Abstract
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.
Highlights
Solid tumors most often exhaust their oxygen supply creating tumor hypoxia [1]
endothelial cells (ECs) take up exogenous lactate Confluent ECs were exposed to 10 mM sodium L-lactate, a concentration that corresponds to the level of lactate most commonly detected in human tumors [25]. 13C-lactate was used in nuclear magnetic resonance (NMR) experiments. 13C NMR spectra of cell lysate collected 6-h after treatment showed a peak at 19 ppm corresponding to intracellular 13C-lactate (Figure 1A)
We examined the signaling effects of lactate added to the growth medium of ECs and we focused on hypoxia-inducible factor-1 (HIF-1), based on previous reports in tumor cells [21,22]
Summary
Hypoxia initially triggers a key metabolic adaptation, the glycolytic switch, during which glycolysis is uncoupled from the TCA cycle and becomes the primary source of ATP production. This process is extremely fast as it initially proceeds through inhibition of the Pasteur effect, a negative feedback exerted by energy metabolites on the glycolytic flux [2]. The angiogenic switch, corresponding to the initiation of vascular extension, aims at increasing oxygen and nutrient supply to hypoxic tumor sites [6] These two adaptations require de novo protein synthesis and share the transcription factor HIF-1 as a master regulator
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