Surgery is a crucial intervention and provides a chance of cure for patients with cancer. The perioperative period is characterized by an increased risk for accelerated growth of micrometastatic ...disease and increased formation of new metastatic foci. The true impact for cancer patients remains unclear. This review summarizes the often fragmentary clinical and experimental evidence supporting the role of surgery and inflammation as potential triggers for disease recurrence. Surgery induces increased shedding of cancer cells into the circulation, suppresses antitumor immunity allowing circulating cells to survive, upregulates adhesion molecules in target organs, recruits immune cells capable of entrapping tumor cells, and induces changes in the target tissue and in the cancer cells themselves to enhance migration and invasion to establish at the target site. Surgical trauma induces local and systemic inflammatory responses that can also contribute to the accelerated growth of residual and micrometastatic disease. Furthermore, we address the role of perioperative factors, including anesthesia, transfusions, hypothermia, and postoperative complications, as probable deleterious factors contributing to early recurrence. Through the admittedly limited understanding of these processes, we will attempt to provide suggestions for potential new therapeutic approaches to target the protumorigenic perioperative window and ultimately improve long-term oncological outcomes.
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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, 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.
While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We ...hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs
by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells.
, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4
and CD8
T cells. We next targeted PD-L1
by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.
Liver Anatomy Quiz: Test Your Knowledge Geller, David A.; Tohme, Samer
Journal of gastrointestinal surgery,
04/2021, Letnik:
25, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Understanding liver anatomy and anatomic hilar vascular variants is important for the practicing surgeon. This knowledge is essential for cholecystectomy, hepatobiliary, pancreatic, and upper GI ...surgery. The attached quiz is intended to provide a liver anatomy teaching guide for surgical oncology, transplant, and HPB fellows; general surgery residents; and medical students, as well as a refresher for general and GI surgeons. It is hoped that dissemination will serve as a valuable teaching tool for surgeons at all levels of training.
Innate immunity plays a crucial role in the response to sterile inflammation such as liver ischemia/reperfusion (I/R) injury. The initiation of liver I/R injury results in the release of ...damage‐associated molecular patterns, which trigger an innate immune and inflammatory cascade through pattern recognition receptors. Neutrophils are recruited to the liver after I/R and contribute to organ damage and innate immune and inflammatory responses. Formation of neutrophil extracellular traps (NETs) has been recently found in response to various stimuli. However, the role of NETs during liver I/R injury remains unknown. We show that NETs form in the sinusoids of ischemic liver lobes in vivo. This was associated with increased NET markers, serum level of myeloperoxidase–DNA complexes, and tissue level of citrullinated‐histone H3 compared to control mice. Treatment with peptidyl‐arginine‐deiminase 4 inhibitor or DNase I significantly protected hepatocytes and reduced inflammation after liver I/R as evidenced by inhibition of NET formation, indicating the pathophysiological role of NETs in liver I/R injury. In vitro, NETs increase hepatocyte death and induce Kupffer cells to release proinflammatory cytokines. Damage‐associated molecular patterns, such as High Mobility Group Box 1 and histones, released by injured hepatocytes stimulate NET formation through Toll‐like receptor (TLR4)‐ and TLR9‐MyD88 signaling pathways. After neutrophil depletion in mice, the adoptive transfer of TLR4 knockout or TLR9 knockout neutrophils confers significant protection from liver I/R injury with a significant decrease in NET formation. In addition, we found inhibition of NET formation by the peptidyl‐arginine‐deiminase 4 inhibitor and that DNase I reduces High Mobility Group Box 1 and histone‐mediated liver I/R injury. Conclusion: Damage‐associated molecular patterns released during liver I/R promote NET formation through the TLR signaling pathway. Development of NETs subsequently exacerbates organ damage and initiates inflammatory responses during liver I/R. (Hepatology 2015;62:600–614
Background & Aims The mechanisms of hypoxia-induced tumor growth remain unclear. Hypoxia induces intracellular translocation and release of a variety of damage associated molecular patterns (DAMPs) ...such as nuclear HMGB1 and mitochondrial DNA (mtDNA). In inflammation, Toll-like receptor (TLR)-9 activation by DNA-containing immune complexes has been shown to be mediated by HMGB1. We thus hypothesize that HMGB1 binds mtDNA in the cytoplasm of hypoxic tumor cells and promotes tumor growth through activating TLR9 signaling pathways. Methods C57BL6 mice were injected with Hepa1-6 cancer cells. TLR9 and HMGB1 were inhibited using shRNA or direct antagonists. HuH7 and Hepa1-6 cancer cells were investigated in vitro to determine how the interaction of HMGB1 and mtDNA activates TLR9 signaling pathways. Results During hypoxia, HMGB1 translocates from the nucleus to the cytosol and binds to mtDNA released from damaged mitochondria. This complex subsequently activates TLR9 signaling pathways to promote tumor cell proliferation. Loss of HMGB1 or mtDNA leads to a defect in TLR9 signaling pathways in response to hypoxia, resulting in decreased tumor cell proliferation. Also, the addition of HMGB1 and mtDNA leads to the activation of TLR9 and subsequent tumor cell proliferation. Moreover, TLR9 is overexpressed in both hypoxic tumor cells in vitro and in human hepatocellular cancer (HCC) specimens; and, injection in mice to knockdown either HMGB1 or TLR9 from HCC cells suppressed tumor growth in vivo. Conclusions Our data reveals a novel mechanism by which the interactions of HMGB1 and mtDNA activate TLR9 signaling during hypoxia to induce tumor growth.
Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which ...can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high‐fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte‐derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4−/−), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. Conclusion: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).
Background
The implementation of the laparoscopic and robotic approaches for major hepatectomy (LMH and RMH) was slower than that for minor hepatectomy, but has significantly increased over the past ...years. The role or advantages of RMH remains controversial, and we aimed to compare the peri-/postoperative outcomes of LMH versus RMH.
Methods
A systematic literature review was conducted using the MEDLINE and Cochrane Library databases according to the PRISMA guidelines (end-of-search date: March 16th, 2020). Only comparative studies (LMH vs. RMH) reporting on outcomes of interest were included. Meta-analysis was performed using the random-effects model when substantial heterogeneity was encountered; otherwise, the fixed-effects model was implemented. Quality of evidence assessment was performed using the Newcastle–Ottawa Scale.
Results
Seven retrospective cohort studies comparing LMH (
n
= 300) versus RMH (
n
= 225) were identified. No significant difference was observed between LMH and RMH regarding overall complications odds ratio (OR) 1.42, 95% confidence interval (CI) 0.90–2.23;
p
= 0.13, severe complications (Clavien-Dindo grade ≥ 3) risk difference (RD) 0.01, 95% CI − 0.03 to 0.05;
p
= 0.72, and overall mortality (RD 0.00, 95% CI − 0.02 to 0.03;
p
= 0.73). The two approaches were also equivalent regarding conversion to open hepatectomy (RD 0.03, 95% CI − 0.01 to 0.08;
p
= 0.15), margin-positive resection (OR 1.34, 95% CI 0.51–3.52;
p
= 0.55), and transfusion rate (RD − 0.03, 95% CI − 0.16 to 0.11;
p
= 0.67). No significant difference was observed for LMH versus RMH regarding blood loss standardized mean difference (SMD) 0.27, 95% CI − 0.24 to 0.77;
p
= 0.30), operative time (SMD − 0.08, 95% CI − 0.51 to 0.34;
p
= 0.70), and length of stay (SMD 0.13, 95% CI − 0.58 to 0.84;
p
= 0.72).
Conclusion
LMH and RMH have equivalent peri-/postoperative outcomes when performed in select patients and high-volume centers.
Minimally invasive surgical (MIS) approaches to liver resection have been increasingly adopted into use for surgery on colorectal cancer liver metastases. The purpose of this review is to evaluate ...the outcomes when comparing laparoscopic liver resection (LLR), robotic liver resection (RLR), and open liver resection (OLR) for colorectal cancer liver metastases (CRLM) in 39 studies (2009-2022) that include a case-matched series, propensity score analyses, and three randomized clinical trials. LLR is associated with less intraoperative blood loss and shorter hospital stay compared with OLR. LLR can be performed with comparable operative time. LLR has similar rates of perioperative complications and mortality as OLR. There were no significant differences in 5-year overall or disease-free survival between approaches. Robotic liver resection (RLR) has comparable perioperative safety to LLR and may improve rates of R0 resection in certain patients. Finally, MIS approaches to the hepatic resection of CRLM reduce the time from liver resection to initiation of adjuvant chemotherapy. Thus, MIS liver surgery should be considered in the array of options for patients with CRLM, though thoughtful patient selection and surgeon experience should be part of that decision.
Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs ...enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1.
, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression. SIGNIFICANCE: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.
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