HiChIP-Based Epigenomic Footprinting Identifies a Promoter Variant of UXS1 That Confers Genetic Susceptibility to Gastroesophageal Cancer.

Genome-wide association studies (GWAS) have identified more than a hundred single nucleotide variants (SNV) associated with the risk of gastroesophageal cancer (GEC). The majority of the identified SNVs map to noncoding regions of the genome. Uncovering the causal SNVs and genes they modulate could help improve GEC prevention and treatment.

Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis.

Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs).

Soluble factors in malignant ascites promote the metastatic adhesion of gastric adenocarcinoma cells.

Background: Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America. It is commonly associated with peritoneal accumulation of malignant ascites (MA), a fluid containing cancer and inflammatory cells and soluble proteins. Peritoneal metastasis (PM) is the most common site of gastric cancer (GC) progression after curative-intent surgery and is the leading cause of death among GC patients.

Inhibition of LPS-mediated TLR4 activation abrogates gastric adenocarcinoma-associated peritoneal metastasis.

Surgical resection, the cornerstone of curative intent treatment for gastric adenocarcinoma, is associated with a high rate of infection-related post-operative complications, leading to an increased incidence of metastasis to the peritoneum. However, the mechanisms underlying this process are poorly understood. Lipopolysaccharide (LPS), an antigen from Gram-negative bacteria, represents a potential mechanism via induction of local and systemic inflammation through activation of Toll-like receptor (TLR).

Neutrophil Extracellular Trap-Associated CEACAM1 as a Putative Therapeutic Target to Prevent Metastatic Progression of Colon Carcinoma.

Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications.

Activation of the pattern recognition receptor NOD1 augments colon cancer metastasis.

While emerging data suggest nucleotide oligomerization domain receptor 1 (NOD1), a cytoplasmic pattern recognition receptor, may play an important and complementary role in the immune response to bacterial infection, its role in cancer metastasis is entirely unknown. Hence, we sought to determine the effects of NOD1 on metastasis. NOD1 expression in paired human primary colon cancer, human and murine colon cancer cells were determined using immunohistochemistry and immunoblotting (WB).

Gram-Negative Pneumonia Augments Non-Small Cell Lung Cancer Metastasis through Host Toll-like Receptor 4 Activation.

Introduction: Surgery is essential for cure of early-stage non-small cell lung cancer (NSCLC). Rates of postoperative bacterial pneumonias, however, remain high, and clinical data suggests that post-operative infectious complications confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis.

Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects.

Targeting the dynamic tumor immune microenvironment (TIME) can provide effective therapeutic strategies for cancer. Neutrophils are the predominant leukocyte population in mice and humans, and mounting evidence implicates these cells during tumor growth and metastasis. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of binding tumor cells to support metastatic progression.

Gram-positive pneumonia augments non-small cell lung cancer metastasis via host toll-like receptor 2 activation.

Surgical resection of early stage nonsmall cell lung cancer (NSCLC) is necessary for cure. However, rates of postoperative bacterial pneumonias remain high and may confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory cascade by recognizing microbial products at the surface of numerous cell types in the lung; however, little is known about how host TLRs influence NSCLC metastasis.

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

Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis.

Simplified Human Neutrophil Extracellular Traps (NETs) Isolation and Handling.

Neutrophil Extracellular Traps (NETs) have been recently identified as part of the neutrophil's antimicrobial armamentarium. Apart from their role in fighting infections, recent research has demonstrated that they may be involved in many other disease processes, including cancer progression. Isolating purified NETs is a crucial element to allow the study of these functions.

Gram negative bacteria increase non-small cell lung cancer metastasis via Toll-like receptor 4 activation and mitogen-activated protein kinase phosphorylation.

Surgery is required for the curative treatment of lung cancer but is associated with high rates of postoperative pneumonias predominantly caused by gram negative bacteria. Recent evidence suggests that these severe infectious complications may decrease long term survival after hospital discharge via cancer recurrence, but the mechanism is unclear. Lung cancer cells have recently been demonstrated to express Toll-like receptors (TLR) that mediate pathogen recognition.

Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis.

The majority of patients with cancer undergo at least one surgical procedure as part of their treatment. Severe postsurgical infection is associated with adverse oncologic outcomes; however, the mechanisms underlying this phenomenon are unclear. Emerging evidence suggests that neutrophils, which function as the first line of defense during infections, facilitate cancer progression.

Lipopolysaccharide-induced toll-like receptor 4 signaling enhances the migratory ability of human esophageal cancer cells in a selectin-dependent manner.

Background: Esophageal cancer is an aggressive malignancy, and emerging data suggest that postoperative infections may promote cancer progression. Systemic exposure to lipopolysaccharide (LPS), a Gram-negative bacterial antigen involved in such infections, has been shown to increase cancer cell adhesion to the hepatic sinusoids in vivo. We investigated the direct impact of LPS on the migratory ability of esophageal cancer cells via the LPS receptor toll-like receptor 4 (TLR4).

