TFEB启动自噬促进结肠癌干样细胞向血管内皮细胞分化的机制

Tumour cells can protect themselves from necrosis and apoptosis through autophagy to get enough energy in nuttition lack, hypoxia, chemotherapy, radiotherapy and other injury. In our previous study, the result showed that the expression level of TFEB, the specific marker of autophagy, had significant correlation with the ability of tumoue angiogenesis and can also predict the survival time of patients in 438 colon cancer patients; Futher research showed that colon cancer stem-like cells can differentiate into vascular endothelial cells. The potency of colon cancer stem-like cells differentiating into vascular endothelial cells can be blockaded or enchanced when their autophagy was blockaded or agitated, so we assumed that TFEB regulate aotophagy and enhanced the differentiation into vascular endothelial cells in colon cancer stem-like cells. It was known that VEGFR-NOTCH1 signal pathway regulate the differentiation of cancer stem cells into vascular endothelial cells. The following study we want to explore the possible mechanism that TFEB activate VEGFR-NOTCH1 signal pathway to regulate the differentiation of colon cancer stem-like cells into vascular endothelial cells through the methods of signal molecules blocking and over-expression, and demonstrate that TFEB may be an important predict factor of anti-angiogensis and survival of colon cancer patients, also the result will rich the theory of anti-angiogensis and may be a new target in colon cancer treatment.

肿瘤细胞通过自噬增加能量和营养供应，保护机体避免发生坏死、凋亡。前期研究结果表明在438例结肠癌患者中肿瘤自噬标记物TFEB（转录因子EB）的表达和肿瘤血管生成能力及预后明显相关；进一步研究发现结肠癌干样细胞能够向血管内皮细胞分化，而阻断和激动结肠癌干样细胞的自噬能够阻断和增强其向血管内皮细胞分化的潜能；在此基础上我们提出TFEB启动自噬促进结肠癌干样细胞向血管内皮细胞分化的设想。而VEGFR-NOTCH1信号通路是介导肿瘤干细胞向血管内皮细胞分化的重要通路，拟进一步通过信号分子阻断和过表达的方法，探讨结肠癌干样细胞是否通过TFEB启动自噬激活VEGFR-NOTCH1信号通路调控其向血管内皮细胞分化；并前瞻性研究TFEB可能是结肠癌抗肿瘤血管生成治疗疗效和预后的重要预测因子，以期进一步丰富结肠癌抗肿瘤血管生成治疗的理论基础和新的可能靶点。

本研究通过构建TFEB 重组慢病毒过表达和干扰载体，建立结肠癌细胞稳定株，并未发现如文献报告的TFEB对自噬有影响，并经过与原作者沟通及三次重复后，还是没有重复出文献的结果。自噬作为细胞保护措施，它在肿瘤大剂量分割放疗中会不会起保护作用？为了回答这个问题，我们将肿瘤细胞分别接种于裸鼠后肢两侧，对其中一侧进行8GY×3f照射后，进行了基因芯片筛查，虽未发现TFEB有变化，但发现了另外一个比较有意义的靶点CXCR4，并构建了CXCL12病毒载体，制备了CAR-T细胞，在体外显示了良好的杀伤功能。下阶段将进行动物实验进行验证。另外我们临床上大剂量分割放疗联合免疫治疗上取得了良好疗效，成功注册了相关的临床研究，注册号：ChiCTR1900026885。.在研究基金资助的基础上已经发表SCI论文2篇，后继的工作估计还会发表1篇。