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 neutrophil-derived 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.

Formation of Neutrophil Extracellular Traps under Low Oxygen Level

“…Recently, Tohme et al showed that NETs promote the development and progression of liver metastases after surgical stress. Importantly, in growing metastatic tumors, the authors found that intratumoral hypoxia accentuated NET formation (53). In line of this study, Alfaro et al (54) demonstrated that tumor-produced IL-8 leads to extrusion of NETs in human myeloid-derived suppressor cells, which are considered an important T-cell immunosuppressive component in cancer-bearing hosts (54).…”

Immunological Consequences of Epithelial–Mesenchymal Transition in Tumor Progression

“…Neutrophils also produce unique structures called neutrophil extracellular traps (NETs) which are composed of extruded DNA and antimicrobial proteins. After surgical stress or infection, cancer cells have been shown to become trapped in NETs which formed in liver and lung capillaries promoting the development of micrometastasis (30, 31). On the other hand, cancer cells were also shown to recruit neutrophils through CXCL15 or HMGB1 secretion (32).…”

Long-term Consequences of the Acute Neural-Inflammatory Stress Response in the Cancer Surgical Patient: New Findings and Perspectives

“…The delayed second peak may relate to the formation of a pre-metastatic niche in distant organs with entrapment of circulating tumor cells (CTC) that are released during surgical manipulation. 9–11 These findings are not too surprising, as critically, neural activation and inflammation is clearly associated with the natural history of cancer 12 and biologic plausibility is found in the pathophysiological stress associated with surgery. 13 Surgical tissue damage accompanied by the systemic release of hormones (eg.…”

“…45 Neutrophils activated by platelets may also release chromatid DNA into the extracellular environment, with the formation of neutrophil extracellular traps (NET) that likely evolved to trap bacteria and parasites but may also promote adhesion of circulating tumor cells in the sinusoids of metastasis prone distant sites such as the lung and liver. 11 …”

“…Platelets may also activate neutrophils to form extracellular traps (NETs) that adhere circulating tumor cells in the sinusoids of distant organs that are prone to metastasis. 11 It has been shown that patients with the lowest platelet nadir after surgery were three times more likely to progress to a higher severity of post-operative kidney injury and had associated increased risk of mortality immediately after cardiac surgery. 49 While this observation is outside the setting of cancer surgery it likely points to the impact of poorly buffered inflammation with microvascular endothelial dysfunction and dysregulated biologic complexity during surgery.…”