联合靶向肿瘤血管生成拟态的肝癌抗血管治疗新策略

Antiangiogenesis therapy is one of the most promising approaches to cancer treatment. Its clinical success has come out but still too limited. Vascularization of tumor is a complex and heterogenous process. Vasculogenic mimicry(VM) as an alternative circulatory system, has been described in multiple malignant tumor types, and considered to be associated with a poor prognosis for the patient. VM serves as an adjunct to the existing vasculature system, thereby aiding tumor growth as well as contributing to the metastatic process. Yet, the current antiangiogenesis strategies, which are directed mainly against the tumor endothelium, have no effect on VM, and might have the unintended effect of promoting tumor metastasis by increasing VM. Thus, treatment strategies that target the tumor microcirculation should not only target endothelium-dependent vessels, but also take VM into account in tumors presenting VM. Further clarifying the formation mechanism of VM and finding specific molecular target are the urgent matters. In our prophase research, we have found that there was a significant positive correlation between migration inducing gene 7（MIG7） expression and VM formation. On the basis of our preliminary studies, this research will be adopt gene recombination and RNAi technology to construct hepatocellular carcinoma(HCC) lines with different MIG7 expression level and HCC three-dimensional culture to investigate the mechanism of the correlation of MIG7 expression with VM formation. Secondly, on the basis of studies in vitro, we will use the screened recombinant MIG7-shRNA expression retrovirus to infect HCC orthotopic transplantation model of nude mice to discovery the possible reason of limitation of classic antiangiogenesis therapy and to propose and verify the hypothesis about a new antiangiogenesis strategy, which is the traditional endothelium-targeted angiogenesis therapy in combination with VM-targeted therapy.

抗肿瘤血管治疗是肿瘤学的研究热点。然而，其体内疗效有限是亟待突破的瓶颈，研究并改进其治疗策略已迫在眉睫。血管生成拟态（VM）的发现使抗肿瘤血管的治疗比原来想象的更为复杂，形成VM的肿瘤预后很差，而传统的抗肿瘤血管药物对其不仅无效还反而促进VM形成及肿瘤转移，故抗肿瘤血管治疗必须同时针对VM。故进一步明确VM形成机制及其特异性分子靶点是当务之急。本课题组前期已证实肝癌中MIG7表达与VM形成关系密切。本项目将在我们前期研究基础之上，拟采用基因重组及RNAi技术构建MIG7不同表达的人肝癌细胞株，通过人肝癌细胞三维培养建立体外VM形成模型，探讨MIG7表达对VM形成的作用及其机制；其次，在体外研究基础之上，通过应用MIG7-shRNA重组病毒感染原位肝癌裸鼠，探索传统抗肿瘤血管治疗体内疗效有限的原因及机制，并在此基础之上探索一种崭新的抗肿瘤血管治疗策略，即"联合靶向VM的抗肿瘤血管治疗策略"。

原发性肝癌（primary liver cancer，简称肝癌）是严重危害人类生命健康的重大疾病，其中肝细胞肝癌（hepatocellular carcinoma，HCC）占肝癌的91.5%，预后差，总的5年生存率不足5%，其主要原因是其高转移率及术后高复发率。目前，肝癌转移复发是肝癌研究的重点。.在肝癌转移复发的研究中，“抗肿瘤血管生成的治疗”是一大研究热点。然而，血管生成拟态（vasculogenic mimicry，VM）理论的提出使“抗肿瘤血管生成的治疗”比原来想象的更为复杂。VM是一种与经典的肿瘤血管生成途径完全不同、不依赖血管内皮细胞（vascular endothelial cell，VEC）的全新肿瘤微循环模式。VM理论向经典的“内皮依赖性肿瘤血管生成理论”提出了挑战，受到国内外学者的普遍重视，是近年来肿瘤学研究的热点。.研究显示在分化程度较低的HCC中也存在VM，有VM形成的HCC预后很差。我们设想：传统的抗肿瘤血管生成药物对HCC治疗作用有限，一个的重要原因是它们仅仅针对肿瘤内皮依赖性血管，而对肿瘤VM未加以考虑。同时，传统的VEC靶向的抗肿瘤药物必然导致肿瘤局部缺血缺氧，然而，肿瘤局部缺血缺氧又是促进VM形成的重要原因，故传统的靶向VEC的治疗可能由于促进了VM的形成，进而增加肿瘤细胞侵袭转移的机会，最终限制了传统抗肿瘤血管生成药物的抗癌效果。基于以上分析，我们提出：在设计抗肿瘤血管生成治疗方案时，必须同时考虑抑制VM的形成，进而设计出抗HCC血管生成及血管生成拟态的联合靶向治疗策略。.目前关于肝癌中VM的研究尚属初级阶段，进一步明确肝癌中VM的形成机制及在肝癌侵袭转移中的作用，进而研制针对肝癌中VM的治疗方法是当务之急。MIG7（migration-inducing protein 7）是新近发现的一种在多种恶性肿瘤细胞膜定位的蛋白质，其表达在调控肿瘤细胞的可塑性及形成VM中具有重要作用。MIG7的发现及研究将使人们进一步理解肿瘤细胞的侵袭特性以及VM形成的机制，对进一步研制靶向VM的治疗具有重大意义。目前，国内外尚无有关肝癌中MIG7表达与VM形成的关系及对肝癌的侵袭转移的作用的研究报道。