Cancer metabolism

Dividing cells need more than energy. To make a daughter cell they must double their proteins, lipids and nucleic acids, which requires carbon skeletons, nitrogen and reducing power in the form of NADPH. Cancer cells rewire their metabolism to supply these building blocks and to survive in tissues where oxygen and nutrients run short. Reprogramming of metabolism became a hallmark of cancer in 2011. This lesson explains the Warburg effect and its modern interpretation, the role of glutamine and other nutrients, how mutations in metabolic enzymes can themselves drive cancer, and how cancer metabolism is used in diagnosis and treatment.

The Warburg effect

In the 1920s, Otto Warburg observed that tumor slices took up far more glucose than normal tissue and converted much of it to lactate even when oxygen was plentiful. Normal differentiated cells, in the presence of oxygen, oxidize most of the pyruvate from glycolysis in the mitochondria, yielding roughly 30 to 32 molecules of ATP per glucose, and switch to lactate production only when oxygen is short. Tumor cells used aerobic glycolysis, producing just 2 ATP per glucose from glycolysis while secreting lactate. Warburg concluded that cancer was caused by damaged mitochondria. That explanation turned out to be wrong for most tumors: their mitochondria work, and many cancers depend on oxidative phosphorylation. But the observation was right, and it has been confirmed in countless tumors and in rapidly dividing normal cells such as activated lymphocytes.

Why would a cell choose such an inefficient route? The modern answer, set out by Matthew Vander Heiden, Lewis Cantley and Craig Thompson in 2009, is that ATP is not the limiting resource for proliferation. A dividing cell has plenty of ATP; what it needs is carbon for biomass and NADPH for biosynthesis. High flux through glycolysis supplies intermediates that branch off into the pentose phosphate pathway (making ribose for nucleotides and NADPH), the serine synthesis pathway (feeding one-carbon metabolism for nucleotides and methylation) and glycerol for lipids. Secreting lactate regenerates NAD+ so glycolysis can keep running fast. The trade-off favors speed and building blocks over yield.

How oncogenes rewire metabolism

Metabolic rewiring is not separate from the oncogenic changes of lessons 2 and 3; it is driven by them. PI3K–AKT signaling increases expression and membrane localization of the glucose transporter GLUT1, activates hexokinase and phosphofructokinase, and through mTOR drives protein and lipid synthesis. MYC induces genes for glucose and glutamine uptake, glycolytic enzymes, ribosome biogenesis and nucleotide synthesis. Under hypoxia, and in tumors that have lost the VHL tumor suppressor, the transcription factor HIF-1 switches on glycolytic genes and pyruvate dehydrogenase kinase, which diverts pyruvate away from mitochondria. Loss of p53 removes a restraint on glycolysis and on the pentose phosphate pathway. Tumor cells also often express the M2 isoform of pyruvate kinase, whose regulated low activity can let glycolytic intermediates accumulate for biosynthesis.

Glutamine and anaplerosis

Many cancer cells consume glutamine avidly, a phenomenon called glutamine addiction. Glutamine supplies nitrogen for nucleotides and non-essential amino acids, and its carbon, as α-ketoglutarate, replenishes the TCA cycle as intermediates are drawn off for biosynthesis, a process called anaplerosis. Citrate leaves the mitochondrion to supply acetyl-CoA for fatty acid synthesis, and oxaloacetate feeds aspartate synthesis. Inhibitors of glutaminase have been tested in trials with limited success, partly because tumors in the body use nutrients differently from cells in culture, where glutamine is abundant. Tracer studies in patients, in which labeled glucose is infused before surgery, have shown that some human lung tumors oxidize glucose in their mitochondria more than expected and also use lactate as a fuel, a reminder that culture conditions can mislead.

Oncometabolites: when metabolic enzymes are the drivers

In some cancers, mutations in metabolic enzymes are themselves the oncogenic event. In 2008 and 2009, sequencing of gliomas and acute myeloid leukemia found recurrent point mutations in isocitrate dehydrogenase genes IDH1 and IDH2, at specific arginine residues (IDH1 R132, IDH2 R140 and R172). The mutant enzymes gain a new activity: instead of converting isocitrate to α-ketoglutarate, they reduce α-ketoglutarate to D-2-hydroxyglutarate (2-HG), which accumulates to millimolar levels. 2-HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including the TET enzymes that demethylate DNA and the JmjC histone demethylases. The result is widespread hypermethylation of DNA and histones that blocks differentiation, a link to the epigenetics of lesson 9. Ivosidenib and enasidenib, inhibitors of mutant IDH1 and IDH2, are approved for IDH-mutant acute myeloid leukemia, and vorasidenib was approved in 2024 in the United States for low-grade IDH-mutant gliomas, with Canadian authorization following (approval status as of 2026; check current labels).

Mutations in succinate dehydrogenase (SDH) and fumarate hydratase (FH), enzymes of the TCA cycle, act as tumor suppressor losses. Germline variants cause hereditary paragangliomas and pheochromocytomas (SDH) and hereditary leiomyomatosis and renal cell cancer (FH). The accumulated succinate and fumarate also inhibit α-ketoglutarate-dependent enzymes and stabilize HIF, mimicking hypoxia. These discoveries confirmed that metabolism can be a cause, not just a consequence, of cancer.

