Tumor cell metabolism: an integral view

Abstract

Cancer is a genetic disease that is caused by mutations in oncogenes, tumor suppressor genes and stability genes. The fact that the metabolism of tumor cells is altered has been known for many years. However, the mechanisms and consequences of metabolic reprogramming have just begun to be understood. In this review, an integral view of tumor cell metabolism is presented, showing how metabolic pathways are reprogrammed to satisfy tumor cell proliferation and survival requirements. In tumor cells, glycolysis is strongly enhanced to fulfill the high ATP demands of these cells; glucose carbons are the main building blocks in fatty acid and nucleotide biosynthesis. Glutaminolysis is also increased to satisfy NADPH regeneration, whereas glutamine carbons replenish the Krebs cycle, which produces metabolites that are constantly used for macromolecular biosynthesis. A characteristic feature of the tumor microenvironment is acidosis, which results from the local increase in lactic acid production by tumor cells. This phenomenon is attributed to the carbons from glutamine and glucose, which are also used for lactic acid production. Lactic acidosis also directs the metabolic reprogramming of tumor cells and serves as an additional selective pressure. Finally, we also discuss the role of mitochondria in supporting tumor cell metabolism.

Figure 1.

Comparison between the metabolism of tumor and normal cells. The main anaplerotic precursors in normal and tumor cells are shown in ovals. In tumor cells, glucose supports cellular growth through nucleotide and lipid biosynthesis. About 90% of R5P and 60% of fatty acids are glucose derived. Glutamine supports cells via anaplerosis of the Krebs cycle and NADPH regeneration, accompanied by lactate production. About 60% of lactate is glutamine derived.

Figure 2.

Schematic representation of the tumor microenvironment in which glucose and oxygen gradients are inevitably formed, with the highest concentrations close to the blood vessels. Left side: metabolic symbiosis is represented, with the lactate transporter MCT1 playing a key role. Under lactic acidosis, aerobic tumor cells express MCT1 and preferentially take up lactate, which is transformed into pyruvate. This metabolite enters the mitochondria to produce ATP, allowing the tumor cells most distant from the blood vessels to acquire glucose and, consequently, produce lactic acid. Right side: metabolic symbiosis is disrupted via the inhibition of MCT1 expression. Aerobic tumor cells take up glucose; the tumor cells most distant from the blood vessels cannot consume glucose and consequently die. HIF-1, hypoxia-inducible factor 1; MCT1, monocarboxylate 1 transporter; GLUT1, glucose transporter 1; LDHA, lactate dehydrogenase A; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; MCT4, monocarboxylate 4 transporter.