Gastric cancer (GC) is a significant challenge for global health. Neutrophils, the predominant white blood cells in the innate immune system, are increasingly becoming known as potential contributors to either tumor-promoting or tumor-suppressive activities within different tumor biology settings. This review highlights such dual roles of neutrophils in GC, where complex interactions occur within the tumor microenvironment. Specifically, we focus on the formation and function of neutrophil extracellular traps (NETs), which have emerged as critical players in GC progression. NETs influence key processes such as inflammation, angiogenesis, and metastasis. This review offers a comprehensive analysis of the polarization of neutrophils into two of its distinct subtypes, namely N1 and N2, which exert opposing influences on tumor biology. While N1 neutrophils exert anti-tumor properties, N2 neutrophils are generally regarded as pro-tumor. We uniquely discuss how these subtypes interact with cancer cells, affecting epithelial-mesenchymal transition and immune evasion mechanisms. These interactions change the tumor microenvironment and impact overall GC progression. In addition, we underscore the potential of neutrophils and their associated molecules as biomarkers and therapeutic targets. Specific neutrophil-derived markers and neutrophil-associated signaling pathways, along with their perspectives in personalized medicine that would pave the way for neutrophil-based anti-GC therapy, have been discussed in this review. Through the integration of these perspectives, we aim to guide future research involving neutrophils and their therapeutic implications, thus establishing strategies to precisely and effectively treat GC and improve prognosis.

Neutrophil extracellular traps (NETs) are reticular ultrastructures released by activated neutrophils. As the reaction products of neutrophils, NETs have been identified as crucial effectors in pathogen defence and autoimmune diseases. Recently, increasing evidence suggest that this process also occurs in cancer. The formation and clearance of NETs are dynamically influenced by the tumour microenvironment, while NETs reciprocally play a dual role in either promoting or inhibiting tumour progression through their DNA scaffold, proteases and other granule-derived proteins. Given the interplay between NETs and tumours, active exploration is currently underway to harness their potential as tumour biomarkers and therapeutic targets. Here, we delve into the biochemical and immunological mechanisms underlying NETs formation within the tumour microenvironment, along with recent advances elucidating their multifaceted roles in tumourigenesis, metastasis and tumour-associated co-morbidities. Furthermore, we present emerging strategies for NETs-based tumour diagnostic approaches and therapeutics, with a special focus on the challenging questions that need to be answered within this field. KEY POINTS: The formation and clearance of NETs are dynamically influenced by the tumor microenvironment. NETs are engaged in tumorigenesis, formation, metastatic spread, and cancer-associated co-morbidities. NETs-based tumor biomarkers and therapeutic strategies warrant significant attention.

Hepatic ischemia‒reperfusion injury (HIRI) occurs during liver surgery, contributing to postoperative complications such as liver failure, prolonged hospital stays, and increased morbidity and mortality rates. Yet, the mechanism underlying HIRI remains unclear. Nicotinamide N-methyltransferase (NNMT) facilitates the conversion of nicotinamide into N1-methylnicotinamide (1-MNA) and plays crucial roles in various pathophysiological processes. In this study, we find a decrease in hepatic NNMT expression and serum 1-MNA levels during HIRI. Both NNMT overexpression and exogenous 1-MNA treatment alleviate HIRI in male mice HIRI models and primary hepatocytes H/R models. Mechanistically, NNMT/1-MNA plays key roles in inflammation, apoptosis, and vascular injury during HIRI through the AKT/FOXO1/ANGPT2/JNK axis. Hepatic-specific depletion of NNMT leads to increased ANGPT2 expression and exacerbates HIRI, effects that can be mitigated by ANGPT2 knockdown. Our findings suggest that NNMT/1-MNA/ANGPT2 may regulate HIRI via the JNK signaling pathway. In summary, we present the function of NNMT and its underlying mechanism in liver injury, providing potential new therapeutical strategies for addressing HIRI.

Neutrophils serve as pivotal effectors and regulators of the intricate immune system. Their contributions are indispensable, encompassing the obliteration of pathogens and a significant role in both cancer initiation and progression. Conversely, malignancies profoundly affect neutrophil activity, maturation, and lifespans. Cancer cells manipulate their biology to enhance or suppress the key functions of neutrophils. This manipulation is one of the most remarkable defensive mechanisms used by neutrophils, including the formation of neutrophil extracellular traps (NETs). NETs are filamentous structures comprising DNA, histones, and proteins derived from cytotoxic granules. In this review, we discuss the bidirectional interplay in which cancer elicits NET formation, and NETs concurrently facilitate cancer progression. Here, we discuss how vascular dysfunction and thrombosis induced by neutrophils and NETs contribute to an elevated risk of mortality from cardiovascular complications in patients with cancer. Ultimately, we propose a series of therapeutic strategies that hold promise for effectively targeting NETs in clinical settings.

