interleukin-8 and Neoplasms

Chemokines are a group of about 50 chemotactic cytokines crucial for the migration of immune system cells and tumor cells, as well as for metastasis. One of the 20 chemokine receptors identified to date is CXCR2, a G-protein-coupled receptor (GPCR) whose most known ligands are CXCL8 (IL-8) and CXCL1 (GRO-α). In this article we present a comprehensive review of literature concerning the role of CXCR2 in cancer. We start with regulation of its expression at the transcriptional level and how this regulation involves microRNAs. We show the mechanism of CXCR2 signal transduction, in particular the action of heterotrimeric G proteins, phosphorylation, internalization, intracellular trafficking, sequestration, recycling, and degradation of CXCR2. We discuss in detail the mechanism of the effects of activated CXCR2 on the actin cytoskeleton. Finally, we describe the involvement of CXCR2 in cancer. We focused on the importance of CXCR2 in tumor processes such as proliferation, migration, and invasion of tumor cells as well as the effects of CXCR2 activation on angiogenesis, lymphangiogenesis, and cellular senescence. We also discuss the importance of CXCR2 in cell recruitment to the tumor niche including tumor-associated neutrophils (TAN), tumor-associated macrophages (TAM), myeloid-derived suppressor cells (MDSC), and regulatory T (T

Topics: Chemokine CXCL1; Chemokines; Humans; Interleukin-8; Neoplasms; Phosphorylation; Receptors, Interleukin-8B; Signal Transduction

Physical exercise has gradually become a focus in cancer treatment due to its pronounced role in reducing cancer risk, enhancing therapeutic efficacy, and improving prognosis. In recent decades, skeletal muscles have been considered endocrine organs, exerting their biological functions via the endocrine, autocrine, and paracrine systems by secreting various types of myokines. The amount of myokines secreted varies depending on the intensity, type, and duration of exercise. Recent studies have shown that muscle-derived myokines are highly involved the effects of exercise on cancer. Multiple myokines, such as interleukin-6 (IL-6), oncostatin M (OSM), secreted protein acidic and rich in cysteine (SPARC), and irisin, directly mediate cancer progression by influencing the proliferation, apoptosis, stemness, drug resistance, metabolic reprogramming, and epithelial-mesenchymal transformation (EMT) of cancer cells. In addition, IL-6, interleukin-8 (IL-8), interleukin-15 (IL-15), brain-derived neurotrophic factor (BDNF), and irisin can improve obesity-induced inflammation by stimulating lipolysis of adipose tissues, promoting glucose uptake, and accelerating the browning of white fat. Furthermore, some myokines could regulate the tumor microenvironment, such as angiogenesis and the immune microenvironment. Cancer cachexia occurs in up to 80% of cancer patients and is responsible for 22%-30% of patient deaths. It is characterized by systemic inflammation and decreased muscle mass. Exercise-induced myokine production is important in regulating cancer cachexia. This review summarizes the roles and underlying mechanisms of myokines, such as IL-6, myostatin, IL-15, irisin, fibroblast growth factor 21 (FGF21) and musclin, in cancer cachexia. Through comprehensive analysis, we conclude that myokines are potential targets for inhibiting cancer progression and the associated cachexia.

Topics: Brain-Derived Neurotrophic Factor; Cachexia; Cysteine; Fibronectins; Glucose; Humans; Inflammation; Interleukin-15; Interleukin-6; Interleukin-8; Muscle, Skeletal; Myostatin; Neoplasms; Oncostatin M; Osteonectin; Tumor Microenvironment

