Metabolic symbiosis in cancer: refocusing the Warburg lens

Abstract

Using relatively primitive tools in the 1920s, Otto Warburg demonstrated that tumor cells show an increased dependence on glycolysis to meet their energy needs, regardless of whether they were well-oxygenated or not. High rates of glucose uptake, fueling glycolysis, are now used clinically to identify cancer cells. However, the Warburg effect does not account for the metabolic diversity that has been observed amongst cancer cells nor the influences that might direct such diversity. Modern tools have shown that the oncogenes, variable hypoxia levels, and the utilization of different carbon sources affect tumor evolution. These influences may produce metabolic symbiosis, in which lactate from a hypoxic, glycolytic tumor cell population fuels ATP production in the oxygenated region of a tumor. Lactate, once considered a waste product of glycolysis, is an important metabolite for oxidative phosphorylation in many tissues. While much is known about how muscle and the brain use lactate in oxidative phosphorylation, the contribution of lactate in tumor bioenergetics is less defined. A refocused perspective of cancer metabolism that recognizes metabolic diversity within a tumor offers novel therapeutic targets by which cancer cells may be starved from their fuel sources, and thereby become more sensitive to traditional cancer treatments.

Figure 1.

Metabolic symbiosis in the tumor microenvironment. During tumor growth, inefficient formation of blood vessels produces areas of normoxia and hypoxia within the tumor. Hypoxic cells generate two ATP per glucose via glycolysis, while oxygenated cells can produce a greater number of ATP from oxidative phosphorylation (29 ATP per two acetyl-CoA). Hypoxic cells import glucose via glucose transporters (Glut-1), and generate two molecules of pyruvate from one molecule of glucose. Hexokinase (HK) is the first rate-limiting enzyme of glycolysis. Under normoxic conditions, pyruvate is metabolized to acetyl-CoA by pyruvate dehydrogenase (PDH) and acetyl-CoA enters the TCA cycle. In hypoxic conditions, PDH is inhibited by PDK and lactate dehydrogenase-5 (LDH-5) converts pyruvate to lactate. Lactate from hypoxic cells is exported through monocarboxylate transporter 4 (MCT-4). Oxygenated cells import lactate via MCT-1, and convert the lactate back to pyruvate via LDH-1. Though not shown in the figure, cancer cells demonstrating the Warburg phenotype of high glycolysis, perhaps those harboring mitochondrial DNA mutations, may be found throughout the hypoxic and oxygenated regions of the tumor.