Table 1.
Effects of Intermittent and Acute/ Chronic Hypoxia on In Vitro models of breast cancer
| Reference | Cell Line/ Mouse Model |
Conduction of Hypoxia | Intermittent Hypoxia (IH) |
Effect of IH | Acute Hypoxia (AH) or Chronic Hypoxia (CH) | Effect of AH/ CH | Hallmark of Cancer [90] |
|---|---|---|---|---|---|---|---|
| [59] Alhawarat et al., 2019 | MCF-7 | AnaecroGen System | 8 h (1% O2), three times per week |
Increase in VEGF secretion Acquired higher chemoresistance Increased stemness properties |
1% O2 for 72 h, once per week | Same results at effects of IH | Inducing angiogenesis |
| [94] Azimi et al., 2017 |
(1) MDA-MB-468 (2) MCF-7 |
Hypoxia Chamber | N/A | N/A | 1% O2 for 24 h |
Increased ROS production Increased mesenchymal markers (Vimentin, N-cadherin, Snail, Twist, AXL and SERPINE1) |
Activating invasion and metastasis |
| [52] Boidot et al., 2014 | 20 tumor cell lines | Hypoxia Chamber | 24 cycles of 30 min incubation under normoxia and 30 min under hypoxia (1% O2) | Cycling hypoxia results in a unique genetic signature that is predictive of clinical outcome in breast cancer patients | 1% O2 for 24 h | One third of the genes comprising the cycling hypoxic signature and reflects a major difference with the chronic hypoxic signature | Genome instability and mutation |
| [9] Chen et al., 2018 |
(1) MMTV-PyMT (2) MCF-7 |
Hypoxia Chamber | 24 h (21% O2) followed by 24 h hypoxia (1% O2) for 9 days |
Increased expression of HIF-1a Increased secretion of tumor growth Promoting cytokine IL-6 |
1% O2 for 9 days |
Loss of HIF-1a expression Increased induction of senescent cells |
Activating invasion and metastasis |
| [95] Cooper et al., 2004 |
(1) MCF-7 (2) ZR-75 |
Hypoxia Chamber | 3 cycles of 64 h hypoxia (0.02 − 0.5% O2) and reoxygenation for 8 h | Increased degradation of ER-a protein through altered proteasomal degradation that persisted through reoxygenation | 0.02 − 0.5% O2 for 24 h | ER-a downregulation | Deregulating cellular energetics |
| [96] Gutsche et al., 2016 | SUM149PT | Hypoxia Chamber | 48 h (20.9% O2) followed by 24 h hypoxia (0.2% O2) for 45 days | Increased expression of pro-metastatic genes (tenascin-C, matrix metalloproteinase 9, COX2) | N/A | N/A | Activating invasion and metastasis |
| [12] Han et al., 2017 |
(1) MDA-MB-231 (2) MCF-7 |
Hypoxia Chamber | 20 h (21% O2) followed by 4 h hypoxia (1% O2) | 164 and 242 genes were specifically down- or upregulated only during acute hypoxia | 1% O2 for 24 h | 300 and 623 genes were uniquely down- or upregulated during chronic hypoxic phase | Genome instability and mutation |
| [11] Jarman et al., 2019 |
(1) MCF-7 (2) MCF-7-HER2 |
Hypoxia Chamber | N/A | N/A | 0.5% O2 for 10 weeks | Overexpression of HER2 leads to upregulation of HIF-2a but not HIF-1a | Sustaining proliferative signaling |
| [97] Karlenius et al., 2012 | MDA-MB-231 | Hypoxia Chamber | 4 cycles of 10 min hypoxia (0.1% O2) and 20 min reoxygenation by placing in 5% CO2/95% air |
Increase in ROS Increased Trx levels Trx gene promoter is activated in the reoxygenation phase through the action of Nrf-2 |
0.1% O2 for 24 h |
Significant decrease in ROS levels No change in Trx levels |
Deregulating cellular energetics |
| [8] Liu et al., 2017 | MDA-MB-231 | Hypoxia Chamber | 12 h (21% O2) followed by 12 h hypoxia (1% O2) for 5–20 cycles |
Significantly increased migration of cells, dependent on the number of cycles Upregulation of HIF-1a and Vimentin |
1% O2 for 48 h | HIF-1a levels remained low for 36 h | Activating invasion and metastasis |
| [98] Louie et al., 2010 |
(1) MDA-MB-231 (2) BCM2 |
Hypoxia Chamber | 1% O2 and nutrient deprivation for 7 days, and reoxygenating surviving cells for 1–3 weeks | Stem-like breast cancer subpopulation is expanded responding to reoxygenation | N/A | N/A | Activating invasion and metastasis |
| [67] Stiehl et al., 2012 | MCF-7 | Hypoxia Chamber | N/A | N/A | 1% O2 for 0–72 h |
HIF-1a levels peaked at 24–48 h AREG and WISP2 expression was strongly HIF-2a-dependent HIF-2a depletion correlated to a reduction in EGF activation |
Sustaining proliferative signaling |
| [99] Verduzco et al., 2015 | MDA-MB-231 | Hypoxia Chamber | 50 cycles of 16 h hypoxia (0.2% O2) followed by 8 h normoxia |
Loss of E-cadherin and p53 Increased drug resistance |
0.2% O2 | Few changes in chronic exposed cultures | Activating invasion and metastasis |