Is cancer a disease of abnormal cellular metabolism? New angles on an old idea

Abstract

In the 1920s, Otto Warburg observed that tumor cells consumed a large amount of glucose, much more than normal cells, and converted most of it to lactic acid. This phenomenon, now known as the "Warburg effect," is the foundation of one of the earliest general concepts of cancer: that a fundamental disturbance of cellular metabolic activity is at the root of tumor formation and growth. In the ensuing decades, as it became apparent that abnormalities in chromosomes and eventually individual genes caused cancer, the "metabolic" model of cancer lost a good deal of its appeal, even as emerging technologies were exploiting the Warburg effect clinically to detect tumors in vivo. We now know that tumor suppressors and proto-oncogenes influence metabolism, and that mutations in these genes can promote a metabolic phenotype supporting cell growth and proliferation. Thus, these advances have unified aspects of the metabolic and genetic models of cancer, and have stimulated a renewed interest in the role of cellular metabolism in tumorigenesis. This review reappraises the notion that dysregulated cellular metabolism is a key feature of cancer, and discusses some metabolic issues that have escaped scrutiny over the years and now deserve closer attention.

Fig. 1. A large increase in tumor cell biomass accompanies tumor growth

Replicative cell division (top) requires that cells double their biomass (proteins, lipids, nucleic acids) each time two daughters are produced. If cell proliferation is exponential, then the production of macromolecules for the entire population is also exponential. Rapid growth of a tumor thus implies that the tumor cells have mechanisms in place to synthesize macromolecules rapidly. For example, in a typical experiment studying the growth of tumors derived from human glioblastoma cells (bottom), 10 million cells (approximately 25 mm³ total cell volume) were injected subcutaneously into nude mice, and growth of the tumor was measured each week. By the end of the fifth week, the average tumor size was 100 mm³, a four-fold increase from time zero. All tumors eventually exceeded 2000 mm³ in size (dashed line), by which time the tumor biomass had increased 80-fold from time zero. Growth of these tumors, particularly the rapid growth over the final few weeks, requires a metabolic platform supporting anabolism.

Fig. 2. Some metabolic activities are required for tumor growth

Among the various metabolic activities that have been observed in tumors or tumor cell lines, the three with the most compelling evidence for a required role in tumor growth are aerobic glycolysis (the Warburg effect), fatty acid/lipid synthesis and mitochondrial glutamine metabolism. Current evidence suggests that these three pathways cooperate in a metabolic platform that supports cell growth and ultimately proliferation. The high rate of glycolysis, in addition to producing ATP, generates glycerol and citrate to be used to synthesize membrane lipids. Meanwhile, mitochondrial metabolism of glutamine supplies the TCA cycle with intermediates to replace those exported for lipid synthesis and other anabolic processes. Cells using this form of metabolism secrete lactate produced from both glucose and glutamine. Ammonia is also produced and secreted in abundance. Recent studies have shown that several of the enzymes participating in these pathways are required for growth of tumors in mice (white ovals), while SDH and FH function genetically as tumor suppressors in humans. Abbreviations: Glc, glucose; DHAP, dihydroxyacetone phosphate; GA3P, glyceraldehyde 3-phosphate; Pyr, pyruvate; Lac, lactate; Ac-CoA, acetyl-CoA; Cit, citrate; α-KG, α-ketoglutarate; Succ, succinate; Fum, fumarate; Mal, malate; OAA, oxaloacetate; Mal-CoA, malonyl-CoA; Gln, glutamine; Glu, glutamate, NH₄⁺, ammonia; PK-M2, pyruvate kinase isoform M2; LDHA, lactate dehydrogenase-A; ACL, ATP citrate lyase, ACC1, acetyl-CoA carboxylase-α; FAS, fatty acid synthase; GLS, glutaminase; SDH, succinate dehydrogenase; FH, fumarate hydratase; PDH, pyruvate dehydrogenase; ME, malic enzyme

Fig. 3. Tumor suppressors and proto-oncogenes regulate the metabolic pathways involved in tumor growth

The major biosynthetic activities used by proliferating tumor cells (synthesis of proteins, nucleic acids and lipids) are outlined in boxes. Supporting pathways, including glycolysis, the oxidative and non-oxidative arms of the pentose phosphate pathway, mitochondrial glutamine metabolism and the TCA cycle are also shown. Alternative metabolic pathways normally used during nutrient deprivation and suppressed during cell proliferation (β-oxidation of fatty acids, autophagy) are indicated by dashed lines. Selected effects of p53, Myc, Ras and the PI3K/Akt/mTOR signaling system (boxed P) are indicated; black symbols indicate supression and white symbols indicate activation. In the case of p53, loss of function mutations in tumor cells have the opposite of the effect shown here (e.g. glucose uptake and glycolysis are no longer suppressed by p53 activity). Abbreviations: Glc, glucose; G6P, glucose-6-phosphate; F6P, fructose-6-phosphate; F1,6biP, fructose-1,6-bisphosphate; F2,6biP, fructose-2,6-bisphosphate; GA3P, glyceraldehyde 3-phosphate; Pyr, pyruvate; Lac, lactate; R5P, ribose-5-phosphate; PRPP, 5-phosphoribosyl pyrophosphate; Ser, serine; Gly, glycine; Ac-CoA, acetyl-CoA; Cit, citrate; α-KG, α-ketoglutarate; Succ, succinate; OAA, oxaloacetate; Mal-CoA, malonyl-CoA; Gln, glutamine; Glu, glutamate, NH₄⁺, ammonia; TIGAR, TP53-induced glycolysis and apoptosis regulator; PFK1, phosphofructokinase-1; PGAM, phosphoglycerate mutase; SHMT, serine hydroxymethyltransferase.