In 1901 Wilhelm Roentgen received the first Nobel Prize in physics for his discovery of a “new kind of ray” . In 1931, 8 years after Roentgen’s death, Otto Warburg received the Nobel Prize for physiology or medicine in part for his discovery of altered glucose metabolism in cancers . There is no evidence that they ever met, although, interestingly, some correspondence exists between Roentgen and Warburg’s father, Emile, who was a noted physicist. Remarkably, in the early 21st century, the seemingly unrelated work of these two scientific giants has spawned a vast clinical and research enterprise in which imaging of cell metabolism is providing new and critical insights into human cancer.
Cellular metabolism serves two primary functions: to generate energy for cellular processes and to provide essential anabolic precursors. The three major substrates serving these purposes are sugars (glucose), amino acids (glutamine), and fatty acids (ketones). For energy production, normal tissues in well-oxygenated environments typically rely on highly efficient forms of aerobic metabolism to generate ATP. Depending on the tissue, the major substrates providing this energy are fatty acids and glucose. To be oxidatively metabolized, the substrates must be transported into mitochondria to supply reducing equivalents for oxidative phosphorylation. Although fatty acids and ketones can be directly imported into mitochondria, most glucose-derived carbons enter mitochondria as pyruvate. Under aerobic conditions, pyruvate is metabolized to produce about 36 moles of ATP per mole of glucose. However, under hypoxic conditions, lack of O 2 as the final acceptor in the electron transport chain prevents aerobic metabolism from progressing. As a result, pyruvate is reduced to lactate to regenerate oxidized nicotinamide adenine dinucleotide (NAD + ) from reduced NADH, to provide an energy source. However, this produces only 2 moles of ATP per mole of glucose. Because of its significantly increased efficiency, aerobic metabolism of glucose, glycolysis is typically upregulated only under in the presence of hypoxia, which was first described by Louis Pasteur in 1857 (before Nobel’s gift) and is known as the Pasteur effect.
Unlike normal tissues, cancers commonly upregulate glycolysis that persists even under normoxic conditions (aerobic glycolysis)—first described by Otto Warburg more than 80 years ago and known the Warburg effect . Although there is still much to learn, the molecular mechanisms that generate the Warburg effect are becoming clearer. Control of the glycolytic pathway is multifactorial, but critical upstream effectors include the c-myc and ras families of oncoproteins, the p53 tumor suppressor and the hypoxia sensitive transcription factor, HIF-1α . Metabolism, in other words, is deeply related to the complex molecular dynamics that govern development and progression of cancer.
In contrast, less is known about why these metabolic changes occur. Because cancers arise through a prolonged sequence of mutations and clonal expansions— a process often described as somatic evolution—aerobic glycolysis must confer a selective proliferation advantage that is significant. This evolutionary advantage is not immediately obvious because aerobic glycolysis is substantially less efficient in energy production than is aerobic glucose metabolism and results in increased acid production, which is potentially toxic. Several possible benefits have been suggested. The glycolytic metabolic pathway, although inefficient, has the benefit of speed allowing more turnover of glucose, which may benefit rapid synthesis of macromolecules necessary for proliferation. We have proposed that the acid produced by upregulated glycolysis benefits the tumor cells by promoting invasion and shielding them from the toxic effects of the immune system . Others have proposed that glycolysis is upregulated to provide anabolic precursors , which was the original theory of Warburg, yet still lacks empirical support.
For decades, Warburg’s seminal observations were generally viewed as an interesting laboratory finding of little clinical relevance. However, this changed when the increased glucose metabolism in cancer was linked to Roentgen’s new kind of rays through F-18-fluorodeoxyglucose positron emission tomography (FDG PET) imaging. Although slow to build, the subsequent tsunami of data has led to stunning realization—the Warburg effect is present in the vast majority of clinical cancers and is greatest in those that are the most malignant. In fact, increased glucose uptake is more common in cancers than any other genetic or phenotypic property. These results have led to substantial increase in interest in the role of altered metabolism in carcinogenesis and cancer progression.
Although fundamentally important, increased glucose metabolism is ultimately a manifestation of complex underlying dynamics that includes the mutations, epigenetic alterations, changes in protein localization, intra- and extracellular enzyme kinetics, and regional microenvironmental conditions such as hypoxia and acidosis. These conditions, which vary significantly between tumors and even with different regions of the same tumor, represent fundamental properties of the tumor that govern its clinical progression and response to therapy. To truly understand cancer metabolism, we need to look beyond glucose, which has gained preeminence because of its consistent alteration and the availability of an imageable analog, FDG. In fact, glucose is only one of many substrates whose metabolism is altered in cancers. A challenge and opportunity in cancer imaging is identification of additional metabolic perturbations at the tissue and subtissue level in individual tumors.
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