当前肿瘤代谢调节治疗面临的问题及思考

Current problems and thinkings on the cancer metabolic modulation therapy

随着肿瘤代谢研究的进展,人们发现单一Warburg效应的糖代谢重编程可能不能代表全局定义的肿瘤代谢重编程。线粒体在肿瘤代谢重编程中起着重要的作用。根据前人的研究,我们总结出线粒体功能障碍可通过三种模式调控肿瘤代谢重编程:包括线粒体功能障碍诱导型、核基因突变诱导型、混合型。肿瘤细胞的代谢重编程又因基因型、肿瘤亚型、分化程度、微环境的差异而表现为灵活的代谢可塑性。肿瘤细胞可窃取肿瘤相关细胞的“代谢废物”,与肿瘤相关细胞相互依存、相互影响,表现出代谢共生的特征。除此之外,肿瘤细胞还可表现出稳定的杂合代谢表型,进而影响肿瘤的生物学行为。本文从当前肿瘤糖代谢调节治疗的研究现状出发,涉及当前代谢调节研究面临的问题,总结了线粒体功能障碍对代谢重编程的影响,并重点从肿瘤细胞的代谢可塑性、肿瘤细胞与肿瘤相关细胞之间的代谢耦联以及肿瘤细胞存在的杂合代谢表型等方面出发,讨论了糖代谢中糖酵解和线粒体氧化对于肿瘤代谢复杂性的影响,并针对复杂肿瘤糖代谢提出相应的对策。

With advances in the research on cancer metabolic modulation therapy,it has been found that metabolic reprogramming of cancer cells with a single Warburg effect may not be representative of globally defined tumor metabolic reprogramming.At the same time,mitochondria play an important role in tumor metabolic reprogramming.Based on previous studies,we conclude that mitochondrial dysfunction can regulate tumor metabolic reprogramming through three modes:mitochondrial dysfunction-induced metabolic reprogramming,nuclear gene mutation-induced metabolic reprogramming,and mixed factors-induced metabolic reprogramming.Metabolic reprogramming of tumor cells is characterized by flexible metabolic plasticity due to differences in tumor genotype,tumor subtype,degree of differentiation,and changes of tumor microenvironment.Cancer cells can steal the metabolic wastes of tumor-related cells,and they are interdependent and interact with each other,showing the characteristics of metabolic symbiosis.In addition,cancer cells can also exhibit a stable heterozygous metabolic phenotype which affects the biological behavior of the tumor.This review begins with the current knowledge of tumor glucose regulation therapy,involves the current research problems,and summarizes the effects of mitochondrial dysfunction on metabolic reprogramming.It focuses on the metabolic plasticity of cancer cells,the metabolic coupling between tumor cells and tumor-associated cells,and the heterozygous metabolic phenotype of tumor cells.The effects of glycolysis and mitochondrial oxidative phosphorylation on the complexity of tumor metabolism are discussed,and the corresponding countermeasures are put forward for the complex tumor glucose metabolism.