Early identification of patients who will benefit from immune checkpoint inhibitors (ICIs) has recently become a hot issue in cancer immunotherapy. Peripheral cytokines are key regulators in the immune system that can induce the expression of immune checkpoint molecules; however, the association between peripheral cytokines and the efficiency of ICIs remains unclear.. A systematic review was conducted in several public databases from inception through 3 February 2022 to identify studies investigating the association between peripheral cytokines (i.e., IL-1β, IL-2, IL-2RA, IL-2R, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF-α, IFN-γ, and TGF-β) and ICI treatment. Survival data, including overall survival (OS) and/or progression-free survival (PFS), were extracted, and meta-analyses were performed.. Twenty-four studies were included in this analysis. The pooled results demonstrated that the pretreatment peripheral levels of IL-6 (univariate analysis: HR = 2.53, 95% CI = 2.21-2.89,. The peripheral level of IL-8 may be used as a prognostic marker to identify patients with inferior response to ICIs. More high-quality prospective studies are warranted to assess the predictive value of peripheral cytokines for ICI treatment.

Topics: Cytokines; Humans; Immune Checkpoint Inhibitors; Interleukin-6; Interleukin-8; Neoplasms; Prognosis

The hypercoagulable state associated with malignancy is well described. However, the mechanisms by which tumors cause this hypercoagulable state are yet to be fully understood. This review summarizes the available literature of human and animal studies examining NETs and cancer-associated thrombosis. The methods for detecting and quantifying NET formation are growing but are not yet standardized in practice. Furthermore, it is important to distinguish between measuring neutrophil activation and NET formation, as the former can be present without the latter. Citrullination of histones by peptidylarginine deiminase 4 (PAD4) is considered one of the key pathways leading to NET formation. Cancer cells can prime neutrophils toward NET formation through the release of soluble mediators, such as interleukin-8, and activation of platelets, and may cause excess NET formation. Dismantling NETs through exogenous deoxyribonuclease has been shown to degrade NETs and reduce thrombus formation in vitro but may simultaneously release prothrombotic NET components, such as DNA and histones. Inhibiting PAD4 is far from clinical trials, but animal models show promising results with a potentially favorable safety profile. Interestingly, results from animal studies suggest that several therapies approved for other indications, such as interleukin-1 receptor blockade and JAK inhibition, may mitigate excessive NET formation or the prothrombotic effects of NETs in cancer. It is yet to be determined if inhibition of NET formation reduces cancer-associated thrombosis also in the clinical setting.

Topics: Animals; Deoxyribonucleases; DNA; Extracellular Traps; Histones; Humans; Interleukin-8; Neoplasms; Neutrophils; Protein-Arginine Deiminases; Receptors, Interleukin-1; Thrombophilia; Thrombosis

In humans, Interleukin-8 (IL-8 or CXCL8) is a granulocytic chemokine with multiple roles within the tumor microenvironment (TME), such as recruiting immunosuppressive cells to the tumor, increasing tumor angiogenesis, and promoting epithelial-to-mesenchymal transition (EMT). All of these effects of CXCL8 on individual cell types can result in cascading alterations to the TME. The changes in the TME components such as the cancer-associated fibroblasts (CAFs), the immune cells, the extracellular matrix, the blood vessels, or the lymphatic vessels further influence tumor progression and therapeutic resistance. Emerging roles of the microbiome in tumorigenesis or tumor progression revealed the intricate interactions between inflammatory response, dysbiosis, metabolites, CXCL8, immune cells, and the TME. Studies have shown that CXCL8 directly contributes to TME remodeling, cancer plasticity, and the development of resistance to both chemotherapy and immunotherapy. Further, clinical data demonstrate that CXCL8 could be an easily measurable prognostic biomarker in patients receiving immune checkpoint inhibitors. The blockade of the CXCL8-CXCR1/2 axis alone or in combination with other immunotherapy will be a promising strategy to improve antitumor efficacy. Herein, we review recent advances focusing on identifying the mechanisms between TME components and the CXCL8-CXCR1/2 axis for novel immunotherapy strategies.