Gastric cancer (GC) is one of the most prevalent malignancies in the world. Most patients are diagnosed at advanced stages of the disease, primarily attributable to the insidious nature of early symptoms and the infrequent occurrence of routine screening. Further biomarkers are still needed for more comprehensive analysis, targeted prognostication, and effective treatment strategies. Plasma proteins are promising biomarkers and potential drug targets in GC. This study aims to identify potential therapeutic targets for GC by conducting a comprehensive proteome-wide Mendelian randomization (MR) and colocalization analyses.

Plasma proteins were obtained from the UK Biobank Pharma Proteomics Project (UKB-PPP), including Genome-Wide Association Study(GWAS)data of 1463 plasma proteins. Genetic associations with cancer were derived from the European Bioinformatics Institute (EBI) database, including 1029 patients and 475,087 controls (dataset: ebi-a-gcst90018849). MR analysis was conducted to assess the association between plasma proteins and the risk of developing cancer. Additionally, colocalization analysis was employed to investigate whether the identified proteins and gastric cancer exhibited shared incidental variants. Finally, using the extensive Finnish database in the R9 version, the potential harmful effects of target proteins on the treatment of gastric cancer were explored through the whole phenomenon association study (PheWAS).

The results showed that 15 proteins may be associated with the risk of gastric cancer, and one protein is expected to become a therapeutic target for gastric cancer. There was a positive genetic association between plasma levels of 11 proteins and increased GC risk, while 4 proteins exhibited an inverse association with GC risk (P < 0.05). Colocalization analysis revealed that PPCDC and GC exhibited shared genetic loci among the 15 proteins examined, indicating that PPCDC may serve as potential direct target for intervention in GC. Further phenotype wide association studies showed that PPCDC (P < 0.05) could be associated with certain potential side effects.

Our research examined the causal relationship between plasma proteins and gastric cancer, shedding light on potential therapeutic targets. These findings have significant implications for the development of early diagnostic markers and targeted therapies for GC, potentially improving patient outcomes and survival rates. Future studies should validate these findings in diverse populations and explore the clinical applications of these targets.

Gastric cancer (GC) is a highly aggressive malignancy associated with poor prognosis, particularly in its advanced stages. Neutrophil extracellular traps (NETs) have been implicated in cancer progression and immune therapy responses; however, the role of NETs-related long non-coding RNAs (lncRNAs) in GC remains poorly understood. This study used data from the Cancer Genome Atlas (TCGA) and previous research to identify NETs-related lncRNAs in GC. A prognostic signature comprising four NETs-related lncRNAs (NlncSig) was developed and validated, serving as a predictor for patient survival and response to immunotherapy. The NlncSig was correlated with poorer outcomes in high-risk patients and demonstrated that those with lower risk scores exhibited more favorable responses to immunotherapy. In vitro experiments confirmed that LINC01150 enhances GC cell proliferation, migration, and invasion. This robust NlncSig provides a reliable tool for predicting survival and immune characteristics in GC, with the potential to guide personalized therapeutic approaches and improve patient care.

The growth of blood vessels from the existing vasculature has a significant impact on the course of multiple myeloma (MM). The ANGPT2 (angiopoietin-2) protein is encoded by the ANGPT2 gene and plays an important role in angiogenesis. The expression of proangiogenic proteins is influenced not only by microenvironmental factors but also by genetic changes. We analyzed two variants/polymorphisms of the ANGPT2 gene, rs1868554 (T>A) and rs7825407 (G>C). Both are located in the intron sequence and can affect the final mRNA sequence by modifying splicing.

Therefore, we assessed the impact of selected variants on ANGPT2 gene expression at the mRNA and protein levels. Additionally, we evaluated the associations of the analyzed genetic changes with the clinical and laboratory parameters of the disease and the response to bortezomib/thalidomide-based therapies. We hypothesize that variants and expression of the ANGPT2 gene may be associated with a greater risk of MM development and may also affect the response to treatment in MM patients.

Genomic DNA extracted from 103 newly diagnosed MM patients and 120 healthy blood donors was used to analyze ANGPT2 variants (via automated DNA sequencing). RNA was subjected to real-time PCR to determine ANGPT2 expression at the mRNA level. The concentration of angiopoietin-2 (in MM sera) was determined by ELISA.

The results of our study showed that individuals with the AA genotype of rs1868554 and the CC genotype of rs7825407 had a greater risk of developing MM (OR=6.12, p=0.02 and OR=6.01, p=0.02, respectively). The ANGPT2 gene variants did not affect ANGPT2 expression at the mRNA level. However, ANGPT2 expression was positively correlated with CRP (Spearman's rho 0.26, p<0.05) and negatively correlated with LDH (Spearman's rho -0.25, p<0.05) in MM patients.

