组织微环境浸润的MSCs促进乳腺癌转移的作用及机制研究

The development and metastasis of malignant tumor not only involves malignant proliferation and migration of tumor cells, but also closely related to the tumor tissue microenvironment. MSCs recruiting immunocyte migrate to tumors, and participate in the construction and remodeling of the tumor tissue microenvironment. We found that MSCs from lung tissue microenvironment formed after breast cancer metastasis, can significantly promote breast cancer metastasis. However, the mechanism among them remain unclear. Based on the interaction between tissue microenvironment and MSCs, we will usecell experiment(in vitro) and breast cancer mouse models( in vivo) to determine (1) status and function changes of MSCs in lung metastatic tissue microenvironment; (2) the key molecules or cell of breast cancer metastasis regulated by MSCs in lung metastatic tissue microenvironment; (3) the mechanism of breast cancer metastasis regulated by interaction between MSCs and lung metastatic tissue microenvironment. The completion of this project is expected to provide not only critical information for understanding of the molecular mechanisms of breast cancer metastasis, but also theoretical basis for new strategies of breast cancer therapy.

肿瘤发生和转移不只涉及肿瘤细胞本身的恶性增殖和迁移，还与其所处的肿瘤组织微环境密切相关。间充质干细胞（MSCs）招募免疫细胞等到肿瘤部位共同参与构建肿瘤组织微环境。我们的前期研究发现，乳腺癌肺转移组织微环境浸润的MSCs能显著促进乳腺癌转移，目前其分子机制尚不明确。本项目拟以肺转移组织微环境与MSCs 相互作用为出发点，利用体外细胞实验和体内小鼠乳腺癌肺转移模型，探讨（1）肺转移组织微环境对MSCs细胞状态及功能的影响；（2）肺转移组织微环境浸润的MSCs促进乳腺癌转移的作用细胞或靶点分子；（3）阐明肺转移组织微环境与MSCs相互作用调控乳腺癌转移的作用机制。本项目将为人们充分认识乳腺癌转移的机制提供了一个新的视角，为临床上乳腺癌的早期诊断和预后提供有效的生物学标志物和靶向治疗的靶点，为进一步探索抗乳腺癌新的治疗策略和方法提供理论依据。

本项目以肺转移组织微环境与MSCs 相互作用为出发点，利用体外细胞实验和体内小鼠乳腺癌肺转移模型，探究组织微环境浸润的MSCs促进乳腺癌转移的作用及机制。研究发现，小鼠乳腺肿瘤肺组织（L-MSCs）和骨髓中的MSCs（BM-MSCs） 细胞形态和细胞表面标记物表达一致。与对照组BM-MSCs相比，L-MSCs组肺部肿瘤结节数量显著增加，提示肿瘤肺转移组织微环境浸润的MSCs显著促进乳腺癌的转移。肺转移组织微环境浸润的L-MSCs促进乳腺癌转移的过程可能与大量招募CD11b+Ly6G+中性粒细胞有关，其作用机制尚在研究中。此外，还发现炎症因子IFNγ和TNFα诱导MSCs细胞凋亡是通过NO实现的；而肝纤维化微环境促进Dll4和SDF-1依赖的T细胞谱系重建；邻苯二甲酸酸酯通过促进间充质干细胞分化诱导小鼠肥胖的发生。在本项目资助下共发表3篇论文，Stem Cell Research and Therapy、Cell Death & Disease和中华微生物学和免疫学杂志（核心期刊）。