Introduction: Hypoxia and the Warburg effect


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Peter Ratcliffe

University of Oxford, UK

Abstract

More than 80 years ago Otto Warburg noted that malignant tumours, unlike normal tissues, consumed high levels of glucose even under aerobic conditions. The strength of the association between this metabolic abnormality and cancer (now the basis of FDG-PET scanning for malignant disease) convinced him that it reflected a fundamental causal link - that cancer was caused by damage to aerobic metabolism and evolved as a series of adaptive responses to this damage. However, at least initially, genetic studies of cancer did not support this concept. Moreover subsequent work demonstrated that the association could be broken down - with rapidly dividing, but non-malignant, cells showing similar metabolic changes.

More recent work has demonstrated the existence of multiple connections between tumour suppressor / oncogene pathways and metabolic dysregulation, which potentially explain Warburgs observations - in particular through perturbation of hypoxia signaling by hypoxia inducible factor (HIF). In addition, mutations in particular Krebs cycle enzymes have been identified in certain hereditary cancer syndromes - essentially confirming Warburgs theory, at least in these rare tumour types. These findings have led to a resurgence of interest in cancer metabolism, if not as the fundamental cause, then perhaps as a therapeutically tractable phenotype. This session will consider a series of recent advances in this field.