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Oxygen availability and metabolic adaptations

Nature Reviews Cancer volume 16, pages 663–673 (2016)Cite this article

Subjects

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 O2-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.

Abstract

Oxygen availability, along with the abundance of nutrients (such as glucose, glutamine, lipids and albumin), fluctuates significantly during tumour evolution and the recruitment of blood vessels, leukocytes and reactive fibroblasts to complex tumour microenvironments. As such, hypoxia and concomitant nutrient scarcity affect large gene expression programmes, signalling pathways, diverse metabolic reactions and various stress responses. This Review summarizes our current understanding of how these adaptations are integrated in hypoxic tumour cells and their role in disease progression.

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Figure 1: Post-translational regulation of hypoxia-inducible factor-α (HIFα) subunits under normoxic and hypoxic conditions.
Figure 2: Glycolysis, the tricarboxylic acid cycle and lipid synthesis.
Figure 3: The mTORC1 and mTORC2 pathways and their interaction with hypoxia.
Figure 4: The autophagic pathway and its regulators.

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Acknowledgements

The authors would like to specifically thank F. Tucker for her assistance in preparing the manuscript. M.S.N.'s research is supported by the US National Cancer Institute (NCI) R01 CA158301; B.K. and M.C.S acknowledge support from NCI P01 CA104838.

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania,

    Michael S. Nakazawa, Brian Keith & M. Celeste Simon

  2. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania,

    Michael S. Nakazawa & Brian Keith

  3. Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, 456 BRB II/III, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    M. Celeste Simon

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  1. Michael S. Nakazawa
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  2. Brian Keith
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Correspondence to Michael S. Nakazawa.

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PowerPoint slides

Glossary

Ischaemic conditions

Tissue environment in which cells are limited for oxygen and other blood-borne nutrients (such as glucose, glutamine, lipids and albumin) simultaneously, as opposed to being merely O2 deprived or hypoxic.

Glycolysis

Central carbon metabolic pathway in which glucose is catabolized to lactate and/or pyruvate.

Redox stress

Pathological setting in which cells and tissues experience an imbalance in oxidant versus antioxidant agents.

Reactive oxygen species

(ROS). Oxygen-containing molecules harbouring an additional unpaired electron; for example, H2O2, OH− and O2−.

Mitophagy

A specialized form of autophagy devoted to breakdown of mitochondria in response to certain stimuli.

Gluconeogenesis

The reverse pathway in central carbon metabolism (relative to glycolysis) in which glucose is generated from precursors, and maintained as free glucose or converted into storage depots such as glycogen.

Anaplerosis

An intracellular process whereby tricarboxylic acid (TCA) cycle intermediates are replenished when they become limiting; for example, when entry of glucose-derived carbons is insufficient to maintain the mitochondrial TCA cycle, glutamine-derived carbons can replenish the pathway, maintaining homeostasis.

Phytanic acid

3,7,11,15-tetramethylhexadecanoic acid, a branched-chain fatty acid that humans obtain via consumption of, for example, diary products, beef and fish.

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Nakazawa, M., Keith, B. & Simon, M. Oxygen availability and metabolic adaptations. Nat Rev Cancer 16, 663–673 (2016). https://doi.org/10.1038/nrc.2016.84

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