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Hypoxia — a key regulatory factor in tumour growth

Key Points

  • Hypoxia is a reduction in the normal level of tissue oxygen tension, and occurs during acute and chronic vascular disease, pulmonary disease and cancer. It induces a transcription programme that promotes an aggressive tumour phenotype.

  • Hypoxia is associated with resistance to radiation therapy and chemotherapy, but is also associated with poor outcome regardless of treatment modality, indicating that it might be an important therapeutic target.

  • Hypoxia-inducible factor-1α (HIF-1α) is a key transcription factor that is induced by hypoxia and regulated by a proline hydroxylase.

  • Pathways that are regulated by hypoxia include angiogenesis, glycolysis, growth-factor signalling, immortalization, genetic instability, tissue invasion and metastasis, apoptosis and pH regulation.

  • Most of the hypoxia-induced pathways promote tumour growth, but apoptosis is also induced by hypoxia. The balance of these pathways might be critical for the effects of hypoxia on tumour growth.

  • Drugs that inhibit HIF-1α expression antagonize HIF-1α interaction with CBP/p300 or block downstream function of genes such as vascular endothelial growth factor and cyclooxygenase-2 have potentially important roles in tumour therapy. Hypoxia can also be used to activate therapeutic gene delivery to specific areas of tissue.


Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.

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Figure 1: HIF-1 pathway.
Figure 2: Other factors involved in HIF-1 activation of hypoxia-response genes.
Figure 3: Hypoxia regulation of cell-death pathways.


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I thank I. Stratford and C. West for their helpful comments, and L. Richards for administrative assistance.

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α-adrenergic receptor

acetoacetyl CoA thiolase

adenylate kinase-3




annexin V






carbonic anhydrase-9









cyclin G2


cytochrome c








epidermal growth factor receptor




ferritin light chain

fibroblast growth factor-3






glyceraldehyde-3-phosphate dehydrogenase


heat-shock factor

heme oxygenase-1

hepatocyte growth factor











IGF binding protein-1

IGF binding protein-2

IGF binding protein-3




intestinal trefoil factor





lactate dehydrogenase-A



low-density lipoprotein receptor-related protein

macrophage inhibitory factor

matrix metalloproteinase-13


metal-regulatory transcription factor-1



monocyte chemotactic protein-1




nitric oxide synthase




p44 mitogen-activated kinase


phosphoglycerate kinase-1

phosphoribosyl pyrophosphate synthetase


placental growth factor

plasminogen activator inhibitor-1

platelet-derived growth factor

platelet-derived growth factor-B

proline-4 hydroxylase


pyruvate kinase-M


spermidine N1-acetyl transferase








transferrin receptor



tyrosine hydroxylase

urokinase receptor








SRI web site on hypoxia in cancer


Lactate dehydrogenase



A renal hormone that is induced by anaemia and that activates haemoglobin synthesis by bone-marrow red-cell precursors.


Non-malignant proliferations of vascular stromal cells in the central nervous system.


A multigene family of extracellular proteins that inhibit angiogenesis through several mechanisms, including upregulation of TGF-β and decreasing the cellular response to VEGF.


A ribonucleoprotein that maintains telomere length. Telomerase activity is repressed in most normal adult human somatic tissues, limiting replicative capacity. Reactivation of telomerase is believed to be a necessary event for the sustained growth of most human tumours.


A site in a chromosome that is susceptible to chromosome breakage and fusion with other chromosomes.


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Harris, A. Hypoxia — a key regulatory factor in tumour growth. Nat Rev Cancer 2, 38–47 (2002).

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