Cell-in-cell介导肿瘤细胞表达巨噬细胞特异性表面标志物的机制研究

Cell-in-cell process is characterized by one or more live cells (reffered to effector cells) internalizing into another cells (reffered to host cells) with the alteration of biological effect of both effector and host cells. Researchers reported cancer expression CD163 is related to early distant recurrence and reduced patient survival. Recently, we observed in tissue specimens many kinds of cancer expression of CD163, a macrophage scavenger receptor, which is correlated with cell-in-cell occurance between CD163+ macrophage and tumor cells. We explored in vitro a novel interaction that macrophages penetrating into tumor cells for tumor cells acquiring macrophage character led to tumor cells invasion. Unlike conventional macrophage engulfing apoptotic cells, this process was initiated by tumor cells uptaking macrophage through cell-in-cell interaction. We supposed that this process might be a manner for tumor cells acquiring cellular identity of macrophage, which is associated with migration. In the present study, we aim to clarify the mechanism of tumor cells expression macrophage marker by cell-in-cell process, which in turn leads to the tumor cells invasion and metastasis. To explore the mechanism of tumor cells acquiring new character and its significance will provide a way to elucidate the tumor cell conversion, as well as potential implication in tumor histogenesis and aggressiveness.

Cell-in-cell指一个或多个细胞主动“钻入”另一个细胞的胞质中形成细胞叠套结构并产生生物效应的过程。我们发现，胃癌、乳腺癌等多种肿瘤组织中肿瘤细胞表达巨噬细胞特异性表面标志物CD163，同时检出高表达CD163的巨噬细胞能与肿瘤细胞形成cell-in-cell，两者呈现相关性；而表达巨噬细胞特异性表面标志物的肿瘤细胞表现出更强的转移侵袭能力同时患者表现出更差的生存预后特点。肿瘤细胞通过何种机制产生巨噬细胞的特性？更新后的肿瘤细胞具有哪些新的功能？这些问题目前仍未知。本课题聚焦cell-in-cell过程参与肿瘤细胞表达巨噬细胞表面标志物的机制研究，探讨具有巨噬细胞特性的肿瘤细胞功能改变的规律，为解析单个细胞水平上巨噬细胞-肿瘤细胞相互作用提供独具特色的研究切入点，也为研究肿瘤转移侵袭提供了全新视角，具有重要的理论基础和临床研究价值。

细胞叠套结构参与肿瘤的发生发展，但其过程中的分子机制及临床意义尚不明确。本项目在前期研究基础上，综合运用分子生物学、细胞生物学手段对cell-in-cell的临床特征及意义、巨噬细胞迁移抑制因子（MIF）及肿瘤细胞高尔基体磷蛋白3（GOLPH3）对肿瘤生长和转移的作用进行了初步研究。主要研究内容如下：（1）我们研究了cell-in-cell在肿瘤组织中的检出情况，阐述了cell-in-cell与病理特征如临床分期、分化程度等高度相关，并且cell-in-cell是预后不良的独立危险因素。（2）我们进一步发现巨噬细胞迁移抑制因子（MIF）通过激活AKT-ERK通路促进肿瘤生长和转移的作用机制。（3）我们在研究cell-in-cell的钻入过程中发现GOLPH3对细胞骨架的调控。体内外实验结果显示，肿瘤细胞高表达GOLPH3通过激活FAK/Raf/MEK和Wnt/β-catenin通路促进其增殖和迁移能力。研究结果将加深人们对cell-in-cell在肿瘤发生发展中的认识，更深入的阐释肿瘤转移复发的分子机制，为肿瘤的治疗提供新的靶标，具有重要的科学意义和临床价值。项目资助发表SCI论文1篇，已接收1篇，待发表1篇。