Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis.
By F. Végran, R. Boidot, Carine Michiels, P. Sonveaux, Olivier Féron. Cancer Research, 2011
764 citations recorded by the source corpus.
Lactate generated from pyruvate fuels production of intracellular NAD(+) as an end result of the glycolytic process in tumors. Elevated lactate concentration represents a good indicator of the metabolic adaptation of tumors and is actually correlated to clinical outcome in a variety of human cancers. In this study, we investigated whether lactate could directly modulate the endothelial phenotype and thereby tumor vascular morphogenesis and perfusion. We found that lactate could enter endothelial cells through the monocarboxylate transporter MCT-1, trigger the phosphorylation/degradation of IκBα, and then stimulate an autocrine NF-κB/IL-8 (CXCL8) pathway driving cell migration and tube formation. These effects were prevented by 2-oxoglutarate and reactive oxygen species (ROS) inhibitors, pointing to a role for prolyl-hydroxylase and ROS in the integration of lactate signaling in endothelial cells. PHD2 silencing in endothelial cells recapitulated the proangiogenic effects of lactate, whereas a blocking IL-8 antibody or IL-8-targeting siRNA prevented them. Finally, we documented in mouse xenograft models of human colorectal and breast cancer that lactate release from tumor cells through the MCT4 (and not MCT1) transporter is sufficient to stimulate IL-8-dependent angiogenesis and tumor growth. In conclusion, our findings establish a signaling role for lactate in endothelial cells and they identify the lactate/NF-κB/IL-8 pathway as an important link between tumor metabolism and angiogenesis.
Subfields: Cancer Research, Genetics, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/a9cffd5eebaa8818d5efc1699088007df54e9e61
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Citations in the corpus
- Acidic extracellular microenvironment and cancer (2013, background): “It can contribute to angiogenesis through induction of IL-8 via nuclear factor-κB (NF-κB) [14] and induction of vascular endothelial growth factor (VEGF/VEGF-A) via hypoxia-inducible transcription factor (HIF)-1 [15].”
- Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions (2015, background): “Findings that endothelial cells and human cytotoxic T lymphocyte (CTL) can take up extracellular lactate [7,8], that lactate inhibits phosphofructokinase (Pfk) [9], and that exposure to lactate leads to a dramatic change in gene expression in L6 muscle cells [10] have shed light on the Lactate Contr”
- The Science and Translation of Lactate Shuttle Theory. (2018, background): “In cancer, lactate stimulates VEGF protein expression in endothelial cells (Dhup et al., 2012; Polet and Feron, 2013; Végran et al., 2011) in a concentration-dependent manner (Beckert et al., 2006).”
- Lactate: a metabolic key player in cancer. (2011, background): “Recently, V egran and colleagues (23) published an article in this journal in which”
- Targeting lactate metabolism for cancer therapeutics. (2013, background): “In support of this model, knockdown or inhibition of MCT1 prevents lactate-mediated stabilization of HIF-1α ex vivo, and CHC inhibits angiogenesis in tumor xenografts (103, 104).”
- Role of PFKFB3-driven glycolysis in vessel sprouting. (2013, neutral): “For instance, lactate stimulates angiogenesis via activation of HIF-1a and upregulation of VEGFR2 (Hunt et al., 2007) or via inhibition of the oxygen sensor PHD2, activating a proangiogenic nuclear factor kB/inter- leukin-8 program (Vé gran et al., 2011).”