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Hypoxia and metabolism

Hypoxia, DNA repair and genetic instability

Nature Reviews Cancer volume 8, pages 180–192 (2008)Cite this article

Key Points

  • The presence of intratumoural hypoxia is a negative prognostic indicator for many patients as it has been associated with increased local failure following radiotherapy and increased distant metastatic spread.

  • Hypoxia can drive the metastatic phenotype secondary to genetic instability, increased angiogenesis, decreased apoptosis and upregulation of a number of genes involved in the metastatic cascade (such as osteopontin, lysyl oxidase and vascular endothelial growth factor).

  • Both acute and chronic hypoxia exist in human tumours and these may have different biological consequences as a function of changes in hypoxia-inducible factor 1α-mediated transcription, altered protein translation and differential activation of hypoxia-associated cell cycle checkpoints.

  • Hypoxic cells can acquire a mutator phenotype that consists of decreased DNA repair, an increased mutation rate and increased chromosomal instability.

  • Defects in homologous recombination and mismatch repair have been documented in tumour cells that are exposed to chronic hypoxia.

  • Defective DNA repair in hypoxic cells could alter the sensitivity to radiotherapy and chemotherapy and render cells susceptible to molecular-targeted agents that are selectively toxic to checkpoint-deficient or repair-deficient tumour cells.

Abstract

Areas of hypoxic tumour tissue are known to be resistant to treatment and are associated with a poor clinical prognosis. There are several reasons why this might be, including the capacity of hypoxia to drive genomic instability and alter DNA damage repair pathways. Significantly, current models fail to distinguish between the complexities of the hypoxic microenvironment and the biological effects of acute hypoxia exposures versus longer-term, chronic hypoxia exposures on the transcription and translation of proteins involved in genetic stability and cell survival. Acute and chronic hypoxia might lead to different biology within the tumour and this might have a direct effect on the design of new therapies for the treatment of hypoxic tumours.

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Figure 1: DNA double-strand break sensing and repair pathways.
Figure 2: DNA double-strand breaks and chromatin in irradiated hypoxic cells.
Figure 3: Hypoxia decreases RAD51 and homologous recombination.
Figure 4: Model of hypoxia-mediated genetic instability.

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Acknowledgements

These studies are supported by National Cancer Institute of Canada with funds raised by the Terry Fox Run. R.G.B. is a Canadian Cancer Society Research Scientist.

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  1. Departments of Medical Biophysics and Radiation Oncology, University of Toronto and Ontario Cancer Institute and Princess Margaret Hospital (University Health Network), 610 University Avenue, Toronto, M5G2M9, Ontario, Canada

    Robert G. Bristow & Richard P. Hill

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Correspondence to Robert G. Bristow.

Supplementary information

Supplementary information S1 ((movie)

A normal diploid fibroblast nucleus with pan-53BP1 staining (red) and minimal γH2AX foci (green) under non-irradiated normoxic conditions in G1 phase. See also Fig. 2a. (MOV 30800 kb)

Supplementary information S2 ((movie)

A non-irradiated anoxic fibroblast nucleus arrested in S-phase with global γH2AX activation (green) throughout the chromatin. See also Fig. 2b. (MOV 37288 kb)

Related links

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DATABASES

National Cancer Institute

breast cancer

cancer of musculoskeletal tissues

cervical cancer

head and neck cancer

prostate cancer

National Cancer Institute Drug Dictionary

18F-EF5

azathioprine

cisplatin

etoposide

flavopiridol

methotrexate

misonidazole

mitomycin C

PR-104

temozolomide

tirapazamine

UCN-01

FURTHER INFORMATION

Richard P. Hill's homepage

Robert G. Bristow's homepage

Spatio-Temporal Targeting and Amplification of Radiation Response

Tumour Microenvironment Group

Glossary

Hypoxic cellular adaptation

Cells can continue to proliferate in decreasing O2 gradients by altering the transcription and translation of genes that are involved in angiogenesis and cell invasion, cell metabolism and cell survival.

Perfusion

Tumours have differential perfusion of oxygen and nutrients based on the extent and function of the intratumoural vasculature and interstitial fluid pressure.

