保护性自噬调控胆管癌等恶性肿瘤细胞血管生成拟态形成的研究现状

Research advances in the role of protective autophagy in regulating vasculogenic mimicry formation in malignancies such as cholangiocarcinoma

胆管癌是起源于肝内胆管和肝外胆管上皮的原发性肝恶性肿瘤,缺氧和营养匮乏等诱发的血管生成拟态(VM)是胆管癌恶性增殖和复发转移的关键因素。在既往研究自噬维护营养匮乏下细胞营养代谢平衡,以及预实验证实胆管癌自噬与VM呈正相关,胆管癌细胞PAT4高表达的基础上,提出胆管癌通过保护性自噬维持细胞内代谢平衡和细胞稳态调控VM形成;作为肿瘤微环境的营养感受器PAT4通过PI3K-Akt-mTORC1信号通路介导保护性自噬调控VM形成的假说。从组织学水平、细胞分子水平和体内实验研究,验证自噬从维持细胞代谢、干细胞特性和细胞外基质重塑三方面调控VM形成,探讨PAT4介导自噬调控VM的信号机制。揭示自噬是胆管癌细胞在营养匮乏状态下真正的能量营养来源,PAT4是自噬调控VM形成的扳机点。为研究胆管癌细胞的代谢提供了思路,为抗血管药物联合自噬抑制剂治疗高侵袭性肿瘤奠定了理论基础。

Cholangiocarcinoma is a primary malignant tumor derived from the epithelium of the intrahepatic and extrahepatic bile ducts, and vasculogenic mimicry induced by hypoxia and lack of nutrition is a key factor for malignant proliferation, recurrence, and metastasis of cholangiocarcinoma. Previous studies have shown that autophagy maintains cell nutrition metabolism under the condition of a lack of nutrition, and preliminary experiments have confirmed that autophagy was associated with VM in cholangiocarcinoma and there was high expression of PAT4 in cholangiocarcinoma cells;on the basis of these studies, it is pointed out that in cholangiocarcinoma, protective autophagy regulates VM formation by maintaining intracellular metabolic balance and cellular homeostasis. As a nutrient sensor in tumor microenvironment, PAT4 mediates protective autophagy via the PI3K-Akt-mTORC1 signaling pathway to regulate VM formation. Histological, cellular molecular, and in vivo experiments have confirmed that autophagy regulates VM formation by maintaining cell metabolism, stem cell features, and extracellular matrix remodeling, which helps to investigate the signal mechanism for PAT4 mediating autophagy to regulate VM. It is suggested that autophagy is the source of energy and nutrition in cholangiocarcinoma cells under the condition of a lack of nutrition, and PAT4 is the trigger point for autophagy in regulating VM formation. These findings provide new thoughts for the metabolism of cholangiocarcinoma cells and lay a theoretical foundation for antiangiogenic drugs combined with autophagy inhibitors in the treatment of highly aggressive tumors.