Topics: Animals; Humans; Immunotherapy; Interleukin-8; Neoplasms; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Tumor Microenvironment

Tumor progression relies on the ability of cancer cells to effectively invade surrounding tissues and propagate. Among the many mechanisms that contribute to tumor progression is the epithelial-to-mesenchymal transition (EMT), a phenotypic plasticity phenomenon that increases the cancer cells' motility and invasiveness and influences their surrounding microenvironment by promoting the secretion of a variety of soluble factors. One such factor is IL-8, a chemokine with multiple pro-tumorigenic roles within the tumor microenvironment (TME), including stimulating proliferation or transformation of tumor cells into a migratory or mesenchymal phenotype. Further, IL-8 can increase tumor angiogenesis or recruit larger numbers of immunosuppressive cells to the tumor. Prognostically, observations in many tumor types show that patients with higher levels of IL-8 at baseline experience worse clinical outcomes. Additionally, studies have shown that the chemokine directly contributes to the development of resistance to both chemotherapy and molecularly targeted agents. More recently, clinical studies evaluating levels of IL-8 in patients receiving immune checkpoint inhibition (ICI) therapy deduced that myeloid tumor infiltration driven by IL-8 contributes to resistance to ICI agents and that peripheral IL-8 can predict outcomes to ICI therapy. Further, pre-clinical data demonstrate that targeting IL-8 or its receptors enables improved tumor killing by immune cells, and treatment strategies combining blockade of the IL-8/IL-8R axis with ICI ultimately improve anti-tumor efficacy. Based on these results and the prognostic capacity of IL-8, there are a number of ongoing clinical trials evaluating the addition of IL-8 targeting strategies to immune-based therapies.

Topics: Chemokines; Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment

One of the most important mechanisms by which cancer fosters its own development is the generation of an immune microenvironment that inhibits or impairs antitumor immune responses. A cancer permissive immune microenvironment is present in a large proportion of the patients with cancer who do not respond to immunotherapy approaches intended to trigger preexisting antitumor immune responses, for instance, immune checkpoint blockade. High circulating levels of IL8 in patients with cancer quite accurately predict those who will not benefit from checkpoint-based immunotherapy. IL8 has been reported to favor cancer progression and metastases via different mechanisms, including proangiogenesis and the maintenance of cancer stem cells, but its ability to attract and functionally modulate neutrophils and macrophages is arguably one of the most important factors. IL8 does not only recruit neutrophils to tumor lesions, but also triggers the extrusion of neutrophil extracellular traps (NET). The relevance and mechanisms underlying the contribution of both neutrophils and NETs to cancer development and progression are starting to be uncovered and include both direct effects on cancer cells and changes in the tumor microenvironment, such as facilitating metastasis, awakening micrometastases from dormancy, and facilitating escape from cytotoxic immune cells. Blockade of IL8 or its receptors (CXCR1 and CXCR2) is being pursued in drug development, and clinical trials alone or in combination with anti-PD-L1 checkpoint inhibitors are already ongoing.

Topics: Animals; Biomarkers; Cell Line, Tumor; Cytokines; Disease Management; Disease Susceptibility; Epithelial-Mesenchymal Transition; Extracellular Traps; Gene Expression Regulation, Neoplastic; Humans; Immunity; Immunotherapy; Interleukin-8; Neoplasms; Neutrophils; Tumor Microenvironment

Interleukin (IL)-8 is a chemokine that is essential for inflammation and angiogenesis. IL-8 expression is elevated in tumor cell lines and tissues, as well as in peripheral blood obtained from cancer patients. Primary works have attempted to determine the biological effect of IL-8 on tumor cells, including cell proliferation, survival, and migration. More recently, IL-8 has acquired considerable attention as an immune modulator in the context of certain tumor microenvironments (TME); specifically, it can support a niche that favors tumor progression and metastasis. Tumor-derived IL-8 stimulates inflammation by interacting with the microenvironmental constituents, including fibroblasts, endothelial cells, and immune cells. However, the tumor immune system is complex, and mechanisms that construct the immune phenotype remain incompletely characterized. Herein, we will (1) address a potential role of IL-8 in regulating gene expression to establish immune landscape in tumor. Then, we will (2) review IL-8 signaling in the maintenance of stem cells and regulation of hematopoietic progenitors. Finally, (3) IL-8 functions will be discussed in naturally occurring animal cancers that offer a clinically realistic model for translational research. This chapter will provide a new insight into the tumor immune niche and help us develop immunotherapies for cancers.

