Abstract
Lactate generated from pyruvate fuels production of intracellular NADþ 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 IkBa, and then stimulate an autocrine NF-kB/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/NFkB/
IL-8 pathway as an important link between tumor metabolism and angiogenesis.
Original language | English |
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Pages (from-to) | 2550-2560 |
Number of pages | 11 |
Journal | Cancer Research |
Volume | 71 |
Issue number | 7 |
DOIs | |
Publication status | Published - 2011 |