Department of Medicine, R.U. in Molecular Medicine and Biotechnology, University Campus Bio-Medico of Rome, 00128 Rome, Italy.
Oncogenomic and Epigenetic Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy.
Cells. 2020 Nov 9;9(11):2439. doi: 10.3390/cells9112439.
Tumor heterogeneity impinges on all the aspects of tumor history, from onset to metastasis and relapse. It is growingly recognized as a propelling force for tumor adaptation to environmental and micro-environmental cues. Metabolic heterogeneity perfectly falls into this process. It strongly contributes to the metabolic plasticity which characterizes cancer cell subpopulations-capable of adaptive switching under stress conditions, between aerobic glycolysis and oxidative phosphorylation-in both a convergent and divergent modality. The mitochondria appear at center-stage in this adaptive process and thus, targeting mitochondria in cancer may prove of therapeutic value. Metformin is the oldest and most used anti-diabetic medication and its relationship with cancer has witnessed rises and falls in the last 30 years. We believe it is useful to revisit the main mechanisms of action of metformin in light of the emerging views on tumor heterogeneity. We first analyze the most consolidated view of its mitochondrial mechanism of action and then we frame the latter in the context of tumor adaptive strategies, cancer stem cell selection, metabolic zonation of tumors and the tumor microenvironment. This may provide a more critical point of view and, to some extent, may help to shed light on some of the controversial evidence for metformin's anticancer action.
肿瘤异质性影响肿瘤发生、转移和复发的各个方面。它越来越被认为是肿瘤适应环境和微环境线索的推动因素。代谢异质性完美地符合这一过程。它强烈促进了代谢可塑性，这种可塑性是癌细胞亚群的特征，能够在有氧糖酵解和氧化磷酸化之间在趋同和发散两种模式下在应激条件下进行适应性切换。线粒体在这个适应过程中处于中心舞台，因此，针对癌症中的线粒体可能具有治疗价值。二甲双胍是最古老、应用最广泛的抗糖尿病药物，其与癌症的关系在过去 30 年中经历了兴衰。我们认为，根据肿瘤异质性的新观点，重新审视二甲双胍的主要作用机制是有用的。我们首先分析其线粒体作用机制的最一致观点，然后将其置于肿瘤适应策略、癌症干细胞选择、肿瘤代谢分区和肿瘤微环境的背景下。这可能提供一个更具批判性的观点，并在一定程度上有助于阐明二甲双胍抗癌作用的一些有争议的证据。
