巨噬细胞介导的Wnt-Numb-Notch信号传导轴调控肝癌组织异质性的机制研究

Liver tumor-initiating cells are a subpopulation of progenitors with self-renewal and differentiation capacity, driving hepatic carcinogenesis and tumor progression. Accumulating evidences have suggested an idea which regards a progenitor can give rise to heterogeneous tumours with a whole range of phenotypes with varying hepatocellular and cholangiocellular differentiation characteristics on its way to differentiation. A niche generated by stomal cells may play important roles in the process. However, detailed mechanism still warrants investigation. Our preliminary data suggests that carbon tetrachloride which stimulates macrophages can induce hepatic differentiation of liver tumor-initiating cells in vivo. The result raises a hypothesis that macrophages can regulate differentiation of liver tumor-initiating cells through paracrine pathways or direct effects. This project aims to verify the hypothesis by using a novel murine liver tumor-initiating cell line and related orthotopic C57BL/6J mouse model. We will investigate the role of macrophages, by secreting Wnt ligands which can stimulate β-catenin-Numb-Notch axis within liver tumor-initiating cells, regulating liver tumor-initiating cell differentiation. The project will give us a deep insight into the mechanism how macrophages take part in regulating heterogeneity of liver cancer, and also suggesting stromal cells as potential therapeutic target for liver cancer.

肝癌起始细胞具备增殖和分化的能力，是肝癌的发生和进展的源头。目前认为肝癌起始细胞分化过程中的不同方向、不同阶段，决定了肝癌组织的异质性。基质细胞创造的微环境是影响该过程的关键因素，但机制仍不清楚。我们前期动物实验发现四氯化碳激活巨噬细胞可诱导肝癌起始细胞向肝细胞癌方向分化，提示巨噬细胞可能对肿瘤起始细胞的分化起调控作用。本课题拟以前期成功建立的C57BL/6J小鼠肝癌起始细胞系及其原位移植肝癌模型为研究对象，围绕激活的巨噬细胞引导肝癌起始细胞分化这一科学问题展开工作，探讨肝脏炎症微环境中单核巨噬细胞表达Wnt配体，作用于肿瘤起始细胞β-catenin-Numb-Notch信号传导轴，调控肿瘤起始细胞向肝细胞癌方向分化的作用及机制。通过研究，将从微环境影响肿瘤发生角度，阐述巨噬细胞参与调控肝癌组织异质性的作用及其机制，有望为以基质细胞为靶点的肝癌干预治疗提供新策略，具有重要的理论与实践意义。