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.

Keywords: acidification; immune response; lactate; therapy; tumor microenvironment (TME).

Figure 1

Role of lactate in cancer. Excessive production of lactate by both, tumor and stromal cells, is associated with increased aggressiveness due to the extracellular acidification that also induces invasion and metastasis, inhibition of the antitumor immune response and resistance to therapy. Moreover, this lactate can be used as an alternative source of fuel by tumor cells.

Figure 2

Metabolic symbiosis. Solid tumors are characterized by metabolic heterogeneity. Glycolytic tumor cancers are sustained by a favorable location with high nutritional availability. This phenotype is regulated by a differential expression of MCTs, where glycolytic cells preferentially express MCT4 favoring lactate export. Meanwhile, oxidative cells express MCT1 transporter which preferentially promotes lactate import. Then, lactate is used by these cells as an energetic source due to its conversion to pyruvate which enters the TCA cycle in the mitochondria. The presence of lactate allows a metabolic symbiosis between hypoxic cancer cells (glycolytic) and with normoxic cancer cells (oxidative).

Figure 3

Reverse Warburg effect. Tumor microenvironment (TME) is an ultrastructure consisting of different cell types including tumor cells, stromal cells, immune cells, blood vessels and cellular metabolites such as lactate. TME promotes different processes aimed to enforce metabolic adaptability, oxidative stress, nutrient competition, immune surveillance. This adaptability to hypoxic and acidic environments stimulates tumor malignancy. Tumor cells and cancer associated fibroblasts (CAFs) with a glycolytic phenotype represent the principal source of lactate production within TME which is favored by the presence of GLUT1. Additionally, CAFs exhibit high expression of MCT4 dedicated to lactate export. In this way, CAFs can interchange lactate with oxidative tumor cells which use lactate as a fuel through the TCA cycle. This phenomenon is known as reverse Warburg effect.

Figure 4

Role of lactate in immune suppression. Lactate secretion by tumor cells promotes acidification of the tumor microenvironment (represented in yellow color). This acidification of the medium, reduces the pH within the immune cells affecting signaling pathways finally causing inhibition of the activation and proliferation of CD4, CD8, NK, NKT, and dendritic cells. Moreover, lactate-induced acidification causes apoptosis in CD8 lymphocytes and NK cells, thus lactate contributes to immune evasion. Furthermore, the acidification of the medium causes the polarization of the macrophages toward the M2 subpopulation, which favors growth, invasion and migration of the tumor.