Lactate in the Tumor Microenvironment: An Essential Molecule in Cancer Progression and Treatment

Abstract

Cancer is a complex disease that includes the reprogramming of metabolic pathways by malignant proliferating cells, including those affecting the tumor microenvironment (TME). The "TME concept" was introduced in recognition of the roles played by factors other than tumor cells in cancer progression. In response to the hypoxic or semi-hypoxic characteristic of the TME, cancer cells generate a large amount of lactate via the metabolism of glucose and glutamine. Export of this newly generated lactate by the tumor cells together with H+ prevents intracellular acidification but acidifies the TME. In recent years, the importance of lactate and acidosis in carcinogenesis has gained increasing attention, including the role of lactate as a tumor-promoting metabolite. Here we review the existing literature on lactate metabolism in tumor cells and the ability of extracellular lactate to direct the metabolic reprogramming of those cells. Studies demonstrating the roles of lactate in biological processes that drive or sustain carcinogenesis (tumor promotion, angiogenesis, metastasis and tumor resistance) and lactate's role as an immunosuppressor that contributes to tumor evasion are also considered. Finally, we consider recent therapeutic efforts using available drugs directed at and interfering with lactate production and transport in cancer treatment.

Keywords: LDH; MCTs; lactate; tumor microenvironment (TME), acidosis.

Figure 1

The main biochemical pathways implicated in cancer cell lactate generation. ME, malic enzyme; MDH, malate dehydrogenase; LDH-A, lactate dehydrogenase A; GLS, glutaminase; GDH, glutamate dehydrogenase.

Figure 2

Intercellular lactate exchange in the tumor microenvironment (TME). The TME is a complex ultrastructure containing different cell types, including tumor cells, stromal cells, immune cells, blood vessels and cellular metabolites such as lactate. Oxidative tumor cells (orange nuclei) and stromal cells (gray cytoplasm) are supported by a favorable location with high nutritional and O₂ availability. Oxidative tumor cells (orange nuclei) express MCT1 transporter which preferentially promotes lactate import. The glycolytic tumor cells (pink nuclei) produce lactate by the glycolytic pathway that culminates in the final reaction mediated by lactate dehydrogenase LDHA, and exhibit high expression of MCT4 favoring lactate export. Lactate can be used as an energetic source through its conversion to pyruvate via LDHB and then go to into the Krebs cycle for energy generation. Thus, the glycolytic tumor cell (pink nuclei), and stromal cell (gray) interchange of lactate with oxidative tumor cells (orange nuclei) increases tumor cell survival and proliferation. CD147: chaperone. CAIX: carbonic anhydrase IX. Made from the original idea [61].

Figure 3

Effect of lactate on the tumor microenvironment (TME). Lactate secretion by tumors and stromal cells mainly acidifies the tumor microenvironment and creates a lactate interchange between them that increases tumor cell survival and proliferation. Lactate also stimulates tumor angiogenesis via endothelial cells and contributes to the immune scape by altering several immune infiltrating cells.