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

Abstract

Neutrophil extracellular traps (NETs) entrap circulating tumor cells (CTCs) and promote metastasis within distant organs in preclinical models1,2. In these models, NETosis is triggered by exogenous massive inflammatory stimuli, and thus it remains unknown whether cancer hosts under physiologic inflammation-free conditions experience NETosis and consequent cancer metastasis. Here we show that plasma redox imbalance caused by albumin oxidation promotes inflammation-independent NETosis and cancer metastasis specifically in the lungs. Albumin is the major source of free thiol that maintains redox balance in vitro and in vivo. 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 CTCs leading to pulmonary metastases in mouse models. These effects are abrogated by pharmacologic inhibition of NET formation. Moreover, albumin oxidation and the resultant decline of plasma free thiol are 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.