Switching to a glycolytic metabolism is a rapid adaptation of
tumor cells to
hypoxia. Although this metabolic conversion may primarily represent a rescue pathway to meet the bioenergetic and biosynthetic demands of proliferating
tumor cells, it also creates a gradient of
lactate that mirrors the gradient of
oxygen in
tumors. More than a metabolic waste, the
lactate anion is known to participate to
cancer aggressiveness, in part through activation of the
hypoxia-inducible factor-1 (HIF-1) pathway in
tumor cells. Whether
lactate may also directly favor HIF-1 activation in endothelial cells (ECs) thereby offering a new druggable option to block angiogenesis is however an unanswered question. In this study, we therefore focused on the role in ECs of monocarboxylate transporter 1 (MCT1) that we previously identified to be the main facilitator of
lactate uptake in
cancer cells. We found that blockade of
lactate influx into ECs led to inhibition of HIF-1-dependent angiogenesis. Our demonstration is based on the unprecedented characterization of
lactate-induced HIF-1 activation in normoxic ECs and the consecutive increase in
vascular endothelial growth factor receptor 2 (VEGFR2) and
basic fibroblast growth factor (bFGF) expression. Furthermore, using a variety of functional assays including endothelial cell migration and tubulogenesis together with in vivo imaging of
tumor angiogenesis through intravital microscopy and immunohistochemistry, we documented that MCT1 blockers could act as bona fide HIF-1 inhibitors leading to anti-angiogenic effects. Together with the previous demonstration of MCT1 being a key regulator of
lactate exchange between
tumor cells, the current study identifies MCT1 inhibition as a therapeutic modality combining antimetabolic and anti-angiogenic activities.