TGF-β与Notch信号通路调控乳腺癌内皮间质转化的作用与机制研究

肿瘤血管生成在肿瘤侵袭、转移中至关重要，其中内皮间质转化(EndMT)作为血管生成的重要环节而备受关注，但EndMT如何参与乳腺癌血管生成、其本身的调控机制等目前尚不明确。我们前期研究发现乳腺癌微环境中肿瘤相关巨噬细胞可通过分泌CCL18诱导内皮细胞发生EndMT，其机制可能与激活了Notch与TGF-β信号通路有关；同时也发现乳腺肿瘤启动细胞中存在内皮祖细胞，能分化成有功能的血管内皮细胞。在此基础上，本课题建立体外诱导内皮细胞EndMT模型及乳腺癌血管内皮祖细胞向血管内皮细胞分化模型，通过免疫组化双染、RNA干扰、体外血管生成实验、动物实验，结合临床样本分析，从正常内皮细胞及肿瘤分化内皮细胞两方面探讨EndMT在乳腺癌血管生成中的作用，明确调控EndMT的关键信号通路，阐明EndMT的发生机制，评价干预EndMT是否具有抗肿瘤血管生成的潜在治疗作用，为抗血管生成治疗乳腺癌提供新靶点。

Tumor angiogenesis plays a pivotal role in tumor invasion and metastasis. Endothelial-mesenchymal transition (EndMT), as an important process of angiogenesis, is of great concern. However, how EndMT is involved in the angiogenesis of breast cancer and its regulatory mechanisms remain to be been fully elucidated. Our preliminary study demonstrated that tumor-associated macrophages (TAMs) could induce endothelial cells to undergo EndMT by secreting CCL18 probably through activating the TGF-β and Notch signaling pathways in the microenvironment of breast cancer. Moreover, endothelial progenitor cells were found in the initiating cells of breast tumor, which could differentiate into functional vascular endothelial cells. In the present study, the models of induction of EndMT from endothelial cells and induced differentiation of vascular endothelial progenitor cells of breast cancer into vascular endothelial cells in vitro were conducted. By using immunohistochemical double-staining, RNA interference, angiogenesis in vitro, animal experiment and combining clinical sample analysis, we investigate the role of EndMT in angiogenesis of breast cancer both in normal and tumorous endothelial cells. This study was aimed at determining the mechanism and key signaling pathway regulating EndMT to evaluate the potential therapeutic strategies of EndMT for anti-tumor angiogenesis, which is desirable for developing novel targets for anti-angiogenesis in breast cancer.