Tie2+巨噬细胞在肺癌化疗后复发转移中的作用与机制研究

Recurrence and metastasis after chemotherapy is still one of the problems of clinical cancer treatment. We found that the proportion of Tie2+ macrophages in peripheral blood of patients with lung cancer after chemotherapy was negatively correlated with their prognosis; Animal models suggested that tumor recurrence was related to the promotion of vascular remodeling by Tie2+ macrophages. This project intends to study in depth the role of Tie2+ macrophages in chemoresistance of lung cancer and provide a new way for the comprehensive treatment of lung cancer（Cancer Research, 2016）. The main contents are as follows: 1) The distribution of Tie2+ macrophages in human tumor before and after lung cancer chemotherapy; 2) The regulation of Tie2 expression on human macrophages in vitro; 3) Interaction of macrophages with tumor cells and other interstitial cells; 4) Construction of a mouse human lung cancer xenograft model to investigate the effect of targeting Tie2 by nanoparticles on tumor recurrence and metastasis. The project will help to elucidate the role and mechanism of macrophages in recurrence and metastasis of lung cancers after chemotherapy, and provide new ideas for clinical diagnosis and therapy.

化疗后复发转移仍是临床肿瘤治疗的难题之一。我们前期发现肺癌患者化疗后外周血中Tie2+巨噬细胞的比例与其预后负相关；动物模型提示肿瘤复发与Tie2+巨噬细胞促进血管重建有关（Cancer Research, 2016）。本项目拟深入研究Tie2+巨噬细胞对肺癌化疗抵抗的作用和机制，为肺癌的综合治疗提供新思路。研究内容有：1）肺癌化疗前后Tie2+巨噬细胞在人肿瘤组织中的分布情况；2) 体外实验研究人巨噬细胞高表达Tie2分子的调控机制；3) 3D细胞培养技术观察Tie2+巨噬细胞与肺癌细胞及其它间质细胞之间的相互作用和分子机制；4）构建小鼠人肺癌移植瘤模型，探讨采用纳米颗粒靶向Tie2对肿瘤复发转移的影响。本项目将有助于进一步阐明巨噬细胞在肺癌化疗后复发转移中的作用和机制，为临床诊治提供新思路。

本项目主要研究Tie2+巨噬细胞在肺癌化疗后复发转移中的作用与机制，收集临床肺癌患者化疗前后的病理组织，通过免疫组织化学染色分析Tie2蛋白表达分布情况，发现患者体化疗后Tie2+巨噬细胞增多且分布在血管交叉部位；研究巨噬细胞上高表达Tie2的分子机制，通过流式细胞技术发现缺氧能够诱导髓样细胞表达Tie2，Tie2能够促进巨噬细胞在缺氧的条件中存活，通过Western实验发现AKT信号通路在这一过程中扮演重要角色，因此巨噬细胞上的Tie2分子对肿瘤血管的重建和肿瘤的复发具有至关重要的促进作用；另外荷瘤小鼠脾脏中CD11b+Ly6C+单核系MDSC表达升高，且伴随远端肺转移，在转移瘤中有大量的AnnexinA1+B细胞，通过测序结果发现AnnexinA1+B细胞高表达促炎性蛋白IL1b,推测单核系MDSC诱导AnnexinA1-B细胞极化为AnnexinA1+B细胞，而AnnexinA1+B细胞反过来促使CD11b+Ly6C+单核系MDSC教化为Tie2+巨噬细胞，进而促进肿瘤复发转移，该研究为改善临床肿瘤化疗抵抗提供新方案。