NHC Key Laboratory of Carcinogenesis and Hunan Key Laboratory of Cancer Metabolism, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China.
Department of General Surgery, Breast Cancer Center, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China.
Int J Oncol. 2022 Jun;60(6). doi: 10.3892/ijo.2022.5357. Epub 2022 Apr 15.
Metabolic reprogramming is one of the main characteristics of malignant tumors. The metabolic reprogramming of tumors is not only related to the characteristics of cancer cells, but also closely related to the tumor microenvironment (TME). 'Aerobic glycolysis' is considered to be the classic metabolic mode of tumor cells. However, recent experiments have shown that the TME plays a key role in carcinogenesis and epithelial‑mesenchymal transition. Cancer‑associated fibroblasts (CAFs) dominate in the microenvironment and affect the homeostasis of the TME. The interaction between cancer cells and the surrounding CAFs markedly affects the growth, metabolism, metastasis, and progression of cancer. Based on this, a 'dual‑chamber' model, also known as the 'Reverse Warburg effect', is proposed. Specifically, cancer cells secrete hydrogen peroxide into the TME to induce oxidative stress in neighboring stromal cells. CAFs undergo aerobic glycolysis and produce high levels of energy‑rich 'fuels' (such as pyruvate, ketone bodies, fatty acids, and lactic acid). In turn, these energy‑rich 'fuels' then 'feed' cancer cells. The mitochondrial oxidative phosphorylation system produces a large quantity of ATP, such that tumor cells have a higher proliferation ability. The proposed 'Reverse Warburg effect' redefines the tumor cell microenvironment and tumor metabolic reprogramming. Therefore, understanding the 'Reverse Warburg effect' of CAFs and its related mechanisms will help us to understand the association between the microenvironment, the matrix, and cancer cells, and may lead to new treatment strategies and targets.
代谢重编程是恶性肿瘤的主要特征之一。肿瘤的代谢重编程不仅与癌细胞的特征有关,而且与肿瘤微环境(TME)密切相关。“有氧糖酵解”被认为是肿瘤细胞的经典代谢模式。然而,最近的实验表明,TME 在致癌和上皮-间充质转化中起着关键作用。癌相关成纤维细胞(CAFs)在微环境中占主导地位,并影响 TME 的动态平衡。癌细胞与周围 CAFs 的相互作用显著影响癌症的生长、代谢、转移和进展。基于此,提出了一种“双室”模型,也称为“反向沃伯格效应”。具体来说,癌细胞将过氧化氢分泌到 TME 中,诱导邻近基质细胞发生氧化应激。CAFs 进行有氧糖酵解,并产生高水平的富含能量的“燃料”(如丙酮酸、酮体、脂肪酸和乳酸)。反过来,这些富含能量的“燃料”又为癌细胞提供营养。线粒体氧化磷酸化系统产生大量的 ATP,使肿瘤细胞具有更高的增殖能力。所提出的“反向沃伯格效应”重新定义了肿瘤细胞微环境和肿瘤代谢重编程。因此,了解 CAFs 的“反向沃伯格效应”及其相关机制将有助于我们理解微环境、基质与癌细胞之间的联系,并可能为新的治疗策略和靶点提供依据。
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