Our results showed that ANGPT2 expression at the mRNA level correlates with CRP, a negative prognostic factor in MM. The ANGPT2 protein is a proangiogenic factor, and its concentration is significantly greater in MM patients than in healthy individuals, which was also confirmed in our research. Therefore, this protein with VEGF and HB-EGF, should be considered in the future as a markers of angiogenesis in MM.

Lung cancer, with its high incidence and mortality rates, has garnered significant attention in the medical community. The tumor microenvironment (TME), composed of tumor cells, stromal cells, extracellular matrix, surrounding blood vessels, and other signaling molecules, plays a pivotal role in the development of lung cancer. Stromal cells within the TME hold potential as therapeutic targets for lung cancer treatment. However, the precise and comprehensive mechanisms by which stromal cells contribute to lung cancer progression have not been fully elucidated. This review aims to explore the mechanisms through which stromal cells in the tumor microenvironment promote lung cancer development, with a particular focus on how immune cells, tumor-associated fibroblasts, and endothelial cells contribute to immune suppression, inflammation, and angiogenesis. The goal is to provide new insights and potential strategies for the diagnosis and treatment of lung cancer.

Background: Stomach adenocarcinoma (STAD) is the fifth most common cancer and the third leading cause of cancer-related deaths worldwide. Cancer-testis antigens (CTAs) participate in the pathogenesis and development of multiple cancers and are aberrantly overexpressed in various types of cancer. This study aimed to develop a CTA-related gene signature (CTARSig) to predict prognosis in STAD patients and explore its underlying mechanisms. Methods: We performed differential and prognostic analyses of CTA-related genes and constructed a CTA-related signature (CTARSig) along with a novel nomogram to predict the prognosis of patients with STAD based on the Cox and The Least Absolute Shrinkage and Selection Operator. CTARSig was further validated in an external cohort (GSE84437). Additionally, univariate and multivariate Cox regression, as well as receiver operating characteristic (ROC) analyses, were performed to assess the CTARSig systematically. Single-sample gene set enrichment analysis and ESTIMATE were used to characterise the Tumor Immune Microenvironment (TIME) in patients with STAD. Furthermore, Gene Set Variation Analysis, Kyoto Encyclopedia of Genes and Genomes, and Gene Ontology analyses revealed the biological functions and signalling pathways associated with CTARSig. Finally, the human gastric cancer cell lines, HCG-27 and AGS, were used for in vitro and in vivo experiments, respectively, to further validate the role of ELOVL4. Results: Eleven CTA-related genes were identified to construct the CTARSig. Kaplan-Meier curves, independent prognostic analysis, and ROC curves revealed that CTARSig could better predict survival in patients with STAD. Moreover, in our study, we demonstrated that ELOVL4 is upregulated in gastric cancer tissues and that its high expression is associated with poor survival. Additionally, in vitro and in vivo experiments demonstrated that ELOVL4 promotes the metastatic and invasive potential of STAD cells, suggesting it may be a potential therapeutic target for STAD. Conclusion: In this study, a novel signature associated with CTAs was constructed for STAD, which may be a good predictor of patient prognosis. Thus, ELOVL4 may be a potential therapeutic target for gastric cancer. This study provides new insights into the potential roles of CTAs in gastric cancer.

Over the past decade, research has prominently established neutrophils as key contributors to the intricate landscape of tumor immune biology. As polymorphonuclear granulocytes within the innate immune system, neutrophils play a pivotal and abundant role, constituting approximately ∼70% of all peripheral leukocytes in humans and ∼10-20% in mice. This substantial presence positions them as the frontline defense against potential threats. Equipped with a diverse array of mechanisms, including reactive oxygen species (ROS) generation, degranulation, phagocytosis, and the formation of neutrophil extracellular traps (NETs), neutrophils undeniably serve as indispensable components of the innate immune system. While these innate functions enable neutrophils to interact with adaptive immune cells such as T, B, and NK cells, influencing their functions, they also engage in dynamic interactions with rapidly dividing tumor cells. Consequently, neutrophils are emerging as crucial regulators in both pro- and anti-tumor immunity. This comprehensive review delves into recent research to illuminate the multifaceted roles of neutrophils. It explores their diverse functions within the tumor microenvironment, shedding light on their heterogeneity and their impact on tumor recruitment, progression, and modulation. Additionally, the review underscores their potential anti-tumoral capabilities. Finally, it provides valuable insights into clinical therapies targeting neutrophils, presenting a promising approach to leveraging innate immunity for enhanced cancer treatment.