Topics: Animals; Humans; Immunotherapy; Interleukin-8; Neoplasms; Tumor Microenvironment

In this review, we will highlight several studies that revolve around interleukin-8 (IL-8) and show the multiple facets that could take in the tumor microenvironment. Chemokines that attract neutrophils (to a large extent, IL-8) can have a bimodal behavior inducing the migration of them in the first place and later favoring the formation of NETs in the place of emission focus of the chemokine. Also, this mechanism occurs when neutrophils migrate to tumor cells and where the extrusion of NETs in the tumor is observed. A possible participation of NETs in cancer progression was considered; however, until now, it is difficult to decide if NETosis plays a pro- or antitumor role, although it is necessary to emphasize that there is more experimentation focused on the protumorigenic aspect of the NETs. The formation of NETs has a relevant role in the inhibition of the immune response against the tumor generated by neutrophils and in turn favoring the processes involved in the development of tumor metastasis. It is striking that we do not have more complete information about the effects of circulating chemokines on neutrophils in cancer patients and hence the suitability of this review. No one has observed to date the impact that it could have on other cell populations to inhibit the arrival of neutrophils and the formation/elimination of NETs. However, the extent to which NETs affect the function of other cells of the immune system in the tumor context has not been directly demonstrated. It is necessary to identify possible combinations of immunotherapy that involve the modulation of neutrophil activity with other strategies (immunomodulatory antibodies or adoptive cell therapy). Therefore, knowing the mechanisms by which tumors take advantage of this ability of neutrophils to form NETs is very important in the search for antitumor therapies and thus be able to take advantage of the possible immunotherapeutic combinations that we currently have in clinical practice.

Topics: Animals; Extracellular Traps; Humans; Interleukin-8; Mice; Neoplasms; Neutrophil Activation; Neutrophils; Tumor Microenvironment

Chronic inflammation is involved in the development of cancer, lifestyle-related diseases, and autoimmune diseases. It also influences the severity of these diseases. Macrophages that accumulate in tumor tissues and adipose tissues of obesity have been shown to increase expression of inflammatory cytokines, thereby inducing inflammatory changes in these tissues. The macrophage phenotype is believed to be important in mediating inflammatory changes in tissues. Recently, monocytes/macrophages activated with low-dose lipopolysaccharide (LPS) were demonstrated to suppress increased expression of monocyte chemotactic protein (MCP)-1 and inflammatory cytokines (interleukin (IL)-1 β, IL-8, and tumor necrosis factor (TNF)-α). By suppressing the increased expression of chemotaxis-related and inflammation-related factors, monocytes/macrophages activated with low-dose LPS are considered to suppress the migration of macrophages into tissues and to regulate inflammatory changes in these tissues, respectively. The effects of macrophages activated with low-dose LPS were different from those of macrophages activated with high-dose LPS. In this review, we discuss the usefulness of monocytes/macrophages activation by low-dose LPS.

Topics: Adipose Tissue; Chemokine CCL2; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; Inflammation; Interleukin-1beta; Interleukin-8; Lipopolysaccharides; Macrophages; Monocytes; Neoplasms; Obesity; Tumor Necrosis Factor-alpha

The rationale for developing histone deacetylase (HDAC) inhibitors (HDACi) as anticancer agents was based on their ability to induce apoptosis and cell cycle arrest in cancer cells. However, while HDACi have been remarkably effective in the treatment of hematological malignancies, clinical studies with HDACi as single agents in solid cancers have been disappointing. Recent studies have shown that, in addition to inducing apoptosis in cancer cells, class I HDACi induce IκB kinase (IKK)-dependent expression of proinflammatory chemokines, such as interleukin-8 (IL8; CXCL8), resulting in the increased proliferation of tumor cells, and limiting the effectiveness of HDACi in solid tumors. Here, we discuss the mechanisms responsible for HDACi-induced CXCL8 expression, and opportunities for combination therapies targeting HDACs and IKK in solid tumors.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Histone Deacetylase Inhibitors; Humans; I-kappa B Kinase; Interleukin-8; Neoplasms; Protein Kinase Inhibitors

