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

Abstract

To sustain their high proliferation rates, most cancer cells rely on glycolytic metabolism, with production of lactic acid. For many years, lactate was seen as a metabolic waste of glycolytic metabolism; however, recent evidence has revealed new roles of lactate in the tumor microenvironment, either as metabolic fuel or as a signaling molecule. Lactate plays a key role in the different models of metabolic crosstalk proposed in malignant tumors: among cancer cells displaying complementary metabolic phenotypes and between cancer cells and other tumor microenvironment associated cells, including endothelial cells, fibroblasts, and diverse immune cells. This cell metabolic symbiosis/slavery supports several cancer aggressiveness features, including increased angiogenesis, immunological escape, invasion, metastasis, and resistance to therapy. Lactate transport is mediated by the monocarboxylate transporter (MCT) family, while another large family of G protein-coupled receptors (GPCRs), not yet fully characterized in the cancer context, is involved in lactate/acidosis signaling. In this mini-review, we will focus on the role of lactate in the tumor microenvironment, from metabolic affairs to signaling, including the function of lactate in the cancer-cancer and cancer-stromal shuttles, as well as a signaling oncometabolite. We will also review the prognostic value of lactate metabolism and therapeutic approaches designed to target lactate production and transport.

Keywords: GPR81; lactate; lactate shuttles; metabolic fuel; monocarboxylate transporters; signaling molecule; warburg effect.

Figure 1

Summary of lactate roles in the tumor microenvironment. Lactate acts as a metabolic fuel, driving metabolic crosstalks involving MCT-mediated lactate shuttles among cancer cells, or between cancer cells and cancer-associated stromal cells. In addition, lactate acts as a signaling oncometabolite, intracellularly activating signaling pathways or acting as an extracellular ligand of the lactate receptor GPR81. Ultimately, cancer aggressiveness features are promoted, such as proliferation, migration, and invasion of cancer cells, extracellular matrix (ECM) degradation, angiogenesis, immunological escape, and resistance to therapy.