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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I thank I. Stratford and C. West for their helpful comments, and L. Richards for administrative assistance.
A renal hormone that is induced by anaemia and that activates haemoglobin synthesis by bone-marrow red-cell precursors.
- CEREBELLAR HAEMANGIOGBLASTOMAS
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.
- FRAGILE SITE
A site in a chromosome that is susceptible to chromosome breakage and fusion with other chromosomes.
- CARBONIC ANHYDRASES
Enzymes that convert carbon dioxide to carbonic acid and then to protons and bicarbonate ions.
A cytoskeletal protein in squamous cells that is involved in their terminal differentiation.
- DEEP-VEIN THROMBOSIS
The process of clot formation in the venous circulation, usually in the lower limbs or pelvis.
- PULMONARY EMBOLISM THROMBOSIS
The occlusion of pulmonary veins by clots dislodged from peripheral deep veins, usually from the lower extremities.
- ACCELERATED RADIOTHERAPY WITH CARBOGEN AND NICOTINAMIDE
Experimental technique to improve blood flow and oxygen delivery to tumours.
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