title: Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-κB/IL-8 pathway that drives tumor angiogenesis.
abstract: 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.
authors.affiliation: Université catholique de Louvain, Pole of Pharmacology & Therapeutics (UCL-FATH), Angiogenesis & Cancer Research Laboratory, Institute of Experimental and Clinical Research (IREC), Brussels, Belgium.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Végran
authors.forename: Romain
authors.initials: R
authors.lastname: Boidot
authors.forename: Carine
authors.initials: C
authors.lastname: Michiels
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonveaux
authors.forename: Olivier
authors.initials: O
authors.lastname: Feron
mesh_terms: D001943:Breast Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020672:I-kappa B Proteins / Q000378:metabolism; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism*; D007656:Ketoglutaric Acids / Q000378:metabolism / Q000494:pharmacology; D019344:Lactic Acid / Q000493:pharmacokinetics* / Q000494:pharmacology; D027501:Monocarboxylic Acid Transporters / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters / Q000378:metabolism*; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D020672:I-kappa B Proteins; D016209:Interleukin-8; D007656:Ketoglutaric Acids; D019344:Lactic Acid; D027501:Monocarboxylic Acid Transporters; D009124:Muscle Proteins; D016328:NF-kappa B; D011393:Procollagen-Proline Dioxygenase; D017382:Reactive Oxygen Species; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1; C508606:CXCL8 protein, human; C406962:SLC16A4 protein, human; C490190:EGLN1 protein, human