Oxygen availability and metabolic adaptations

Key Points Tumour microenvironments harbour multiple microdomains whereby cells experience limited (and highly variable) access to oxygen and nutrients. Oxygen and nutrient availability affect tumour evolution via altered metabolism, blood vessel recruitment, inflammatory cell infiltration and metastasis. Although much of hypoxia research has previously focused on hypoxia-inducible factor (HIF) transcriptional regulators, multiple additional O 2 -sensing mechanisms are at play, including those regulated by mTOR complex 1 (mTORC1), endoplasmic reticulum stress responses, autophagy and numerous oxygen-consuming metabolic pathways. The HIFs, as central regulators of metabolic adaptations in hypoxic tumours, significantly influence intracellular metabolism but are also in turn governed by changes in metabolite accumulation. The human genome encodes up to 70 2-oxoglutarate-dependent dioxygenases that probably contribute to tumour phenotypes at the biosynthetic, metabolic, genetic and epigenetic levels.