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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.

Abstract

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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Acknowledgements

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

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Authors

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Related links

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DATABASES

CancerNet:

breast cancer

cervical cancer

colon carcinoma

endometrial tumours

gastric carcinoma

glioblastoma

head and neck tumours

oesophageal cancer

ovarian cancer

pancreatic carcinoma

prostate carcinoma

renal cancer

skin carcinoma

 GenBank:

HSV-TK

LocusLink

α-integrin

α-adrenergic receptor

acetoacetyl CoA thiolase

adenylate kinase-3

adrenomedullin

AKT

angiopoietin-2

annexin V

APAF-1

ARNT

ARNT2

BAD

BAX

carbonic anhydrase-9

caspase-3

caspase-9

CBP

CD99

ceruloplasmin

collagen-5α1

CREB

CUL2

cyclin G2

cyclooxygenase-2

cytochrome c

DEC1

EGR-1

elongin-B

elongin-C

endothelin-1

endothelin-2

enolase-1

epidermal growth factor receptor

ERBB2

erythtopoietin

ETS

ferritin light chain

fibroblast growth factor-3

fibronectin

FOS

GADD153

GLUT1

GLUT3

glyceraldehyde-3-phosphate dehydrogenase

HAP-1

heat-shock factor

heme oxygenase-1

hepatocyte growth factor

hexokinase-1

hexokinase-2

Hif-1α

HIF-1α

Hif-2α

HIF-2α

hnRNP

IAP2

IGF-1

IGF-2

IGF binding protein-1

IGF binding protein-2

IGF binding protein-3

IGF-1R

interleukin-6

interleukin-8

intestinal trefoil factor

JUN

Ku70

Ku80

KIP1

lactate dehydrogenase-A

L1CAM

lipocortin

low-density lipoprotein receptor-related protein

macrophage inhibitory factor

matrix metalloproteinase-13

MDM2

metal-regulatory transcription factor-1

metalloproteinases

metallothionein

monocyte chemotactic protein-1

MOP3

NF-κB

NIP3

nitric oxide synthase

NIX

osteopontin

p300

p44 mitogen-activated kinase

p53

phosphoglycerate kinase-1

phosphoribosyl pyrophosphate synthetase

PI3K

placental growth factor

plasminogen activator inhibitor-1

platelet-derived growth factor

platelet-derived growth factor-B

proline-4 hydroxylase

PTEN

pyruvate kinase-M

RBX1

spermidine N1-acetyl transferase

SRC

TGF-α

TGF-β1

TGF-β3

thioredoxin

Tie-2

transferrin

transferrin receptor

transgelin

transglutaminse-2

tyrosine hydroxylase

urokinase receptor

VEGF

VEGFR1

VEGFR2

VHL

vimentin

WAF1

FURTHER INFORMATION

SRI web site on hypoxia in cancer

LINKS

Lactate dehydrogenase

Glossary

ERYTHROPOIETIN

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.

THROMBOSPONDINS

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

TELOMERASE

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.

INVOLUCRIN

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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Harris, A. Hypoxia — a key regulatory factor in tumour growth. Nat Rev Cancer 2, 38–47 (2002). https://doi.org/10.1038/nrc704

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