The chemokine receptors CXCR1/2 and their ligand CXCL8 are essential for the activation and trafficking of inflammatory mediators as well as tumor progression and metastasis. The CXCL8-CXCR1/2 signaling axis is involved in the pathogenesis of several diseases including chronic obstructive pulmonary diseases (COPD), asthma, cystic fibrosis and cancer. Interaction between CXCL8 secreted by select cancer cells and CXCR1/2 in the tumor microenvironment is critical for cancer progression and metastasis. The CXCL8-CXCR1/2 axis may play an important role in tumor progression and metastasis by regulating cancer stem cell (CSC) proliferation and self-renewal. During the past two decades, several small-molecule CXCR1/2 inhibitors, CXCL8 releasing inhibitors, and neutralizing antibodies against CXCL8 and CXCR1/2 have been reported. As single agents, such inhibitors are expected to be efficacious in various inflammatory diseases. Several preclinical studies suggest that combination of CXCR1/2 inhibitors along with other targeted therapies, chemotherapies, and immunotherapy may be effective in treating select cancers. Currently, several of these inhibitors are in advanced clinical trials for COPD, asthma, and metastatic breast cancer. In this review, we provide a comprehensive analysis of the role of the CXCL8-CXCR1/2 axis and select genes co-expressed in this pathway in disease progression. We also discuss the latest progress in developing small-molecule drugs targeting this pathway.

Topics: Animals; Humans; Inflammation; Interleukin-8; Neoplasms; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Signal Transduction

Interleukin-8 (CXCL8) was originally described asa chemokine whose main function is the attraction of a polymorphonuclear inflammatory leukocyte infiltrate acting on CXCR1/2. Recently, it has been found that tumors very frequently coopt the production of this chemokine, which in this malignant context exerts different pro-tumoral functions. Reportedly, these include angiogenesis, survival signaling for cancer stem cells and attraction of myeloid cells endowed with the ability to immunosuppress and locally provide growth factors. Given the fact that in cancer patients IL-8 is mainly produced by tumor cells themselves, its serum concentration has been shown to correlate with tumor burden. Thus, IL-8 serum concentrations have been shown to be useful asa pharmacodynamic biomarker to early detect response to immunotherapy. Finally, because of the roles that IL-8 plays in favoring tumor progression, several therapeutic strategies are being developed to interfere with its functions. Such interventions hold promise, especially for therapeutic combinations in the field of cancer immunotherapy.

Topics: Biomarkers, Tumor; Follow-Up Studies; Humans; Immunotherapy; Interleukin-8; Neoplasms

