靶向肿瘤胆固醇代谢:机遇与挑战

Targeting cholesterol metabolism in cancer:opportunities and challenges

胆固醇是细胞膜的重要组成成分,异常的胆固醇代谢不仅和心血管疾病密切相关,也和肿瘤的发生、发展密不可分。肿瘤细胞在侵袭和转移的过程中,需要大量的胆固醇来满足自身快速生长的物质需求。胆固醇不能在体内代谢为二氧化碳和水,参与供能。大量累积的胆固醇会代谢为不同生物功能的次级产物,参与微环境里的代谢调控和免疫调控,进一步促进肿瘤的发生、发展。在肿瘤发生、发展过程中,肿瘤细胞内或者细胞外的改变会触发胆固醇的代谢改变,从而促进肿瘤的生长。另外,微环境里的免疫细胞,也需要胆固醇来维持自身正常功能的需要,单纯的降低血清胆固醇可能会损害免疫功能,促进肿瘤生长。肿瘤细胞和免疫细胞对微环境中胆固醇的抢夺以及胆固醇的代谢产物相互之间的影响,构成了微环境中胆固醇调控的复杂体系。因此,阐明肿瘤细胞和免疫细胞胆固醇代谢的特点,是靶向胆固醇代谢的抗肿瘤策略的关键,而基于靶向胆固醇代谢的联合治疗有望提高某些特定胆固醇代谢特征的肿瘤患者疗效。

Cholesterol is an essential component of cell membrane.Abnormal cholesterol metabolism is not only closely related to cardiovascular diseases,but also closely related to the occurrence and progression of cancer.In the process of invasion and metastasis,cancer cells need a large amount of cholesterol to meet their rapid growth.Cholesterol is not metabolized into carbon dioxide and water and cannot be directly involved in energy supply.Cholesterol⁃derived metabolites participate in metabolic and immune regulation of tumor microenvironment in supporting cancer progression.To further promote tumor growth,intrinsic drivers in tumor cells or extrinsic factors in microenvironment can trigger changes in cholesterol metabolism during tumor progression.Furthermore,immune cells in the microenvironment also need cholesterol to maintain their normal functions.Simply lowering serum cholesterol may impair immune function and lead to tumor progression.The complex system of cholesterol regulation in microenvironment is formed by the grabbing of cholesterol by tumor cells and immune cells and the influence of cholesterol metabolites on each other.Therefore,to elucidate the characteristics of cholesterol metabolism in tumor cells and immune cells is the key to target cholesterol metabolism for cancer therapy.This review focuses on the effects of cholesterol metabolism changes on tumor cells and immune cells as well as the strategies of targeting cholesterol metabolism for cancer therapy.Combination therapy based on targeted cholesterol metabolism is expected to improve the efficacy of patients with certain characteristics of cholesterol metabolism.