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Tumor hypoxia as a driving force in genetic instability.

Luoto KR, Kumareswaran R, Bristow RG - Genome Integr (2013)

Bottom Line: Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis.Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy.Hypoxia can also increase the rate of mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute, Radiation Medicine Program, Princess Margaret Cancer Centre (University Health Network), Toronto, ON, Canada. rob.bristow@rmp.uhn.on.ca.

ABSTRACT
Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination-mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells.

No MeSH data available.


Related in: MedlinePlus

Decreased repair of DNA double strand breaks (DNA-DSBs) under continual hypoxia. A, Despite a decrease in the initial number of induced and sensed DSBs measured by γ-H2AX foci at 30 minutes following 2 Gy, hypoxic (0.2% O2) G0/G1 synchronized human fibroblasts have an increased number of residual γ-H2AX foci at 24 hours. The asterisk represents a significant difference (*P < 0.05) between oxic control (solid) and hypoxic treatment (dashed). Plot is adapted from data published in Kumareswaran et al. [82]. B, Two dimensional (top panels) and three dimensional (bottom panel) confocal images of G0/G1 fibroblasts with increased number of residual γ-H2AX foci under continual hypoxia at 24 hours following 2 Gy of irradiation. Scale bar = 10 μm.
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Figure 2: Decreased repair of DNA double strand breaks (DNA-DSBs) under continual hypoxia. A, Despite a decrease in the initial number of induced and sensed DSBs measured by γ-H2AX foci at 30 minutes following 2 Gy, hypoxic (0.2% O2) G0/G1 synchronized human fibroblasts have an increased number of residual γ-H2AX foci at 24 hours. The asterisk represents a significant difference (*P < 0.05) between oxic control (solid) and hypoxic treatment (dashed). Plot is adapted from data published in Kumareswaran et al. [82]. B, Two dimensional (top panels) and three dimensional (bottom panel) confocal images of G0/G1 fibroblasts with increased number of residual γ-H2AX foci under continual hypoxia at 24 hours following 2 Gy of irradiation. Scale bar = 10 μm.

Mentions: The function of NHEJ in hypoxia-driven genetic instability and radiation response is more controversial. Inhibited expression of DNA-PKcs, Ku70, Ku80 and DNA-ligase IV has been observed under hypoxia [101,114]. NHEJ factors are downregulated in hypoxic wild-type MEFs and in normoxic HIF1α−/− MEFs [115]. In cervical tumors, KU70/KU80 expression correlates with oxygen pressure and is inhibited with increasing distance to blood vessels [116]. We observed an increase in residual DSBs in G0/G1 synchronized human fibrobalsts under hypoxic conditions following exogenous DNA damage (Figures 2 and 3) [82]. On the other hand, induction of Ku70 may occur under hypoxia in some cell lines [114]. KU70 could indeed contribute to hypoxic tumor cell resistance to radiation, as expression of a dominant negative form of KU70 sensitizes hypoxic glioma and colorectal cells to radiation [117]. Other reports have proposed redundancy or increased NHEJ under hypoxia [118-120]. An outstanding question in the field is whether the MRN complex, ATM and DNA-PKcs kinases differentially sense DSBs under oxia vs hypoxia (Figure 1). Varying model systems and tumor microenvironment conditions might explain the differing observations, and further investigation will clarify the role of hypoxia in NHEJ control.


Tumor hypoxia as a driving force in genetic instability.

Luoto KR, Kumareswaran R, Bristow RG - Genome Integr (2013)

Decreased repair of DNA double strand breaks (DNA-DSBs) under continual hypoxia. A, Despite a decrease in the initial number of induced and sensed DSBs measured by γ-H2AX foci at 30 minutes following 2 Gy, hypoxic (0.2% O2) G0/G1 synchronized human fibroblasts have an increased number of residual γ-H2AX foci at 24 hours. The asterisk represents a significant difference (*P < 0.05) between oxic control (solid) and hypoxic treatment (dashed). Plot is adapted from data published in Kumareswaran et al. [82]. B, Two dimensional (top panels) and three dimensional (bottom panel) confocal images of G0/G1 fibroblasts with increased number of residual γ-H2AX foci under continual hypoxia at 24 hours following 2 Gy of irradiation. Scale bar = 10 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 2: Decreased repair of DNA double strand breaks (DNA-DSBs) under continual hypoxia. A, Despite a decrease in the initial number of induced and sensed DSBs measured by γ-H2AX foci at 30 minutes following 2 Gy, hypoxic (0.2% O2) G0/G1 synchronized human fibroblasts have an increased number of residual γ-H2AX foci at 24 hours. The asterisk represents a significant difference (*P < 0.05) between oxic control (solid) and hypoxic treatment (dashed). Plot is adapted from data published in Kumareswaran et al. [82]. B, Two dimensional (top panels) and three dimensional (bottom panel) confocal images of G0/G1 fibroblasts with increased number of residual γ-H2AX foci under continual hypoxia at 24 hours following 2 Gy of irradiation. Scale bar = 10 μm.
Mentions: The function of NHEJ in hypoxia-driven genetic instability and radiation response is more controversial. Inhibited expression of DNA-PKcs, Ku70, Ku80 and DNA-ligase IV has been observed under hypoxia [101,114]. NHEJ factors are downregulated in hypoxic wild-type MEFs and in normoxic HIF1α−/− MEFs [115]. In cervical tumors, KU70/KU80 expression correlates with oxygen pressure and is inhibited with increasing distance to blood vessels [116]. We observed an increase in residual DSBs in G0/G1 synchronized human fibrobalsts under hypoxic conditions following exogenous DNA damage (Figures 2 and 3) [82]. On the other hand, induction of Ku70 may occur under hypoxia in some cell lines [114]. KU70 could indeed contribute to hypoxic tumor cell resistance to radiation, as expression of a dominant negative form of KU70 sensitizes hypoxic glioma and colorectal cells to radiation [117]. Other reports have proposed redundancy or increased NHEJ under hypoxia [118-120]. An outstanding question in the field is whether the MRN complex, ATM and DNA-PKcs kinases differentially sense DSBs under oxia vs hypoxia (Figure 1). Varying model systems and tumor microenvironment conditions might explain the differing observations, and further investigation will clarify the role of hypoxia in NHEJ control.

Bottom Line: Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis.Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy.Hypoxia can also increase the rate of mutation.

View Article: PubMed Central - HTML - PubMed

Affiliation: Ontario Cancer Institute, Radiation Medicine Program, Princess Margaret Cancer Centre (University Health Network), Toronto, ON, Canada. rob.bristow@rmp.uhn.on.ca.

ABSTRACT
Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation of a number of DNA damage response and repair genes. This can lead to inhibition of recombination-mediated repair of DNA double-strand breaks. Hypoxia can also increase the rate of mutation. Therefore, tumor cell adaptation to the hypoxic microenvironment can drive genetic instability and malignant progression. In this review, we focus on hypoxia-mediated genetic instability in the context of aberrant DNA damage signaling and DNA repair. Additionally, we discuss potential therapeutic approaches to specifically target repair-deficient hypoxic tumor cells.

No MeSH data available.


Related in: MedlinePlus