Monocarboxylate transporter 1 is a key player in glioma‐endothelial cell crosstalk

Abstract

Glioblastoma (GBM) is one of the most glycolytic and angiogenic human tumors, characteristics that contribute to the poor prognosis associated with this type of tumor. A lactate shuttle has been described between tumor cells and endothelial cells (ECs), with the monocarboxylate transporters (MCTs) acting as important players in this tumor-EC communication. In this study, we aimed to understand how the tumor microenvironment modulates EC metabolism, and to characterize the role of MCTs in the glioma-brain EC crosstalk. Exposure of human brain microvascular ECs (HBMEC) to GBM cell-conditioned media increased the expression of MCT1, which corresponded to activation of oxidative metabolism and an increase in angiogenic capacity, as determined by increased proliferation, migration, and vessel assembly. Lactate depletion from the microenvironment or inhibition of lactate uptake in HBMEC induced an increase in lactate production and a decrease in proliferation, migration, and vessel assembly. Moreover, addition of lactate to HBMEC media promoted activation of AKT and AMPK pathways and increased expression in NFκB, HIF-1α, and the lactate receptor GPR81. Here, we demonstrate a role for MCT1 as a mediator of lactate signaling between glioma cells and brain ECs. Our results suggest that MCT1 can mediate EC metabolic reprograming, proliferation, and vessel sprouting in response to tumor signaling. Thus, targeting MCT1 in both tumor cells and brain EC may be a promising therapeutic strategy for the treatment of GBM.

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review

“…), but 20 mmol/L lactate applied to human brain endothelial cells induced a marked response to cellular lactate uptake and cellular proliferation (Miranda‐Gonçalves et al . ). Gordon et al .…”

“…Furthermore, Miranda‐Gonçalves et al . () showed that glucose uptake was down‐regulated in favor of lactate uptake in response to high extracellular concentrations of lactate in immortalized cells derived from of human brain endothelium. In addition, large increases in mitochondrial activity, cell migration, and formation of capillary‐like structures and associated pro‐angiogenic factors such as hypoxia inducible factor‐1α (HIF‐1α), a transcriptional regulator of VEGF‐A occurred (Semenza ).…”

Lactate Increases Renal Cell Carcinoma Aggressiveness through Sirtuin 1-Dependent Epithelial Mesenchymal Transition Axis Regulation

“…Lactate produced and exported by tumor cells can be used by adjacent tumor cells, as well as other cells in the tumor microenvironment, including endothelial cells and stromal cancer-associated fibroblasts, reprogramming their functions and contributing to tumor progression [52,53]. Consequently, we hypothesized that lactate might also modulate the same epigenetic mechanisms in adjacent normal cells.…”

Lactate Beyond a Waste Metabolite: Metabolic Affairs and Signaling in Malignancy

“…Lactate also mediates polarization of macrophages from an M1-(anti-tumoral type) to an M2-like phenotype (pro-tumoral type) (101, 102); induction of VEGF (vascular endothelial growth factor) expression has been linked to this pro-tumoral state (103). Moreover, it was proposed that endothelial cells rely on extracellular lactate uptake, via MCT1, as a fuel source for their oxidative metabolism, promoting VEGF/VEGFR-2 production through HIF-1α stabilization, endothelial cell migration and tube formation (104)(105)(106).…”