁共振功能成像评价栓塞后缺氧状态与上皮间质转化在不同时间点的变化和关系，结合活体显微镜和病理学证据，分析肝癌栓塞后不同阶段缺氧动态变化及肝癌转移的进展，为科学的治疗方案的设计、个体化巩固栓塞时机的选择提供依据，在改进栓塞疗效、减少临床并发症的同时避免不必要的过度治疗，以期提高病人远期缓解率和无疾病进展时间。

TACE后肝癌缺氧微环境对肝癌生物学特性的影响具有重要意义。围绕TACE对肝癌转移的影响，本课题通过体外实验、动物实验研究介入栓塞对肝癌侵袭和转移潜能的影响，建立可用于介入栓塞研究的Buffalo大鼠肝癌模型，明确了缺氧能促进残癌发生上皮间质转化，增强肿瘤的侵袭转移潜能。我们采用3.0TMRI高分辨体素内非相干运动成像（IVIM）扫描技术来评价介入栓塞后缺氧状态，通过对表观扩散系数（ADC）各参数的深入分析，明确了fMRI 监测介入栓塞后缺氧状态及肿瘤进展和转移的可行性。为肝癌TACE治疗后的预后的评价和重复治疗时机的选择提供了一种有效的方法。