In this review article, we examine the importance of low levels of
oxygen (
hypoxia) in
cancer biology. We provide a brief description of how mammalian cells sense
oxygen. The
hypoxia-inducible factor (HIF) pathway is currently the best characterised
oxygen-sensing system, but recent work has revealed that mammals also use an
oxygen-sensing system found in plants to regulate the abundance of some
proteins and
peptides with an amino-terminal
cysteine residue. We discuss how the HIF pathway is affected during the growth of solid tumours, which develop in microenvironments with gradients of
oxygen availability. We then introduce the concept of 'pseudohypoxia', a state of constitutive,
oxygen-independent HIF system activation that occurs due to oncogenic stimulation in a number of specific tumour types that are of immediate relevance to diagnostic histopathologists. We provide an overview of the different methods of quantifying tumour
hypoxia, emphasising the importance of pre-analytic factors in interpreting the results of tissue-based studies. Finally, we review recent approaches to targeting
hypoxia/HIF system activation for therapeutic benefit, the application of which may require knowledge of which
hypoxia signalling components are being utilised by a given tumour. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.