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

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. Contents1. Introduction 2. Origin and differentiation of CAFs 3. 'Reverse Warburg effect' of CAFs 4. Effect of 'Reverse Warburg effect' on metabolic signaling pathways related to CAFs 5. lncRNAs and microRNAs associated with the 'Reverse Warburg effect' of CAFs 6. CAFs and potential therapeutic targets 7. Conclusions

Recent advances in understanding the metabolic plasticity of ovarian cancer: A systematic review

“…On the other hand, in some cancer cells (“C” in Figure 3 ) that produce high levels of lactate in the tumor microenvironment, lactate fuels the adjacent cancer cell proliferation (“D” in Figure 3 ) [ 55 ]. In addition, like non-CSCs, lactate production in glycolytic CSCs (“A” in Figure 3 ) was reported to fuel non-glycolytic CSCs (“B” in Figure 3 ), providing evidence to support the reverse Warburg effect [ 82 ]. There seems to be no difference between ovarian CSC and non-CSC in terms of the metabolic stress response.…”

“…The metabolic phenotype of malignant cells and non-malignant cells in the tumor microenvironment is also heterogeneous, and such crosstalk is bidirectional. Collectively, metabolic reprogramming in cancer cells and adjacent host cells results in the spatiotemporal fine-tuning of the phenotypes of “the Warburg effect” and “the Reverse Warburg effect” [ 82 ].…”

“…Both ovarian CSCs and non-CSCs can predominantly utilize catabolites from adjacent host cells through the reverse Warburg effect [ 87 ]. Specifically, cancer cells secrete ROS into the tumor microenvironment through OXPHOS-dominant metabolic reprogramming and sensitize neighboring CAFs to oxidative stress [ 82 ]. CAFs undergo glycolysis and provide fuel to cancer cells (i.e., lactate, pyruvate, ketone, and fatty acids) [ 34 , 82 , 90 ].…”

“…Specifically, cancer cells secrete ROS into the tumor microenvironment through OXPHOS-dominant metabolic reprogramming and sensitize neighboring CAFs to oxidative stress [ 82 ]. CAFs undergo glycolysis and provide fuel to cancer cells (i.e., lactate, pyruvate, ketone, and fatty acids) [ 34 , 82 , 90 ]. Survival strategies for cancer cells themselves and for neighboring host stromal cells include metabolic plasticity and hijacking [ 91 ].…”

Investigation of the apoptosis‐inducing effect of docetaxel by comprehensive LC–MS–based metabolomics and network pharmacology approaches

“…Cancer cells rely on plenty of energy to increase their biomass and genome (Mukhopadhyay et al, 2020). The Warburg effect tells us that cancer cells utilize large amounts of glucose and maintain high rates of glycolysis (Liang et al, 2022). Besides, a high demand of amino acids is required for protein synthesis by cancer cells at the same time (Filippini et al, 2022).…”