Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress

Abstract

Risks of tumor recurrence after surgical resection have been known for decades, but the mechanisms underlying treatment failures remain poorly understood. Neutrophils, first-line responders after surgical stress, may play an important role in linking inflammation to cancer progression. In response to stress, neutrophils can expel their protein-studded chromatin to form local snares known as neutrophil extracellular traps (NET). In this study, we asked whether as a result of its ability to ensnare moving cells NET formation might promote metastasis after surgical stress. Consistent with this hypothesis, in a cohort of patients undergoing attempted curative liver resection for metastatic colorectal cancer, we observed that increased postoperative NET formation was associated with a >4-fold reduction in disease-free survival. In like manner, in a murine model of surgical stress employing liver ischemia-reperfusion, we observed an increase in NET formation that correlated with an accelerated development and progression of metastatic disease. These effects were abrogated by inhibiting NET formation in mice, through either local treatment with DNAse or inhibition of the enzyme peptidylarginine deaminase (PAD4), which is essential for NET formation. In growing metastatic tumors, we found that intratumoral hypoxia accentuated NET formation. Mechanistic investigations in vitro indicated that mouse neutrophilderived NET triggered HMGB1 release and activated TLR9-dependent pathways in cancer cells to promote their adhesion, proliferation, migration and invasion. Taken together, our findings implicate NET in the development of liver metastases after surgical stress, suggesting that their elimination may reduce risks of tumor relapse. HHS Public Access

Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice

“…21 In another study, NETs induced by postsurgical stress in cancer patients with liver metastases correlated with reduced disease-free survival. 22 This is in line with an earlier study by Cools-Lartigue, showing that infection-induced NETs sequester circulating tumor cells and promote metastasis. 23 This finding may provide a mechanistic explanation for the clinical observation that postsurgical infections in cancer patients are associated with worse outcome, independent of the direct problems caused by the infection.…”

“…35 NETs have also been described as promoters of metastasis in situations where infection or inflammation, induced for example by surgery, puts an extra strain on the individual with cancer. 22,23 Data from our own group show that tumor-induced intravascular NETs promote endothelial activation in distant organs. 8 The endothelium serves as an essential barrier regulating trafficking of immune cells, but also for extravasating tumor cells attempting to invade and colonize a secondary organ.…”

Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions

“…In a recent publication, Tohme et al implicated NETs as potential contributors to metastatic cancer progression in the context of surgical stress. 45 Indeed, they observed NET formation in the liver following surgical stress, and they found that this was associated with an increase in liver metastasis. Following treatment of those mice with DNase or PAD4 inhibitors (or using a PAD4 deficient mice) they observed an improved oncological outcome in vivo.…”

Hypoxic regulation of neutrophil function and consequences for Staphylococcus aureus infection

“…As NETosis is predominantly dependent on NADPH production of ROS [75], and therefore reliant on availability of molecular oxygen, it seems likely that NET production under hypoxia would be reduced in line with the ROS data, though it appears that HIF1a signalling also has a role to play. Furthermore, other cells in a hypoxic environment may also impact on neutrophil function; for example, in a mouse hepatic tumour model, neutrophils incubated with media from hypoxic tumour cells showed increased NETosis, and this was associated with increased metastatic disease [76].…”