Imaging cancer metabolism: FDG-PET

The high glucose uptake of tumors is used every day in clinics. 18F-fluorodeoxyglucose (FDG) is a glucose analog labeled with a positron-emitting fluorine isotope. Cells take it up through glucose transporters and hexokinase phosphorylates it, but it cannot proceed further down glycolysis and is trapped. Positron emission tomography (PET), usually combined with computed tomography (CT), shows where FDG accumulates. Uptake is often summarized as a standardized uptake value (SUV), the tissue activity concentration divided by the injected activity per kilogram of body weight. FDG-PET is used to stage cancers such as lung cancer and lymphoma, to look for distant spread and to monitor response. It has limits: the brain, inflamed tissue and healing wounds also take up glucose avidly, and some slow-growing tumors, such as many prostate cancers, take up little FDG. Other tracers, such as PSMA-targeted agents for prostate cancer, fill those gaps.

# ATP per glucose, lactate output and the FDG standardized uptake value (illustrative numbers).
glucose_uptake = {'differentiated cell': 1.0, 'proliferating tumour cell': 10.0}   # relative uptake
frac_to_lactate = {'differentiated cell': 0.05, 'proliferating tumour cell': 0.85}
ATP_glycolysis, ATP_oxidative = 2, 30          # per glucose, approximate
for cell in glucose_uptake:
    g = glucose_uptake[cell]; f = frac_to_lactate[cell]
    atp = g * (ATP_glycolysis + (1 - f) * ATP_oxidative)
    lactate = g * f * 2                        # 2 lactate per glucose fermented
    print(f"{cell:26s} ATP {atp:5.1f}  lactate {lactate:5.1f}  ATP per glucose {atp / g:4.1f}")
# SUV = tissue activity (kBq/mL) / (injected activity (kBq) / body weight (g)), taking 1 mL of tissue as about 1 g
injected_MBq, weight_kg = 300.0, 75.0
for tissue, kBq_per_mL in [('lung tumour', 32.0), ('normal lung', 2.0), ('liver', 9.6)]:
    suv = kBq_per_mL / (injected_MBq * 1000 / (weight_kg * 1000))
    print(f"SUV {tissue:12s} = {suv:4.1f}")

differentiated cell        ATP  30.5  lactate   0.1  ATP per glucose 30.5
proliferating tumor cell  ATP  65.0  lactate  17.0  ATP per glucose  6.5
SUV lung tumor  =  8.0
SUV normal lung  =  0.5
SUV liver        =  2.4

The numbers make Warburg's paradox concrete. Per molecule of glucose, the tumor cell makes much less ATP, yet with ten times the uptake it still makes more ATP overall, while exporting large amounts of lactate and keeping glycolytic intermediates available for biosynthesis. An SUV of about 8 in a lung nodule, against about 0.5 in normal lung, is the kind of contrast that makes FDG-PET useful for staging, though thresholds depend on the scanner and protocol.

The metabolic microenvironment

Metabolism also shapes the space around tumor cells. Lactate and protons exported by glycolytic cells acidify the extracellular space, which favors invasion by activating proteases and harms immune cells; T cells, which also rely on glycolysis when activated, compete with tumor cells for glucose and are suppressed by lactate. Poorly perfused regions are short of oxygen, glucose and amino acids, and cells there may scavenge nutrients by macropinocytosis, engulfing extracellular proteins, a behavior seen in KRAS-mutant pancreatic cancer. Neighboring stromal cells can feed tumor cells with lactate, ketone bodies or amino acids. These interactions link this lesson to the tumor microenvironment of lesson 7 and to tumor immunology in BIOL-380.

Measuring metabolism in tumors

How do researchers know what tumors actually do with nutrients? Steady-state metabolomics measures the levels of hundreds of metabolites by mass spectrometry, but levels alone do not reveal fluxes, because a metabolite can be abundant because it is made quickly or because it is used slowly. Stable isotope tracing solves this. Cells, mice or patients are given glucose, glutamine or lactate labeled with carbon-13, and the pattern of label appearing in downstream metabolites shows which pathways carried it. Such studies, including infusions of labeled glucose into patients shortly before surgery, revealed that tumors in the body use mixtures of fuels that differ from cells in culture, that lactate can be a major fuel for the TCA cycle, and that the same oncogene can produce different metabolic programs in different tissues. Hyperpolarized carbon-13 magnetic resonance imaging, which follows the conversion of labeled pyruvate to lactate in real time, is being tested as a way to measure tumor metabolism in patients without radiation.

Targeting metabolism

Antimetabolites were among the first chemotherapy drugs and are still central: methotrexate blocks dihydrofolate reductase and thus one-carbon metabolism, 5-fluorouracil blocks thymidylate synthase, and gemcitabine and cytarabine are nucleoside analogues that halt DNA synthesis. Sidney Farber's use of the folate antagonist aminopterin to induce remissions in children with acute leukemia in 1948 is often counted as the start of modern chemotherapy. Newer approaches target mutant IDH, nutrient transporters, glutaminase, fatty acid synthesis and the dependence of some tumors on particular amino acids, such as asparagine in acute lymphoblastic leukemia, which is treated with the enzyme asparaginase. Diet has also been studied: ketogenic diets, fasting-mimicking diets and restriction of specific amino acids show effects in mouse models, but evidence in patients is limited, and no diet has been shown to cure cancer.

Maya's staging illustrates the clinical side. Her FDG-PET-CT showed an avid primary tumor in the right upper lobe with an SUV of about 9 and an FDG-avid lymph node on the same side of the chest, but no distant uptake. That placed her in stage III, a decision that shaped her treatment as described in lesson 11.