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Why do cancers have high aerobic glycolysis?

Key Points

  • Widespread clinical use of 18fluorodeoxyglucose positron-emission tomography has demonstrated that the glycolytic phenotype is observed in most human cancers.

  • The concept of carcinogenesis as a process that occurs by somatic evolution clearly implies that common traits of the malignant phenotype, such as upregulation of glycolysis, are the result of active selection processes and must confer a significant, identifiable growth advantage.

  • Constitutive upregulation of glycolysis is likely to be an adaptation to hypoxia that develops as pre-malignant lesions grow progressively further from their blood supply. At this stage, the blood supply remains physically separated from the growing cells by an intact basement membrane.

  • Increased acid production from upregulation of glycolysis results in microenvironmental acidosis and requires further adaptation through somatic evolution to phenotypes resistant to acid-induced toxicity.

  • Cell populations that emerge from this evolutionary sequence have a powerful growth advantage, as they alter their environment through increased glycolysis in a way that is toxic to other phenotypes, but harmless to themselves. The environmental acidosis also facilitates invasion through destruction of adjacent normal populations, degradation of the extracellular matrix and promotion of angiogenesis.

  • We propose that the glycolytic phenotype, by conferring a powerful growth advantage, is necessary for evolution of invasive human cancers.

Abstract

If carcinogenesis occurs by somatic evolution, then common components of the cancer phenotype result from active selection and must, therefore, confer a significant growth advantage. A near-universal property of primary and metastatic cancers is upregulation of glycolysis, resulting in increased glucose consumption, which can be observed with clinical tumour imaging. We propose that persistent metabolism of glucose to lactate even in aerobic conditions is an adaptation to intermittent hypoxia in pre-malignant lesions. However, upregulation of glycolysis leads to microenvironmental acidosis requiring evolution to phenotypes resistant to acid-induced cell toxicity. Subsequent cell populations with upregulated glycolysis and acid resistance have a powerful growth advantage, which promotes unconstrained proliferation and invasion.

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Figure 1: Glucose metabolism in mammalian cells.
Figure 2: Positron-emission tomography imaging with 18fluorodeoxyglucose of a patient with lymphoma.
Figure 3: Pasteur and Warburg effects in non-invasive and metastatic breast cancer cell lines.
Figure 4: Hyperacidity of tumours.
Figure 5: Late-stage ductal carcinoma in situ.
Figure 6: Model for cell–environment interactions in carcinogenesis.

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Acknowledgements

We wish to acknowledge the invaluable contributions of E. Gawlinski and T. Vincent for their efforts in the mathematical modelling that led to the insights presented here. We also thank E. Racker for stimulating this research by posing to us the question in the title.

Author information

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Correspondence to Robert A. Gatenby.

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DATABASES

National Cancer Institute

breast cancer

cervical cancer

colon cancer

gastric cancer

head and neck cancer

oesophageal cancer

Entrez Gene

caspase-3

GLUT1

GLUT3

HRAS

HIF1α

KRAS

MYC

p53

VEGF

VHL

FURTHER INFORMATION

DMetrix digital imaging program

Glossary

HEXOKINASES

Enzymes that catalyse the transfer of phosphate from ATP to glucose to form glucose-6-phosphate. This is the first reaction in the metabolism of glucose and prevents efflux of glucose from the cell.

HYPOXIA

Refers to a low oxygen level. This means different levels to different investigators, but for radiation biologists hypoxia occurs at levels less than 0.1% oxygen in the gas phase. Normoxia refers to normal levels of oxygen (>10%) and anoxia refers to no oxygen.

WINDOW CHAMBER

A metal chamber with a glass window that is placed on the dorsal skin of an animal. This allows in vivo tumour growth to be continuously observed microscopically.

HAEMATOCRIT

A measure of the concentration of red cells in the blood. A reduced haematocrit decreases the oxygen-carrying capacity of the blood.

VASOMOTION

Rhythmic oscillations in vascular tone caused by local changes in smooth muscle.

VASCULAR REMODELLING

The active process of altering structure and arrangement in blood vessels through cell growth, cell death, cell migration and production or degradation of the extracellular matrix.

VMAX and KM

Terms from the Michaelis–Menten model. Applied to transport, Vmax is the maximum possible rate of uptake of a specific substrate. Km is the substrate concentration at which the substrate uptake is half of Vmax. Cell populations with low Km are better adapted to maintaining substrate uptake in conditions in which substrate concentrations are low.

CLASTOGENIC

Describing any substance or processes that increases alterations in the structure of chromosomes.

GAP JUNCTIONS

Linked channels through contiguous cell membranes that interconnect the cytoplasm of adjacent cells and allow direct exchange of ions and small molecules.

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Gatenby, R., Gillies, R. Why do cancers have high aerobic glycolysis?. Nat Rev Cancer 4, 891–899 (2004). https://doi.org/10.1038/nrc1478

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