肿瘤与胆固醇:千丝万缕低相诉

Cancer and cholesterol: friend or foe

胆固醇在机体内发挥重要作用,LXR与SREBP2所介导的调节通路可通过影响胆固醇合成及代谢过程,调控胞内胆固醇稳态。而肿瘤细胞可通过代谢重编程,增强其恶性增殖、侵袭、转移和适应不利生存环境的能力,其中胆固醇代谢重编程发挥一定作用,主要表现为肿瘤细胞内胆固醇合成水平上调及其代谢产物异常堆积。近期研究显示,肿瘤微环境中免疫细胞也存在胆固醇代谢改变,以抑制胆固醇合成途径为靶点的治疗策略同样会干扰免疫细胞正常代谢稳态。因此,寻找靶向胆固醇代谢途径的抗肿瘤药物,在抑制肿瘤细胞与维持免疫细胞活性之间找到平衡,是目前抗肿瘤代谢免疫治疗中亟待解决的问题。本综述通过探究胞内胆固醇稳态调节途径、胆固醇及其代谢产物在肿瘤发生、发展中的作用及机制,发现针对胆固醇酯、27-羟胆固醇和Dendrogenin A等的调节剂可能是抗肿瘤代谢治疗的潜在靶点,其中胆固醇酯化抑制剂阿伐麦布,在研究中显示可增强免疫系统功能,在抗肿瘤代谢治疗策略中受到关注。这种抑制肿瘤细胞,同时调节肿瘤微环境中免疫细胞胆固醇代谢、延缓肿瘤进展和转移的抗肿瘤代谢治疗策略,可能为肿瘤患者的治疗带来新希望。

Cholesterol plays an important role in the body.The regulatory pathways mediated by LXR and SREBP2 can regulate intracellular cholesterol homeostasis by affecting cholesterol synthesis and metabolism.The tumor cells can enhance their ability of malignant proliferation,invasion,metastasis and adapt to the unfavorable living environment through metabolic reprogramming,in which the reprogramming of cholesterol metabolism plays a role,mainly manifested in the up-regulation of cholesterol synthesis in cancer cells and abnormal accumulation of their metabolites.Recent studies have shown that in the microenvironment of tumors,there is a reprogramming of cholesterol metabolism in the opposite trend of change,and its normal function is affected.Therapeutic strategies targeting cholesterol synthesis pathways also interfere with the normal metabolic homeostasis of immune cells.Therefore,looking for new antitumor drugs targeting different metabolic pathways is imminent.This review explores the roles and mechanisms of intracellular cholesterol homeostasis,cholesterol and its metabolites in the development of cancer,finding that modulators targeting cholesterol esters,27-hydroxycholesterol,and Dendrogenin A may be potential targets of antitumor metabolic treatments.The cholesterol esterification inhibitor,Avasimibe has been shown to enhance immune system function and gets attention in antitumor metabolic therapy strategies.The proposed concept of anti-tumor metabolic therapy,which mainly regulates cholesterol metabolism of immune cells in the tumor microenvironment,delays cancer progression and metastasis,may bring new hope for the treatment of cancer patients.