肿瘤相关巨噬细胞对乳腺癌干细胞化疗耐药的调控机制研究

Studies have shown that cancer stem cells(CSCs) played an important role in chemo-resistance of breast cancer and its biological characteristics were regulated by the strmal cells in the tumor microenvironment. Our previous study found that tumor-associated macrophages (TAMs)are the moust abundant inflammatory cells in breast cancer microenvironment and it could promote the metastasis of breast cancer via the secretion of CCL18. However, whether TAMs regulated the biological characteristics of CSCs is still unclear. Recently, we also found that there is a positive feedback loop between the activation of TAMs and the epithelial - mesenchymal transition (EMT) of breast cancer cells. The exist of this loop maintains the EMT phenotype of tumor cells, and is significantly correlated to the generation of cancer stem cells. Based on these, this subject will study whether TAMs enrich CSCs and induce chemo-resistance in breast cancer and further explore the underlying molecular mechanisms. This study will helps us to reveal the molecular regulation network of tumor cells plasticity regulated by the uncontrolled inflammatory microenvironment and provides a theoretical basis for the development of new molecule targets for breast cancer targeted therapy.

研究表明肿瘤干细胞是参与乳腺癌化疗耐药的重要机制，其生物学特性受肿瘤微环境间质细胞的调控。我们前期研究发现肿瘤微环境中数目最多的炎症细胞肿瘤相关巨噬细胞（TAMs）通过CCL18促进肿瘤细胞迁移。但TAMs是否调控肿瘤干细胞的生物学特性和化疗耐药目前尚不清楚。最近我们又发现TAM的激活与肿瘤细胞上皮-间质转化（EMT）形成正反馈环路，维持肿瘤细胞EMT表型，并与肿瘤干细胞生成密切相关。在此基础上，本课题将通过TAMs与肿瘤细胞体外共培养模型、人源化小鼠肿瘤模型和术前化疗病人标本的分析，研究TAMs诱导肿瘤干细胞富集和化疗耐药的生物学现象，并进一步探索其潜在的分子机制。本研究有助于进一步揭示非可控性炎症微环境对肿瘤细胞可塑性调控的分子网络，为针对相关节点分子发展新型乳腺癌靶向治疗提供理论依据。

乳腺癌是女性最常见的恶性肿瘤之一，严重危害女性健康，威胁女性生命。根据我国肿瘤登记中心发表的《 2017 中国肿瘤登记年报》数据显示，我国每天约1万人确诊癌症，每分钟约7人确诊患癌，与2012年相比，癌症新发人数继续上升，从358万增加到368万，增幅3%，而全世界新发病例约1409万，中国新发癌症病例占世界的1/4，乳腺癌的发病率居中国女性恶性肿瘤首位。项目分责人团队围绕乳腺癌肿瘤微环境、长非编码RNA、侵袭迁移及治疗耐药展开了一些列研究，并取得良好成果：1. 首次揭示内分泌治疗耐药的乳腺癌细胞引起化疗耐受的机制；2.揭示肿瘤微环境中淋巴细胞和巨噬细胞导致免疫抑制的机制，为肿瘤免疫治疗提供了新的治疗方案和靶点；3. 报道长非编码RNA可直接与信号分子结合调控信号通路；4.miRNAs可调控免疫细胞功能；5. E2F7过表达导致乳腺癌细胞对他莫昔芬耐药。以上研究成果提出了乳腺癌耐药的新视角，负责人已根据研究成果设计并展开了相关临床研究，有望提高相关乳腺癌患者的治愈率和生存率。