Oxygen enhancement ratio

(OER). The ratio of radiation dose required for the same biological effect (for example, cell survival or the number of DNA breaks) in the absence versus the presence of O2. This varies for different tumour cell lines and tumour tissues and reflects the radioresistance observed in acutely anoxic cells.

Interstitial fluid pressure

(IFP). High IFP (for example, in the range 10–20 mm Hg) is characteristic many human tumours and is thought to be partly due to abnormal and highly permeable tumour vessels and decreased lymphatic drainage.

2-nitroimidazoles

Pimonidazole, misonidazole, CCI103F and EF5 are examples of 2-nitroimidazoles that are bioreduced through a series of one-electron reactions in low O2 environments and create stably bound cellular adducts. These O2-dependent adducts can then be detected in vivo using immunohistochemistry or non-invasive imaging.

Bleomycin

Bleomycin is a cytotoxic glycopeptide antibiotic used in chemotherapy. It acts by inhibiting DNA synthesis and creating oxygen-dependent DNA breaks, leading to mitotic catastrophe and cell death.

Etoposide

Etoposide is an epipodophyllotoxin that inhibits DNA synthesis by forming a complex with topoisomerase II and DNA. This complex induces DNA double-strand breaks with resulting cell cycle-dependent toxicity (that is, S and G2 phase cells).

Alkylating agents

Alkylating agents (for example, temozolomide, chlorambucil and ifosfamide) add alkyl groups to the bases of DNA, which can lead to DNA breaks and crosslinks and interference with DNA replication and transcription, all resulting in cell death.

Carboplatin

Carboplatin is an alkylating agent that covalently binds to DNA to create intra-strand and inter-strand DNA–DNA crosslinks. These crosslinks inhibit DNA synthesis and transcription leading to cell death.

Chronic obstructive pulmonary disease

(COPD). A group of diseases, including chronic bronchitis and emphysema, that are characterized by the pathological limitation of airflow in the airway that is not fully reversible.

Positron-emission tomography

(PET). PET is a non-invasive imaging technique that can create three-dimensional mapping of hypoxia within the body by detecting the γrays given off by a positron-emitting isotope (for example, 18F).

Single photon emission computed tomography

(SPECT). SPECT is a nuclear medicine tomographic imaging technique that the detects γ rays that are given off by radiopharmaceuticals (for example, 99Tc) and can provide three-dimensional and functional imaging.

Functional computed tomography

Functional computed tomography (CT) is a non-invasive imaging technique that can measure blood flow, angiogenesis and other physiologic parameters in tissues using image analysis with fast CT scanning and intravenous contrast agents.

Blood oxygenation level-dependent magnetic resonance imaging

(BOLD MRI). BOLD MRI is a non-invasive technique for indirectly measuring tissue perfusion and oxygenation based on the paramagnetic qualities of deoxyhaemoglobin. BOLD MRI does not require exogenous contrast materials and one can obtain serial images at high spatial resolution over time.

Polarographic O2 electrode measurements

A microelectrode needle can be placed into normal or tumour tissue and can determine partial pressure of O2 (pO2) measurements as it moves forward through the tissue. This can be used to compare tumour hypoxia within a cohort of patients.

Fanconi anaemia

Fanconi anemia is an autosomal recessive disorder that leads to aplastic anaemia and increased sensitivity to DNA-damaging agents. The disorder is caused by altered activity of one of at least 13 genes that encode the FANC proteins that function within a pathway as part of the DNA damage response.

Nucelotide-excision repair

This pathway recognizes bulky distortions in the DNA that occur after ultraviolet radiation or chemotherapy. Recognition of these distortions leads to the removal of a short single-stranded DNA segment that includes the lesion, creating a single-strand gap in the DNA, which is subsequently filled by a DNA polymerase.

Polysomal fractionation analysis

This technique can determine the mRNA translation efficiency of specific genes following cellular hypoxia or other stressors.

Base-excision repair

Base-excision repair uses DNA glycosylases and AP endonucleases to remove DNA bases (caused by exogenous or endogenous ROS and alkylation) in order to prevent cytotoxicity or DNA polymerase errors. Once the damaged DNA base is removed, DNA polymerase and ligase activities regenerate the DNA strand and seal the DNA.

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Bristow, R., Hill, R. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer 8, 180–192 (2008). https://doi.org/10.1038/nrc2344

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