Ischemia reperfusion injury (IRI) is a major obstacle in liver resection and liver transplantation. The initial step of IRI is mediated through ischemia which promotes the production of reactive oxygen species in Kupffer cells. This furthermore promotes the activation of pro-inflammatory signaling cascades, including tumor necrosis factor-alpha, IL-6, interferon, inducible nitric oxide synthase, TLR9/nuclear-factor kappa B pathway, and the production of damage-associated molecular patterns (DAMPs), such as ATP, histone, high mobility group box 1 (HMGB1), urate, mitochondrial formyl peptides and S100 proteins. With ongoing cell death of hepatocytes during the ischemic phase, DAMPs are built up and released into the circulation upon reperfusion. This promotes a cytokines/chemokine storm that attracts neutrophils and other immune cells to the site of tissue injury. The effect of IRI is further aggravated by the release of cytokines and chemokines, such as epithelial neutrophil activating protein (CXCL5), KC (CXCL1) and MIP-2 (CXCL2), the complement proteins C3a and C5a, mitochondrial-derived formyl peptides, leukotriene B4 and neutrophil extracellular traps (NETs) from migrating neutrophils. These NETs can also activate platelets and form Neutrophil-platelet microthrombi to further worsen ischemia in the liver. In this review we aim to summarize the current knowledge of mediators that promote liver IRI, and we will discuss the role of neutrophils and neutrophil extracellular traps in mediating IRI.

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

In recent years, liver transplantation has emerged as a treatment for patients with stage IV colorectal liver metastases (CRLM). Given the limited number of available deceased donor grafts, the use of living donor liver transplantation (LDLT) can be an important option. We performed a retrospective analysis of 10 patients that underwent LDLT for CRLM at our institution. 90% of patients were male with median age of 58 years and median MELD of 11 (range:6-32). The rectum was the most common primary location (40%). Synchronous liver tumors were found in 50%. Pre-transplant patients underwent resection (60%), HAI pump (50%) and/or RFA (50%). Everybody underwent adjuvant chemotherapy. Median cold ischemia time was 103 min (range:93-207 min), median total OR time was 11.5 h (range:8.5-13.9 h). 30% of patients had postoperative complications requiring re-operation. Mean RFS was 2.2 years (95%CI 1.2-3.2 y), mean OS was 3.0 years (95%CI 2.5-3.6 y). 30% of patients suffered a recurrence and 90% of patients are currently alive. This study represents the largest single center analysis in North America on patients undergoing LDLT for CRLM. LDLT is a safe and effective alternative for patients with CRLM who do not have progressive disease or extrahepatic metastasis.

Cancer surgery is a double-edged sword, as it can induce an inflammatory response that promotes tumor recurrence and progression. In this study, we explored the effects of surgery-induced neutrophil extracellular traps (NET) in reprogramming cancer metabolism to foster metastatic tumor growth. To model the effect of surgery on tumor progression, mice bearing subcutaneous tumors underwent a midline laparotomy with mesenteric exploration for 30 minutes. Mice subjected to surgery showed accelerated primary subcutaneous and lung metastatic tumor growth. Perioperative inhibition of NET formation utilizing DNAse, GSK484, or peptidyl arginine deiminase 4 knockout mice prevented surgically induced tumor growth, whereas pretreating cancer cells with NETs in vitro before inoculation increased tumor burden. Cancer cells exposed to surgical stress in vivo or treated with NETs in vitro showed activation of the MYC oncogenic pathway and fatty acid (FA) oxidation (FAO). NETs also stimulated the uptake of long-chain FAs and upregulation of CD36, the main long-chain FA transporter. Blocking FAO with etomoxir, a carnitine palmitoyl transferase Iα inhibitor, prevented metastatic tumor growth induced by surgical NETs. FA metabolism was crucial for cancer cells under anoikis stress, allowing the survival of circulating cancer cells exposed to NETs. Analysis of patient data substantiated the correlation between NET abundance and lipid metabolism, and plasma from postoperative patients upregulated CD36 expression and promoted the proliferation of colorectal cancer cells. Together, these findings show that the systemic NETosis response triggered by surgery promotes tumor progression by activating the MYC transcriptional program and reprogramming FAO metabolism in cancer cells. Significance: Surgery stimulates formation of neutrophil extracellular traps that promote fatty acid oxidation to support survival of disseminated cancer cells and metastasis, indicating that targeting this inflammation-metabolism axis may prevent tumor progression.