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

SIMPLE SUMMARY: The role of lactate in cancer described by Otto Warburg in 1927 states that cancer cells uptake high amount of glucose with a marked increase in lactate production, this is known as the “Warburg effect”. Since then lactate turn out to be a major signaling molecule in cancer progression. Its release from tumor cells is accompanied by acidification ranging from 6.3 to 6.9 in the tumor microenvironment (TME) which favors processes such as tumor promotion, angiogenesis, metastasis, tumor resistance and more importantly, immunosuppression which has been associated with a poor outcome. The goal of this review is to examine and discuss in deep detail the recent studies that address the role of lactate in all these cancerous processes. Lastly, we explore the efforts to target the lactate production and its transport as a promising approach for cancer therapeutics. 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.