Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties

Treating metastasis has been challenging due to tumors complexity and heterogeneity. This complexity is partly related to the crosstalk between tumor and its microenvironment. Endothelial cells -the building blocks of tumor vasculature- have been shown to have additional roles in cancer progression than angiogenesis and supplying oxygen and nutrients. Here, we show an alternative role for endothelial cells in supporting breast cancer growth and spreading independent of their vascular functions. Using endothelial cells and breast cancer cell lines MDA-MB231 and MCF-7, we developed co-culture systems to study the influence of tumor endothelium on breast tumor development by both in vitro and in vivo approaches. Our results demonstrated that endothelial cells conferred survival advantage to tumor cells under complete starvation and enriched the CD44HighCD24Low/- stem cell population in tumor cells. Moreover, endothelial cells enhanced the pro-metastatic potential of breast cancer cells. The in vitro and in vivo results concordantly confirmed a role for endothelial Jagged1 to promote breast tumor through notch activation. Here, we propose a role for endothelial cells in enhancing breast cancer progression, stemness, and pro-metastatic traits through a perfusion-independent manner. Our findings may be beneficial in developing novel therapeutic approaches.鉴于肿瘤的复杂性与异质性，转移瘤的治疗始终极具挑战性。这种复杂性在一定程度上源于肿瘤与其微环境之间的交互串扰。内皮细胞作为肿瘤血管的核心构成单元，现有研究表明其在癌症进展中还承担着除血管生成、供氧供能之外的额外功能。本研究揭示了内皮细胞不依赖自身血管功能，在支持乳腺癌增殖与扩散中的另一重作用。本研究使用内皮细胞与乳腺癌细胞系MDA-MB-231、MCF-7构建共培养体系，通过体外（in vitro）与体内（in vivo）实验手段，探究肿瘤内皮细胞对乳腺癌发生发展的调控作用。研究结果显示，在完全饥饿培养条件下，内皮细胞可赋予肿瘤细胞生存优势，并富集肿瘤细胞中CD44HighCD24Low/-干细胞群。此外，内皮细胞可增强乳腺癌细胞的促转移潜能。体外与体内实验结果一致证实，内皮细胞表面的Jagged1可通过激活Notch信号通路促进乳腺癌发生发展。本研究提出，内皮细胞可通过不依赖灌注的方式，增强乳腺癌进展能力、维持肿瘤细胞干细胞干性并强化其促转移表型。本研究结果可为新型抗肿瘤治疗策略的开发提供理论依据。