Is cancer a metabolic disease?

Abstract

Although cancer has historically been viewed as a disorder of proliferation, recent evidence has suggested that it should also be considered a metabolic disease. Growing tumors rewire their metabolic programs to meet and even exceed the bioenergetic and biosynthetic demands of continuous cell growth. The metabolic profile observed in cancer cells often includes increased consumption of glucose and glutamine, increased glycolysis, changes in the use of metabolic enzyme isoforms, and increased secretion of lactate. Oncogenes and tumor suppressors have been discovered to have roles in cancer-associated changes in metabolism as well. The metabolic profile of tumor cells has been suggested to reflect the rapid proliferative rate. Cancer-associated metabolic changes may also reveal the importance of protection against reactive oxygen species or a role for secreted lactate in the tumor microenvironment. This article reviews recent research in the field of cancer metabolism, raising the following questions: Why do cancer cells shift their metabolism in this way? Are the changes in metabolism in cancer cells a consequence of the changes in proliferation or a driver of cancer progression? Can cancer metabolism be targeted to benefit patients?

Figure 1

Cancer metabolism. Scheme shows central carbon metabolism. Metabolic reactions that tend to be faster in tumors are identified in red, whereas reactions that tend to be slower in tumors are identified in green. DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; KG, α-ketoglutarate; OAA, oxaloacetate; PEP, phosphoenolpyruvate.

Figure 2

Metabolic approaches to treating cancer. Scheme shows some of the compounds being explored as anticancer agents and the metabolic reactions that they target. Red lines indicate inhibition; green lines, activation. BPTES, bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; GLS, glutamine synthetase; GOT, glutamate oxaloacetate transaminase; HK, hexokinase; MCT, monocarboxylate transporters; OAA, oxaloacetate; PD, pyruvate dehydrogenase; PEP, phosphoenolpyruvate; PK, pyruvate kinase.

Figure 3

Metabolic effects of oncogenes and tumor suppressors. Scheme shows the metabolic reactions in central carbon metabolism affected by AKT (orange), MYC (blue), HIF (green) and p53 (red). Arrows indicate activation; lines, repression. DHAP, dihydroxyacetone phosphate; GAP, glyceraldehyde 3-phosphate; GDH, glutamate dehydrogenase; GLS, glutamine synthetase; HK, hexokinase; KG, α-ketoglutarate; LDH, lactate dehydrogenase; OAA, oxaloacetate; PEP, phosphoenolpyruvate.