Cancer's Fuel Choice: New Flavors for a Picky Eater

Abstract

Otto Warburg discovered that cancer cells exhibit a high rate of glycolysis in the presence of ample oxygen, a process termed aerobic glycolysis, in 1924 (Warburg et al., 1924). Since then we have significantly advanced our understanding of cancers' fuel choice to meet their demands for energy and for the production of biosynthetic precursors. In this review, we will discuss the preferred nutrients of cancer cells and how they are utilized to satisfy their bioenergetic and biosynthetic needs. In addition, we will describe how cell intrinsic and extrinsic factors such as oncogene mutations, nutrient and oxygen availability, and other microenvironmental factors influence fuel choice.

Figure 1

Cancer’s fuel choice. Cancer cells can take up glucose, glutamine, amino acids, lysophospholipids, acetate, and extracellular protein and use these fuels to supply their pools of macromolecular precursors for cellular proliferation.

Figure 2

Nutrient delivery can affect the metabolism of tumor cells. (Left) Under conditions of adequate nutrient delivery, glucose and glutamine are used as primary fuel sources to feed glycolysis and the TCA cycle to support proliferation. Amino acid uptake supports protein synthesis and other anabolic processes. (Right) Under conditions of poor nutrient delivery the cell relies on alternative fuel sources including lysosomal degradation of both intracellular cargo and extracellular protein obtained via macropinocytosis to supply intracellular amino acid pools. Fatty acid pools are obtained via scavenging lysophospholipids and de novo synthesis via acetate-derived acetyl-coA.

Figure 3

The interaction of tumor cells with the microenvironment can be symbiotic or competitive. (Left) Metabolic symbiosis may occur between tumor cells and fibroblasts, whose metabolism may be reprogrammed by tumor cells due to secretion of growth factors (GF) or other signaling molecules such as exosomes (Exo). Fibroblasts may feed lactate, amino acids, and other metabolites to tumor cells. Lactate produced from fibroblasts via glycolysis may be taken up by tumor cells, converted to pyruvate, and metabolized in the TCA cycle. Amino acids such as glutamine may also be supplied to tumor cells following autophagic breakdown of fibroblast protein. Furthermore, fibroblasts may take up cystine from the microenviroment and reduce it to cysteine, which tumor cells use to make glutathione and protein. (Right). Tumor cells and activated T-cells compete for glucose and glutamine, which they both need for proliferation. This can result in an immunosuppressive environment if T-cell proliferation is inadequate.