Notch信号通路通过调控肝血窦内皮细胞介导的血管微环境参与肝癌发生发展的作用机制研究

It has been demonstrated that endothelial cell-mediated microenvironment has profound influence on tumor development and progression not only through delivering nutrition and oxygen but also through the paracrine mechanism. As a kind of tissue-specific endothelium, liver sinusoidal endothelial cells (LSECs) possess unique characteristics compared with common endothelial cells. Mounting evidence showed that vascular microenvironment mediated by LSECs control the pathological process of the liver under acute or chronic injuries. However, the regulation and the mechanisms of LSECs mediated vascular microenvironment on hepatocellular carcinoma (HCC) development and progression remain largely unknown. We previously reported that Notch signaling participates in invasion and metastasis of HCC through different pathways and that Notch signaling plays a key role in maintaining homeostasis and biological function of hepatic sinusoid and LSECs. Our unpublished data also found that LSECs from peri-HCC tissue possess relatively higher activation of Notch signaling compared with their normal counterparts. Besides, the biological behavior of HCC cells can be augmented by LSECs-derived Notch signaling in a paracrine way. In this project, we seek to explore the contribution of hepatic specific LSECs modulated vascular microenvironment to the development and progression of HCC using the endothelium-oriented Notch modification model. This study will help to reveal novel mechanisms involved in HCC progression and help to discover new strategies for targeting this deadly disease.

血管内皮细胞介导的血管微环境对肿瘤的发生发展发挥重要作用，其不仅为肿瘤生长带来营养物质和氧气，也可通过旁分泌作用参与肿瘤细胞演进。肝血窦内皮细胞（LSECs）是肝脏组织特化的血管内皮细胞，与普通血管内皮相比具有其特殊性。LSECs通过旁分泌途径介导的肝脏血管微环境，在各种急慢性肝损伤的病理发展进程中发挥关键调节作用。但LSECs对肝癌的发生发展有何影响？机制如何？尚不清楚。我们前期发现：Notch信号能通过多条途径影响肝癌侵袭转移；更重要的是，Notch信号参与调控了肝血窦及LSECs的稳态和功能。前期预实验结果也表明：癌旁中的LSECs存在Notch信号活化，并通过Notch信号介导的旁分泌引起肝癌细胞生物学行为和功能改变。基于此，本项目拟利用内皮特异性Notch信号修饰的动物模型，研究组织特化LSECs介导的血管微环境对肝癌发生发展的影响及分子机制，为提出新的肝癌防治策略提供理论依据。

血管内皮细胞介导的血管微环境对肿瘤的发生发展发挥重要调节作用。在本项目的研究中，我们发现癌旁组织中，肝血窦内皮细胞会发生明显的毛细血管化现象，且其表达谱特征会发生一定程度的改变。体内外实验证实肝血窦内皮细胞能够参与调节肿瘤细胞的生物学功能，包括促进肿瘤细胞生长、增强肿瘤细胞的迁移和侵袭能力。此外，在肝癌临床标本和荷瘤小鼠模型中，我们还发现癌旁的肝血窦内皮Notch信号存在激活现象。为进一步研究血管Notch活化对肿瘤演进的影响，我们对血管特异性Notch活化小鼠的肝血窦内皮转录组测序数据进行了深入的生物信息学分析。我们发现内皮特异性Notch信号活化重塑了肝血窦内皮细胞的旁分泌谱系，其可能机制是Notch信号激活促进血管内皮细胞发生老化，进而老化相关炎症因子分泌增多，造成肿瘤血管微环境向促炎性方向发生改变，最终造成炎性细胞的募集增多，肿瘤生长加快。相反，Notch信号特异性阻断剂治疗能够使荷瘤小鼠肿瘤血管内皮细胞老化现象减少，炎性指标下降，且肿瘤生长受到显著抑制。因此，我们的研究发现，在肝癌发生发展过程中，血管内皮特异性Notch信号激活能够促进细胞发生老化进而释放过多炎症因子，通过增强肿瘤中炎性细胞的募集最终促进肿瘤生长。