Neutrophil extracellular trap (NET) is one of the defense functions of neutrophils, which has a rapid ability to kill infections and is also crucial in a variety of immune-associated diseases including infections, tumors and autoimmune diseases. Recent studies have shown that NETs are closely related to the development of tumors. The regulatory role of NETs in tumors has been of interest to researchers. In addition to awakening latent tumor cells, NETs can also promote the proliferation and development of tumor cells and their metastasis to other sites. At the same time, NETs also have the effect of inhibiting tumors. At present, there are some new advances in the impact of NETs on tumor development, which will provide a more theoretical basis for developing NET-targeted drugs. Therefore, this review just summarized the formation process of NETs, the regulation of tumor development and the treatment methods based on NETs.

The tumor microenvironment, particularly the immune microenvironment, plays an indispensable role in the malignant progression and metastasis of gastric cancer (GC). As our understanding of the GC microenvironment continues to evolve, we are gaining deeper insights into the biological mechanisms at the single-cell level. This, in turn, has offered fresh perspectives on GC therapy. Encouragingly, there are various monotherapy and combination therapies in use, such as immune checkpoint inhibitors, adoptive cell transfer therapy, chimeric antigen receptor T cell therapy, antibody-drug conjugates, and cancer vaccines. In this paper, we review the current research progress regarding the GC microenvironment and summarize promising immunotherapy research and targeted therapies.

Angiogenic growth factors (AGFs) are a class of secreted cytokines related to angiogenesis that mainly include vascular endothelial growth factors (VEGFs), stromal-derived factor-1 (SDF-1), platelet-derived growth factors (PDGFs), fibroblast growth factors (FGFs), transforming growth factor-beta (TGF-β) and angiopoietins (ANGs). Accumulating evidence indicates that the role of AGFs is not only limited to tumor angiogenesis but also participating in tumor progression by other mechanisms that go beyond their angiogenic role. AGFs were shown to be upregulated in the glioma microenvironment characterized by extensive angiogenesis and high immunosuppression. AGFs produced by tumor and stromal cells can exert an immunomodulatory role in the glioma microenvironment by interacting with immune cells. This review aims to sum up the interactions among AGFs, immune cells and cancer cells with a particular emphasis on glioma and tries to provide new perspectives for understanding the glioma immune microenvironment and in-depth explorations for anti-glioma therapy.

Although antiangiogenic therapy has been used in gastric cancer, disease progression due to drug resistance remains common. Neutrophils play an important role in the occurrence and progression of cancer via neutrophil extracellular traps (NETs). However, few studies have investigated angiogenic regulation in gastric cancer. We aimed to determine the role of NETs in promoting angiogenesis in gastric cancer. Multiple immunohistochemical staining was used to analyze the spatial distribution of NETs and microvessels in patient tissue samples. A mouse subcutaneous tumor model was established to determine the effect of NETs on tumor growth, and changes in microvessel density were observed via immunohistochemical staining. We screened differentially expressed proteins in HUVECs stimulated by NETs via proteomics. Cell Counting Kit-8, EdU labeling, and tubule formation assays were used to verify the effect of NETs on HUVEC proliferation, migration, and tubule formation. Blocking NETs, which was related to decreased microvessel density, significantly inhibited tumor growth in the murine subcutaneous tumor model. Compared with those of the control group, tumor volume and mass among mice in the inhibition group decreased by 61.3% and 77.9%, respectively. The NET-DNA receptor CCDC25 was expressed in HUVECs, providing a platform for NETs to promote HUVEC proliferation, migration, and tubulation. In an in vitro rat aortic explant model, NETs induced HUVEC proliferation, survival, and chemotaxis, which were not significantly different from those observed in the VEGF stimulation group. Our results confirm that NETs promote angiogenesis in gastric cancer, providing a theoretical basis for identifying new anti-vascular therapeutic targets. Video Abstract.

Neutrophil extracellular traps (NETs) are extracellular fibrous networks consisting of depolymerized chromatin DNA skeletons with a variety of antimicrobial proteins. They are secreted by activated neutrophils and play key roles in host defense and immune responses. Gastrointestinal (GI) malignancies are globally known for their high mortality and morbidity. Increasing research suggests that NETs contribute to the progression and metastasis of digestive tract tumors, among them gastric, colon, liver, and pancreatic cancers. This article explores the formation of NETs and reviews the role that NETs play in the gastrointestinal oncologic microenvironment, tumor proliferation and metastasis, tumor-related thrombosis, and surgical stress. At the same time, we analyze the qualitative and quantitative detection methods of NETs in recent years and found that NETs are specific markers of coronavirus disease 2019 (COVID-19). Then, we explore the possibility of NET inhibitors for the treatment of digestive tract tumor diseases to provide a new, efficient, and safe solution for the future therapy of gastrointestinal tumors.