Monocarboxylate transporters in cancer

Abstract

Background: Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different metabolic phenotypes. For energy production, cancer cells may use 4 main fuels that are shuttled in 5 different metabolic pathways. Glucose fuels glycolysis that can be coupled to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in oxidative cancer cells or to lactic fermentation in proliferating and in hypoxic cancer cells. Lipids fuel lipolysis, glutamine fuels glutaminolysis, and lactate fuels the oxidative pathway of lactate, all of which are coupled to the TCA cycle and OXPHOS for energy production. This review focuses on the latter metabolic pathway.

Scope of review: Lactate, which is prominently produced by glycolytic cells in tumors, was only recently recognized as a major fuel for oxidative cancer cells and as a signaling agent. Its exchanges across membranes are gated by monocarboxylate transporters MCT1-4. This review summarizes the current knowledge about MCT structure, regulation and functions in cancer, with a specific focus on lactate metabolism, lactate-induced angiogenesis and MCT-dependent cancer metastasis. It also describes lactate signaling via cell surface lactate receptor GPR81.

Major conclusions: Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT^+/- and MCT^-/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

Keywords: Angiogenesis; Cancer metabolism; GPR81; Metabolic symbiosis; Metastasis; Monocarboxylate transporters (MCTs).

Figure 1

Main characteristics of lactate transporters MCT1-4. The cartoon depicts the predicted structure of functional MCT1 that, as a dimer, interacts with 2 CD147/basigin ancillary proteins at the cell membrane. Like MCT2-4, MCT1 is a passive symporter that shuttles lactate together with a proton along their concentration gradients across membranes. On the bottom is a summary of know regulators of MCT expression and stability, together with MCT affinities for lactate. + indicates induction/stabilization; - indicates repression/destabilization; * refers to pathways that are not yet fully characterized; ^# refers to indirect influence; ^$ refers to an unlikely still existing possibility; ^§ refers to a situation reported only in cancer cells. For abbreviations, see list.

Figure 2

Metabolic symbiosis and commensalism based on the exchange of lactate in cancer. The cartoon depicts a tumor-feeding blood vessel delivering glucose and oxygen to cancer cells. An oxidative cancer cell is represented close to the blood vessel, a hypoxic cancer cells remotely, and a host cell on the bottom. From a metabolic standpoint, the hypoxic cancer cell has no choice but to perform anaerobic glycolysis to survive, which implies having access to high amounts of glucose. Comparatively, the oxidative cancer cell can use several different metabolic fuels. When nearby glycolytic cells provide lactate (usually a MCT4-dependent process), it uses lactate as an oxidative fuel preferentially to glucose (usually a MCT1-dependent process), which increases glucose availability for the glycolytic cancer cell. The oxidative cancer cell can obtain additional lactate by forcing the host cell to adopt a glycolytic metabolism. When lactate is not available or when MCTs are inhibited, the oxidative cancer cell switches to a glucose-based metabolism, thus depriving other cells from this important resource, which ultimately kills the hypoxic cancer cell. MCT1 and MCT4 inhibitors can, thus, destroy both the metabolic symbiosis and the commensalism based on the exchange of lactate in cancer. For abbreviations, see list. Adapted from reference .

Figure 3

Lactate is a signaling molecule in cancer and endothelial cells. The cartoon depicts on endothelial cell in close proximity of an oxidative cancer cell, and a hypoxic/glycolytic cancer cell is further away. Lactate is produced from glucose in the hypoxic/glycolytic cancer cell, and intracellular lactate activates a NDRG3-Raf-ERK1/2 tumor growth-promoting pathway. Once exported (usually a MCT4-dependent process), lactate diffuses along its concentration gradient and influences the oxidative cancer cell and the endothelial cell. Extracellular lactate can bind to lactate receptor GPR81 in the oxidative cancer cell, supporting mitochondrial biogenesis, lactate transport and signaling. It can also enter into the cell (usually a MCT1-dependent process), where it promotes pro-angiogenic signaling and glutaminolysis. Similarly, the endothelial cell expresses MCT1 and can therefore take up lactate. There, lactate triggers additional pro-angiogenic pathways. Plain lines and dotted lines represent well-established and presumptive cascades, respectively. + refers to stimulation. For abbreviations, see list.