活性氧调节肝癌干细胞向血管内皮细胞分化

Studies from us and others have shown that there may be new vessels composed of endothelial cells originated from cancer stem cells(CSC) in liver cancer. Forming new functional vessels by endothelial cells differentiated from CSC is another mode of neovascularization. Having different mechanisms from angiogenesis, forming new blood vessels from pre-existing vascular, vessels generated by this mode is resistant to anti-angiogenic treatment.It is reported that reactive oxygen species (ROS) level in CSC is closely related to their differentiation grade as in their normal counterparts, which indicates that ROS may also serve as a signal molecular regulating self-renew and differentiation of CSC. However, how ROS affecting the CSC differentiation into endothelial cells has not been reported up to now.This project will aim to liver cancer stem cell, study the differentiation process of liver CSC into endothelial cells in vitro and in vivo. The regulating actions and mechanisms of ROS on the differentiation of CSC to endothelial cells will also be investigated by evaluating the effect of adding exogenous H2O2 or inhibiting endogenous antioxidant capability on the differentiation process and the expression of molecules involved in NF-κB and Notch signaling pathways in vitro, and by detecting the effect of antioxidant NAC on the vessel number and distribution formed from the two nonvascular modes in xenograft tumor. The results will contribute to reveal the resistance mechanisms of anti-angiogenic therapy and offer important theoretical and experimental foundation for seeking new therapeutic option.

前期研究表明肝癌中部分血管内皮细胞可能由肝癌干细胞分化产生。肿瘤干细胞分化成内皮细胞进而形成功能血管与正常内皮细胞通过血管生成途径形成血管机制不同，因而对目前的抗血管生成治疗不敏感。与正常组织干细胞相似，肿瘤干细胞活性氧(ROS)水平与其分化程度密切相关，因此ROS同样是调节肿瘤干细胞自我更新和分化的信号分子。而ROS如何影响肿瘤干细胞向内皮细胞分化目前未有报道。本项目将以肝癌干细胞作为研究对象，在体内、体外研究肝癌干细胞向内皮细胞分化过程，通过观察加入外源性H2O2或抑制内源性抗氧化系统在体外对分化过程及NF-κB、Notch信号通路相关分子表达的影响、观察抗氧化剂N-乙酰半胱氨酸对移植瘤中两种血管生成模式所形成血管的数量、分布等特征的影响以探讨ROS的调节作用及分子机制。结果将有助于揭示抗血管生成治疗产生耐药的机制，为寻找新的治疗靶点提供重要的理论和实验依据。