Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches

Abstract

Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as "Warburg effect or aerobic glycolysis." As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.

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

“…Intratumoral lactate levels seem to be prognostic in several cancers. In fact, it has been demonstrated that high lactate levels are associated with higher incidence of distant metastasis in different cancer types [11], although the mechanism is not completely understood.…”

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

“…Lactate is formed exclusively from pyruvate regardless of oxygen availability, and robustly exported to the TME, reaching concentrations that can be 20-fold higher (about 40 mM) (74) than in non-tumoral tissues (about 1.5-3 mM) (13,15). Lactate is a major fuel source, providing energetic and anabolic support to cancer cells, and an important oncometabolite with both extracellular and intracellular signaling functions that equally contribute to cancer progression (Figure 1) (75,76).…”

“…Interestingly, the levels of lactate were inversely correlated with the levels of glucose, and directly correlated with the expression of MCT4. Later studies have also linked intratumoral lactate levels with higher incidence of distant metastasis and poor patient survival (76).…”

Glucose Metabolism on Tumor Plasticity, Diagnosis, and Treatment

“…Intrinsic traits (e.g., genetic programs in cancer cells) and extrinsic factors (e.g., nutrient availability, oxygen tension, pH) contribute to the deregulated metabolism in TME. TME enforces metabolic plasticity to adapt to hypoxic and acidic environment, nutrient deprivation and competition, oxidative stress, and immune surveillance (52). Reprogramming of the metabolism occurs in tumor and non-tumor cells.…”