肿瘤相关巨噬细胞分泌Exosome包裹的microRNA对肿瘤细胞干性特性的调控机制研究

The maintenance of Cancer stem cells (CSCs) characteristic depends on the tumor microenvironment (TME) support, including tumor associated macrophage (TAMs) is an important factor to keep the CSCs stemness. It was found that the Exosome that released from cells can as a message to regulate cell functions in the cell-cell interaction. Our previous studies have found that TAMs can maintain the stemness characteristics of CSCs; Exosome derived from TAMs can increase the expression of stemness molecule in breast cancer cells; the Exosome from the peripheral blood of breast cancer patients can package microRNA-100 to regulate tumor cell functions. However, the Exosome secretion pattern and deep regulating mechanism of TAMs in TME; and the mechanism of the package of free microRNAs and its functional role in maintaining CSCs stemness were not clear. In this study, we will use breast cancer cell model to determine that the Exosome types which specificity from TAMs; explore the mechanisms that the Exosome as transmission carrier packages specific microRNAs which adjust and maintain CSCs stemness characteristics, finally promote the growth and metastasis of tumor cells; furthermore this study will provide theoretical basis for the tumor treatment strategy by use or control Exosome.

肿瘤干细胞(CSCs)特性维持依赖于肿瘤微环境(TME)的支撑，其中肿瘤相关巨噬细胞（TAMs）是保持CSCs干性的重要因素。细胞分泌的外泌体(Exosome)可在细胞相互作用中传递分子信号，参与调控细胞功能。我们前期研究发现TAMs可以维持CSCs的干性特征；TAMs来源的Exosome可以包裹分泌型microRNA-100发挥表观调控作用,促进乳腺癌细胞中干性分子的表达。然而，TME中TAMs分泌Exosomes，以及包裹游离microRNAs对CSCs干性和功能的维持作用及调控机制并不清楚。本课题以乳腺癌为疾病模型, 研究TME中的TAMs分泌Exosome的类型和特异性；深入探讨Exosome作为传输载体包裹特定的microRNAs传递调控信号，调节和维持CSCs干性特性, 促进肿瘤生长转移的新机制；为利用Exosome为手段的肿瘤治疗策略提供依据。

肿瘤干细胞（CSCs）是引起肿瘤复发转移的关键因素，肿瘤相关巨噬细胞（TAMs）是肿瘤微环境主要组成部分，是保持CSCs干性特征及促进肿瘤发生发展及转移的重要因素。本研究旨在探索肿瘤相关巨噬细胞与CSCs通过miRNA及外泌体等方式相互作用，进而调控CSCs干性特性及肿瘤生长转移的机制。我们发现，TAMs高表达miR-100，此miRNA通过上调IL-1ra的表达促进乳腺癌细胞的干性特征及肺转移。此外，外泌体可以在巨噬细胞和肿瘤间进行传递。乳腺癌细胞来源的外泌体通过传递miR-183至TAMs，抑制靶基因TAMs中的PPP2CA表达，激活NF-κB信号通路，刺激TAMs分泌IL-1β, IL-6, TNFα，进而促进肿瘤的发生发展和转移。TAMs的外泌体中包裹mir-223-3p等miRNA，其中miR-223-3p可以增强乳腺癌细胞的转移能力。在此探索过程中，我们还发现与正常人相比，乳腺癌患者血清中miR-1915-3p的水平显著升高，而miR-455-3p显著降低，并且该趋势在淋巴结转移乳腺癌者和非转移患者的对比中也存在。此两个miRNA是乳腺癌诊断和预后的潜在标志物。本课题以乳腺癌为疾病模型，研究了TAMs和CSCs通过外泌体及miRNA等方式，传递调控信号，调节和维持CSCs干性特征，促进肿瘤生长转移的机制，为乳腺癌的诊断和治疗策略提供了新理论依据。