Neutrophils promote liver metastasis via Mac-1-mediated interactions with circulating tumor cells.

Although circulating neutrophils are associated with distant metastasis and poor outcome in a number of epithelial malignancies, it remains unclear whether neutrophils play an active causal role in the metastatic cascade. Using in vivo models of metastasis, we found that neutrophils promote cancer cell adhesion within liver sinusoids and, thereby, influence metastasis. Neutrophil depletion before cancer cell inoculation resulted in a decreased number of gross metastases in an intrasplenic model of liver metastasis.

LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis.

Infectious complications resulting from resection of colorectal cancer (CRC) elevates the risk of cancer recurrence and metastasis, but the reason for this risk relationship is unknown. Defining the mechanisms responsible may offer opportunities to improve outcomes in a majority of patients whose tumors are resected as part of their therapy. The complex formed between Toll receptor TLR4 and myeloid differentiation factor MD2 defines a major cell surface receptor for lipopolysaccharide (LPS), a gram-negative bacterial antigen that has been implicated in infectious complications after CRC resection.

L-selectin shedding in sepsis limits leukocyte mediated microvascular injury at remote sites.

Background: Increased soluble L-selectin levels have been shown to attenuate local inflammation-mediated microvascular leakage, and failure to generate high levels has been associated with increased risk of acute respiratory distress syndrome in septic patients. We hypothesized that failure to shed L-selectin in systemic inflammation would result in increased local inflammation-induced leukocyte adherence and microvascular leakage.

Methods: Using intraperitoneal lipopolysaccharide (LPS) or control bicarbonate buffered saline (BBS) and intrascrotal TNFalpha or BBS, mice were randomized to systemic inflammation (LPSip + BBSis), local inflammation (BBSip + TNFis), both (LPSip + TNFis), or control (BBSip+BBSis).

Intra-abdominal sepsis attenuates local inflammation-mediated increases in microvascular permeability at remote sites in mice in vivo.

Background: Given that leukocyte delivery to remote sites is diminished in states of systemic inflammation, such as sepsis, and activated leukocytes may be responsible for endothelial injury leading to vascular leakage, we hypothesized that intra-abdominal sepsis would diminish microvascular leakage at remote sites by altering leukocyte-endothelial interactions.

Methods: Using a murine intravital microscopy model, we examined leukocyte-endothelial interactions and vascular leakage at a peripheral site in the presence of local and/or systemic inflammation. Forty mice were randomized to 1 of 4 study groups: local infection (orchitis), systemic infection (intra-abdominal sepsis by cecal ligation and puncture), local and systemic infection, and control.

Hypertonic saline resuscitation attenuates neutrophil lung sequestration and transmigration by diminishing leukocyte-endothelial interactions in a two-hit model of hemorrhagic shock and infection.

Background: Hypertonic saline (HTS) attenuates polymorphonuclear neutrophil (PMN)-mediated tissue injury after hemorrhagic shock. We hypothesized that HTS resuscitation reduces early in vivo endothelial cell (EC)-PMN interactions and late lung PMN sequestration in a two-hit model of hemorrhagic shock followed by mimicked infection.

Methods: Thirty-two mice were hemorrhaged (40 mm Hg) for 60 minutes and then given intratracheal lipopolysaccharide (10 microg) 1 hour after resuscitation with shed blood and either HTS (4 mL/kg 7.

Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil rolling and adherence to endothelium and reduces in vivo vascular leakage.

Objective: To evaluate the in vivo effects of hypertonic saline (HTS) resuscitation on the interactions of endothelial cells (ECs) and polymorphonuclear neutrophils (PMNs) and vascular permeability after hemorrhagic shock.

Summary Background Data: The PMN has been implicated in the pathogenesis of EC damage and organ injury following hemorrhagic shock. Compared to Ringer's lactate (RL), HTS resuscitation diminishes PMN and EC adhesion molecule expression and organ sequestration of PMNs.

Alteration of chemoattractant receptor expression regulates human neutrophil chemotaxis in vivo.

Objective: To elucidate the mechanisms that regulate human neutrophil delivery in vivo, as well as the mechanisms that lead to observed reduction in polymorphonuclear (PMN) delivery to remote sites in septic patients.

Methods: Alterations in human PMN chemoattractant receptor expression and chemotactic function in vivo were evaluated in two distinct experiments: exudate PMNs (PMNs that have undergone transmigration to skin window blisters in controls) and septic PMNs (circulating PMNs from septic patients in the intensive care unit) were both separately compared with control circulating PMNs.

Results: Exudate PMNs displayed increased C5a receptors and C5a chemotaxis, and reduced interleukin-8 receptors (both IL-8 RA and IL-8 RB) and IL-8 chemotaxis.