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

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.

SUBMITTER: Inoue M

PROVIDER: S-EPMC6269536 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Inoue Minoru M Nakashima Ryota R Enomoto Masahiro M Koike Yuhki Y Zhao Xiao X Yip Kenneth K Huang Shao Hui SH Waldron John N JN Ikura Mitsuhiko M Liu Fei-Fei FF Bratman Scott V SV

Nature communications 20181130 1

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 ...[more]

PMID: 30504805

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Project description:S-cysteinylated albumin and methionine-oxidized apolipoprotein A-I (apoA-I) have been posed as candidate markers of diseases associated with oxidative stress. Here, a dilute-and-shoot form of LC-electrospray ionization-MS requiring half a microliter of blood plasma was employed to simultaneously quantify the relative abundance of these oxidized proteoforms in samples stored at -80 °C, -20 °C, and room temperature and exposed to multiple freeze-thaw cycles and other adverse conditions in order to assess the possibility that protein oxidation may occur as a result of poor sample storage or handling. Samples from a healthy donor and a participant with poorly controlled type 2 diabetes started at the same low level of protein oxidation and behaved similarly; significant increases in albumin oxidation via S-cysteinylation were found to occur within hours at room temperature and days at -20 °C. Methionine oxidation of apoA-I took place on a longer time scale, setting in after albumin oxidation reached a plateau. Freeze-thaw cycles had a minimal effect on protein oxidation. In matched collections, protein oxidation in serum was the same as that in plasma. Albumin and apoA-I oxidation were not affected by sample headspace or the degree to which vials were sealed. ApoA-I, however, was unexpectedly found to oxidize faster in samples with lower surface-area-to-volume ratios. An initial survey of samples from patients with inflammatory conditions normally associated with elevated oxidative stress-including acute myocardial infarction and prostate cancer-demonstrated a lack of detectable apoA-I oxidation. Albumin S-cysteinylation in these samples was consistent with known but relatively brief exposures to temperatures above -30 °C (the freezing point of blood plasma). Given their properties and ease of analysis, these oxidized proteoforms, once fully validated, may represent the first markers of blood plasma specimen integrity based on direct measurement of oxidative molecular damage that can occur under suboptimal storage conditions.

Dataset Information

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

Publications

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

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