Lactate in the tumour microenvironment: From immune modulation to therapy

Wang, Zi-Hao; Peng, Wen-Bei; Zhang, Pei; Yang, Xun; Zhou, Qiong

doi:10.1016/j.ebiom.2021.103627

Cited by 176 publications

(130 citation statements)

References 126 publications

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“…To survive, tumor cells must adapt to the harsh environments of nutrient stress and reduced pH and oxygen by increasing glucose uptake and lactate production; known as the Warburg effect (4). The increase in lactate production strongly supports diverse cancer cell activities, including cell proliferation, angiogenesis, and tumor invasion activity, promoting tumor aggressiveness (46,47). HIF-1 is a crucial element in the Warburg effect, which promotes disconnection of the TCA cycle from glycolysis and reductive glycolysis.…”

Section: Discussionmentioning

confidence: 99%

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming

Xie¹,

Feng²,

Fan³

et al. 2022

Transl Lung Cancer Res

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Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD).Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR).Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2.Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming.Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.

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Section: Discussionmentioning

confidence: 99%

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming

Xie¹,

Feng²,

Fan³

et al. 2022

Transl Lung Cancer Res

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“…The CAA phenotype further associates with increased releases of metabolites such as lactate, pyruvate, free fatty acids, and ketone bodies [ 9 ]. Such adaptive metabolic state is believed to mimic the hypoxic status and to contribute to immunosuppressive events within the TME, in part through the upregulation of hypoxia-inducible factor-1α (HIF-1α) and c-Myc [ 10 , 11 , 12 ]. In terms of TME localization, these cells have been ascribed to the invasive front of human breast cancer tumors [ 6 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

EGCG Prevents the Onset of an Inflammatory and Cancer-Associated Adipocyte-like Phenotype in Adipose-Derived Mesenchymal Stem/Stromal Cells in Response to the Triple-Negative Breast Cancer Secretome

et al. 2022

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Background: Triple-negative breast cancer (TNBC) cells secretome induces a pro-inflammatory microenvironment within the adipose tissue, which hosts both mature adipocytes and adipose-derived mesenchymal stem/stromal cells (ADMSC). The subsequent acquisition of a cancer-associated adipocyte (CAA)-like phenotype is, however, unknown in ADMSC. While epidemiological studies suggest that consuming a polyphenol-rich diet reduces the incidence of some obesity-related cancers, the chemopreventive impact of green tea-derived epigallocatechin-3-gallate (EGCG) against the cues that trigger the CAA phenotype remain undocumented in ADMSC. Methods: Human ADMSC were exposed to human TNBC-derived MDA-MB-231 conditioned media (TNBC cells secretome) supplemented or not with EGCG. Differential gene expression was assessed through RNA-Seq analysis and confirmed by RT-qPCR. Protein expression levels and the activation status of signal transduction pathways mediators were determined by Western blotting. ADMSC chemotaxis was assessed by a real-time cell migration assay. Results: The TNBC cells secretome induced in ADMSC the expression of the CAA cytokines CCL2, CCL5, IL-1β, and IL-6, and of immunomodulators COX2, HIF-1α, VEGFα, and PD-L1. The epithelial-to-mesenchymal biomarker Snail was found to control the CAA phenotype. EGCG inhibited the induction of CAA genes and the activation status of Smad2 and NF-κB. The induced chemotactic response was also inhibited by EGCG. Conclusion: The induction of an inflammatory and CAA-like phenotype in ADMSC can be triggered by the TNBC cells secretome, while still efficiently prevented by diet-derived polyphenols.

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“…Especially in a tumor microenvironment (TME), altered glucose metabolism is characterized by enhanced lactate generation with a decrease in pH value and an increase in hypoxia [ 10 , 11 , 12 ]. Early studies of the immunosuppressive environment identified that extracellular lactate supports the generation of suppressive macrophages and regulatory T cells [ 13 , 14 ]. Further, lactate secretion is proton-coupled, leading to extracellular acidosis suppressing effector reduction [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

Effection of Lactic Acid Dissociation on Swelling-Based Short-Chain Fatty Acid Vesicles Nano-Delivery

Chen

Zhao

Xue

et al. 2022

Foods

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Functionalized small-molecule assemblies can exhibit nano-delivery properties that significantly improve the bioavailability of bioactive molecules. This study explored the self-assembly of short-chain fatty acids (FA, Cn < 8) to form novel biomimetic nanovesicles as delivery systems. Lactic acid is involved in the regulation of multiple signaling pathways in cancer metabolism, and the dissociation of lactic acid (LA) is used to regulate the delivery effect of short-chain fatty acid vesicles. The study showed that the dissociation of lactic acid caused pH changes in the solution environment inducing hydrogen ion permeability leading to rapid osmotic expansion and shape transformation of FA vesicles. The intrinsic features of FA vesicle formation in the LA environment accompanied by hydrogen ion fluctuations, and the appearance of nearly spherical vesicles were investigated by transmission electron microscopy (TEM) and Fourier Transform Infrared Spectroscopy (FTIR). Compared with the vesicle membrane built by surfactants, the FA/LA composite system showed higher permeability and led to better membrane stability and rigidity. Finally, membrane potential studies with the IEC cell model demonstrate that lactate dissociation capacity can effectively increase the cellular adsorption of FA vesicles. Altogether, these results prove that FA vesicles can function as a stand-alone delivery system and also serve as potential development strategies for applications in a lactate environment.

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Lactate in the tumour microenvironment: From immune modulation to therapy

Cited by 176 publications

References 126 publications

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming

EGCG Prevents the Onset of an Inflammatory and Cancer-Associated Adipocyte-like Phenotype in Adipose-Derived Mesenchymal Stem/Stromal Cells in Response to the Triple-Negative Breast Cancer Secretome

Effection of Lactic Acid Dissociation on Swelling-Based Short-Chain Fatty Acid Vesicles Nano-Delivery

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