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Nat Commun. 2018 Nov 30;9(1):5116. doi: 10.1038/s41467-018-07550-x.

Plasma redox imbalance caused by albumin oxidation promotes lung-predominant NETosis and pulmonary cancer metastasis.

Author information

1
Princess Margaret Cancer Centre Research Institute, University Health Network, Toronto, M5G2M9, ON, Canada.
2
Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu City, 514-8507, Mie Prefecture, Japan.
3
Radiation Medicine Program, Princess Margaret Cancer Centre, University Healthy Network, Toronto, M5G2M9, ON, Canada.
4
Department of Radiation Oncology, University of Toronto, Toronto, M5G2M9, ON, Canada.
5
Department of Medical Biophysics, University of Toronto, Toronto, M5G2M9, ON, Canada.
6
Princess Margaret Cancer Centre Research Institute, University Health Network, Toronto, M5G2M9, ON, Canada. scott.bratman@rmp.uhn.ca.
7
Radiation Medicine Program, Princess Margaret Cancer Centre, University Healthy Network, Toronto, M5G2M9, ON, Canada. scott.bratman@rmp.uhn.ca.
8
Department of Radiation Oncology, University of Toronto, Toronto, M5G2M9, ON, Canada. scott.bratman@rmp.uhn.ca.
9
Department of Medical Biophysics, University of Toronto, Toronto, M5G2M9, ON, Canada. scott.bratman@rmp.uhn.ca.

Abstract

Neutrophil extracellular traps (NETs) promote cancer metastasis in preclinical models following massive exogenous inflammatory stimuli. It remains unknown whether cancer hosts under physiologic conditions experience NETosis and consequent metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis. Albumin is the major source of free thiol that maintains redox balance. Oxidation of albumin-derived free thiol is sufficient to trigger NETosis via accumulation of reactive oxygen species within neutrophils. The resultant NETs are found predominantly within lungs where they contribute to the colonization of circulating tumor cells leading to pulmonary metastases. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation is associated with pulmonary metastasis in a cohort of head and neck cancer patients. These results implicate plasma redox balance as an endogenous and physiologic regulator of NETosis and pulmonary cancer metastasis, providing new therapeutic and diagnostic opportunities for combatting cancer progression.

PMID:
30504805
PMCID:
PMC6269536
DOI:
10.1038/s41467-018-07550-x
[Indexed for MEDLINE]
Free PMC Article

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