研究表明肿瘤干细胞（CSC）是导致肿瘤化疗耐药的根源；CSC的维持和发展受到肿瘤微环境的调控。近来研究提示肿瘤微环境中的巨噬细胞（mø）是CSC调节网络的核心部分，但mø对CSC调控的机理研究还处于起步阶段。化疗是否改造了乳腺肿瘤微环境里的mø，以及CSC的化疗耐药是否与这种改造相关等关键科学问题有待解决。本项目将研究化疗诱导的细胞因子IL-6, MIP-3a和MCP-1等对mø极化或形成新功能亚群的影响，以及极化的mø及其相关细胞因子对乳腺肿瘤干细胞（BCSC）的调控机制；进而阐明化疗相关mø对BCSC和乳腺肿瘤发展的影响及机制研究，最终利用乳腺移植瘤和临床样品，探明拮抗化疗诱导的mø相关细胞因子的临床意义。真正从细胞到临床阐明化疗对mø的改变如何影响CSC及肿瘤的发生发展，是本项目最重要的目标。这些研究的顺利实施，将会为用干预化疗诱导的mø的改变从而逆转肿瘤的化疗抗性提供新的理论基础。

Research has shown that cancer stem cells (CSCs) play important roles in chemo-resistance, and the maintenance and the progression of CSCs are tightly regulated by tumor microenvironment. Recently, some studies have shown that macrophages (mø) in tumor microenvironment play an essential role in the regulation network of CSCs, but the regulation mechanisms are still not clear. Some key questions in this field need to be answered: Can chemotherapies reform the macrophages in breast tumor microenvironment? Is this reformation related to the CSC chemo-resistance? In this proposed study, we will study the effects of chemotherapy-induced cytokines IL-6, MIP-3 alpha and MCP-1 and more on macrophage polarization or novel functional macrophage formation, and the mechanisms of these macrophages and related cytokines on the regulation of breast cancer stem cells (BCSCs); furthermore, we will define the effects and mechanisms of chemotherapy-related macrophages on regulation of BCSCs and breast cancer progression, and elucidate the clinical implications of antagonizing chemotherapy-induced and macrophage-related cytokines utilizing breast cancer PDX models and clinical samples. The most important object of this proposal is to clarify how the reformation of macrophages by chemotherapies affect the BCSCs as well as breast cancer formation and progression at the levels from the in-vitro cells to the clinic. Successful carry-out of these studies will provide novel and strong theoretical support for how to solve the chemotherapy resistance of cancer by antagonizing chemotherapy-induced macrophage reformation.