Skip to main content

Table 1 Evidence linking hypoxia to tumor cell genetic instability

From: Tumor hypoxia as a driving force in genetic instability

Author % Oxygen Cell system Assays Key findings
Rice et al. [70] 0% AA8 (CHO) Flow cytometry, gene copy analyses - Anoxia induces S-phase overreplication and increases the frequency of dihydrofolate reductase gene amplification
Young et al. [71] 0% (<10 ppm) KHT-C2-LP1 (M-fibrosarcoma), Metastasis assay, flow cytometry - Anoxia induces DNA overreplication and increases metastatic potential
B16F10-A1 (M-melanoma)
Reynolds et al. [61] 0% (<10 ppm) LN12 (M-fibroblasts) Chromosome based λ shuttle vector, PCR, DNA sequence analysis - Anoxia induces 3–4 fold increase in supF tRNA suppressor gene mutation (transversions and deletions) frequency
Rofstad et al. [72] 0% (<10 ppm and <100 ppm) BEX-c (H-melanoma), Flow cytometry, Giemsa - Anoxia followed by reoxygenation induces diplochromosomes and tetraploidization
SAX-c (H-melanoma)
Coquelle et al. [73] 0.02% GMA32 (Chinese hamster fibroblasts) Fluorescence in situ hybridization (FISH) - Severe hypoxia induces fragile sites and generates homogeneously stained regions (HSRs)
Yuan et al. [74] 0% (<10 ppm) 3340 (M-fibroblast) Host cell reactivation (HCR) assay, UV mutagenesis assay - Anoxia induces 2-fold increase in supFG1 mutation frequency
Coquelle et al. [75] 0.02% GMA32 (Chinese hamster fibroblasts), 112 (Chinese hamster fibroblasts) Fluorescence in situ hybridization (FISH) - Severe hypoxia activates fragile sites and generates double minutes and dicentric chromosomes
Mihaylova et al. [76] 0% <10 ppm 3340 (M-fibroblasts), HeLa (H-cervix adenocarcinoma), EMT6 (M-breast carcinoma) β-galactosidase and supFG1 mutation assays - Anoxia induces 2-fold increase in supFG1, cII and lacZ mutation frequency
Banath et al. [77] i.p. pimonidazole V79-VE (Chinese hamster fibroblasts), Flow cytometry, γ-H2AX foci, HPRT mutation assay, alkaline comet assay - Hypoxia (cells distant to the blood vessels) followed by reoxygenation does not alter mutation frequency at HPRT locus, DNA strand break rejoining or resolution of γ-H2AX foci following ionizing radiation (IR)
HCT116 (H-colon carcinoma),
SCCVII (M-squamous cell carcinoma)
Koshiji et al. [78] 1% HCT116 (H-colon carcinoma), β-galactosidase mutation assay, microsatellite analysis - Hypoxia increases the frequency of microsatellite mutations
HEC59 (H-endometrial carcinoma)
Papp-Szabo et al. [59] 0% ME (R-mammary epithelial cells), cII mutagenicity assay - Anoxia increases the mutation frequency by 2-fold at cII locus without affecting colonogenic survival
MFib (R-mammary fibroblasts)
Fischer et al. [79] 0% TX3868 (H-glioblastoma) Fluorescence in situ hybridization (FISH) - Anoxia induces double minutes, fragile sites and anaphase-bridges and initiates gene amplification on chromosome 12q
Rodriguez-Jimenez et al. [80] 1% C17.2 (M-multipotent neural precursor cells), M-primary neurospheres from CD31, BMMSC (H-mesenchymal stem cells), DPSC (H-mesenchymal stem cells) Host cell reactivation (HCR) assay, microsatellite instability analysis - Hypoxia increases mutation frequency of the β-galactosidase reporter gene and causes microsatellite instability
Keysar et al. [60] <0.1% AL(N) (CHO) Complement cytotoxic assay, flow cytometry mutation assay - Anoxia results in a significant induction of mutations especially large deletions in CD59 gene
Lee et al. [81] 3% Primary lymphocytes from healthy donors Sister chromatid exchange (SCE) assay, microsatellite instability assay - Hypoxia increases SCE but does not alter microsatellite instability
Pires et al. [38] <0.02% RKO (H-colon carcinoma), HCT116 (H-colon carcinoma), U2OS (H-osteosarcoma), IBR3 (H-fibroblast) DNA fiber analysis, immunofluorescence - Anoxia blocks DNA replication at the initiation and elongation stages and compromises DNA replication restart - Acute anoxia following reoxygenation (cycling hypoxia) does not affect DNA replication restart
Kumareswaran et al.* [82] 0.2% GM05757 (H-fibroblasts) Giemsa, Multicolor fluorescence in situ hybridization (M-FISH) - Hypoxia increases the frequency of fragmented DNA, ring chromosomes, telomeric fusions, chromosomal translocations and marker chromosomes following exogenous DNA damage
  1. CHO – Chinese hamster ovary cells; M – mouse; H – human; R – rat.
  2. *only study investigating DNA repair under continual hypoxic conditions.