Tumor hypoxia as a driving force in genetic instability - PubMed (original) (raw)
Tumor hypoxia as a driving force in genetic instability
Kaisa R Luoto et al. Genome Integr. 2013.
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.
Figures
Figure 1
Mechanism (s) of hypoxia-driven genetic instability. Hypoxia/anoxia signalling and subsequent adaptive biology is mediated by HIF1α transcription factors and altered protein through the unfolded protein response (UPR). These transcriptional and translational responses inhibit DNA repair by homologous recombination, non-homologous end-joining, and mismatch repair. The proteins downregulated by hypoxia are underlined. As a result, increased unrepaired double-strand breaks, replication errors and decreased centrosome function can accelerate genetic instability and lead to an aggressive, mutator phenotype.
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.
Figure 3
Hypoxia induces chromosomal aberrations following exogenous damage. A, Chromatin bridges or anaphase bridges in fibroblasts maintained under continual hypoxic (0.2% O2) conditions following 2 Gy of irradiation. These bridges can break into fragments and give rise to micronuclei [121]. The type, the number, and the fate of chromosome bridges under hypoxia is not known and requires further investigation. Representative DAPI stained and M-FISH images of fibroblasts are shown. Scale bar = 10 μm. B, M-FISH karyotype of fibroblasts maintained under oxic (21% O2) conditions following 2 Gy of irradiation or hypoxic (0.2% O2) conditions following 2 Gy of irradiation. Shown are reciprocal translocation between chromosomes 2 and 17, loss of chromosome 20 and two extra copies of chromosome Y in hypoxic cells following 2 Gy of irradiation. C, Percentages of chromosomal aberrations in oxic and hypoxic fibroblasts as measured by Giemsa staining analysis. NIR = non-irradiated; white columns = oxia (21% O2); black columns = hypoxia (0.2% O2). D, Percentages of chromosomal aberrations in oxic and hypoxic fibroblasts as measured by M-FISH analysis. NIR = non-irradiated; white columns = oxia (21% O2); black columns = hypoxia (0.2% O2). Plots are based on quantitative assessment of data published in Kumareswaran et al. [82].
Figure 4
Targeting of hypoxic cells in cancer treatment. Hypoxic cells can be quantitated in situ by staining for antibodies that measure uptake of nitroimidazole compounds (which are reduced in hypoxic environments and bind to SH-containing molecules such as glutathione and proteins); one such compound is pimonidazole (PIMO). These studies, in addition to direct measurements of pO2, have linked the proportion of hypoxic cells to aggressive tumor cell variants that are resistant to radiotherapy, chemotherapy and have an increased propensity for metastases. Direct targeting with agents that create DNA damage solely under hypoxic conditions (e.g. TH-302) or inhibit selective pathways activated in hypoxic cells (e.g. HIF1α and mTOR signaling) may improve the overall cell kill within a tumor volume when used alone or with radiotherapy or chemotherapy. Hypoxia may also lead to differential transcription or translation of DNA repair or replication genes which can reduce the function of the repair pathway. These repair-deficient hypoxic cells can be killed by agents that target remaining back-up pathways leading to cell death. Given the repair defect is secondary to the effects of hypoxia as opposed to a primary somatic or germline defect, this type of cell kill is denoted, “contextual synthetic lethality” given it is contextual on the local tumor microenvironment and varies depending on the metabolic state of the cancer cell.
References
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