‘Reverse Warburg effect’ of cancer‑associated fibroblasts (Review)

Liang,Lin; Li,Wentao; Li,Xin; Jin,Xi; Liao,Qianjin; Li,Yanling; Zhou,Yanhong

doi:10.3892/ijo.2022.5357

‘Reverse Warburg effect’ of cancer‑associated fibroblasts (Review)

Authors:
- Lin Liang
- Wentao Li
- Xin Li
- Xi Jin
- Qianjin Liao
- Yanling Li
- Yanhong Zhou
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Affiliations: 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, Department of Nuclear Medicine, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, P.R. China
Published online on: April 14, 2022 https://doi.org/10.3892/ijo.2022.5357
Article Number: 67

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Abstract

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.

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