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Open AccessArticle

Long-Term Deleterious Effects of Short-term Hyperoxia on Cancer Progression—Is Brain-Derived Neurotrophic Factor an Important Mediator? An Experimental Study

1
TRANSCEND Research Centre, Regional Institute of Oncology, 700483 Iasi, Romania
2
Department of Anaesthesia and Intensive Care, School of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
3
Department of Anaesthesia and Intensive Care, Regional Institute of Oncology, 700483 Iasi, Romania
4
Department of Immunology, School of Medicine, “Grigore T Popa” University of Medicine and Pharmacy, 700400 Iasi, Romania
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(3), 688; https://doi.org/10.3390/cancers12030688
Received: 16 January 2020 / Revised: 11 March 2020 / Accepted: 11 March 2020 / Published: 14 March 2020
Perioperative factors promoting cancer recurrence and metastasis are under scrutiny. While oxygen toxicity is documented in several acute circumstances, its implication in tumor evolution is poorly understood. We investigated hyperoxia long-term effects on cancer progression and some underlying mechanisms using both in vitro and in vivo models of triple negative breast cancer (TNBC). We hypothesized that high oxygen exposure, even of short duration, may have long-term effects on cancer growth. Considering that hyperoxic exposure results in reactive oxygen species (ROS) formation, increased oxidative stress and increased Brain-Derived Neurotrophic Factor (BDNF) expression, BDNF may mediate hyperoxia effects offering cancer cells a survival advantage by increased angiogenesis and epithelial mesenchymal transition (EMT). Human breast epithelial MCF10A, human MDA-MB-231 and murine 4T1 TNBC were investigated in 2D in vitro system. Cells were exposed to normoxia or hyperoxia (40%, 60%, 80% O2) for 6 h. We evaluated ROS levels, cell viability and the expression of BDNF, HIF-1α, VEGF-R2, Vimentin and E-Cadherin by immunofluorescence. The in vivo model consisted of 4T1 inoculation in Balb/c mice and tumor resection 2 weeks after and 6 h exposure to normoxia or hyperoxia (40%, 80% O2). We measured lung metastases and the same molecular markers, immediately and 4 weeks after surgery. The in vitro study showed that short-term hyperoxia exposure (80% O2) of TNBC cells increases ROS, increases BDNF expression and that promotes EMT and angiogenesis. The in vivo data indicates that perioperative hyperoxia enhances metastatic disease and this effect could be BDNF mediated. View Full-Text
Keywords: cancer progression; breast cancer; hyperoxia; perioperative; metastasis; BDNF; Vimentin; E-Cadherin; epithelial mesenchymal transition; angiogenesis cancer progression; breast cancer; hyperoxia; perioperative; metastasis; BDNF; Vimentin; E-Cadherin; epithelial mesenchymal transition; angiogenesis
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Tiron, A.; Ristescu, I.; Postu, P.A.; Tiron, C.E.; Zugun-Eloae, F.; Grigoras, I. Long-Term Deleterious Effects of Short-term Hyperoxia on Cancer Progression—Is Brain-Derived Neurotrophic Factor an Important Mediator? An Experimental Study. Cancers 2020, 12, 688.

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