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; 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Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; Heart Failure; Heart Rate; Heart Transplantation; Heart-Assist Devices; HEK293 Cells; Heme; Heme Oxygenase-1; Hemolysis; Hemorrhage; Hepatitis B; Hepatitis B e Antigens; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Hexoses; High-Throughput Nucleotide Sequencing; Hippo Signaling Pathway; Histamine; Histamine Agonists; Histidine; Histone Deacetylase 2; HIV Infections; HIV Reverse Transcriptase; HIV-1; Homebound Persons; Homeodomain Proteins; Homosexuality, Male; Hospice and Palliative Care Nursing; HSP70 Heat-Shock Proteins; Humans; Hyaluronan Receptors; Hydrogen; Hydrogen Peroxide; Hydrogen-Ion Concentration; Hydrolysis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypoglycemia; Hypoglycemic Agents; Hypoxia; Idiopathic Interstitial Pneumonias; Imaging, Three-Dimensional; Imatinib Mesylate; Immunotherapy; Implementation Science; Incidence; INDEL Mutation; Induced Pluripotent Stem Cells; Industrial Waste; Infant; Infant, Newborn; Inflammation; Inflammation Mediators; Infliximab; Infusions, Intravenous; Inhibitory Concentration 50; Injections; Insecticides; Insulin-Like Growth Factor Binding Protein 5; Insulin-Secreting Cells; Interleukin-1; Interleukin-17; Interleukin-8; Internship and Residency; Intestines; Intracellular Signaling Peptides and Proteins; Ion Transport; Iridaceae; Iridoid Glucosides; Islets of Langerhans Transplantation; Isodon; Isoflurane; Isotopes; Italy; Joint Instability; Ketamine; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Kidney Neoplasms; Kinetics; Klebsiella pneumoniae; Knee Joint; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lactate Dehydrogenase 5; Laparoscopy; Laser Therapy; Lasers, Semiconductor; Lasers, Solid-State; Laurates; Lead; Leukocyte L1 Antigen Complex; Leukocytes, Mononuclear; Light; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Liver; Liver Cirrhosis; Liver Neoplasms; Liver Transplantation; Locomotion; Longitudinal Studies; Lopinavir; Lower Urinary Tract Symptoms; Lubricants; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating; Lymphoma, Mantle-Cell; Lysosomes; Macrophages; Male; Manganese Compounds; MAP Kinase Kinase 4; Mass Screening; Maternal Health; Medicine, Chinese Traditional; Melanoma, Experimental; Memantine; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cell Transplantation; Metal Nanoparticles; Metalloendopeptidases; Metalloporphyrins; Methadone; Methane; Methicillin-Resistant Staphylococcus aureus; Mexico; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Nude; Mice, SCID; Mice, Transgenic; Microarray Analysis; Microbial Sensitivity Tests; Microbiota; Micronutrients; MicroRNAs; Microscopy, Confocal; Microsomes, Liver; Middle Aged; Milk; Milk, Human; Minority Groups; Mitochondria; Mitochondrial Membranes; Mitochondrial Proteins; Models, Animal; Models, Molecular; Molecular Conformation; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Epidemiology; Molecular Structure; Molecular Weight; Multilocus Sequence Typing; Multimodal Imaging; Muscle Strength; Muscle, Skeletal; Muscular Diseases; Mutation; Mycobacterium tuberculosis; Myocardial Stunning; Myristates; NAD(P)H Dehydrogenase (Quinone); Nanocomposites; Nanogels; Nanoparticles; Nanotechnology; Naphthalenes; Nasal Cavity; National Health Programs; Necrosis; Needs Assessment; Neoadjuvant Therapy; Neonicotinoids; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Recurrence, Local; Neoplasm Staging; Neoplasm Transplantation; Neoplasms; Neoplastic Stem Cells; Netherlands; Neuroblastoma; Neuroprotective Agents; Neutrophils; NF-kappa B; NFATC Transcription Factors; Nicotiana; Nicotine; Nitrates; Nitrification; Nitrites; Nitro Compounds; Nitrogen; Nitrogen Dioxide; North Carolina; Nuclear Magnetic Resonance, Biomolecular; Nuclear Proteins; Nucleic Acid Hybridization; Nucleosomes; Nutrients; Obesity; Obesity, Morbid; Oceans and Seas; Oncogene Protein v-akt; Oncogenes; Oocytes; Open Reading Frames; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporosis, Postmenopausal; Outpatients; Ovarian Neoplasms; Ovariectomy; Overweight; Oxazines; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxides; Oxidoreductases; Oxygen; Oxygen Inhalation Therapy; Oxygenators, Membrane; Ozone; Paclitaxel; Paenibacillus; Pain Measurement; Palliative Care; Pancreatic Neoplasms; Pandemics; Parasympathetic Nervous System; Particulate Matter; Pasteurization; Patient Preference; Patient Satisfaction; Pediatric Obesity; Permeability; Peroxiredoxins; Peroxynitrous Acid; Pharmaceutical Services; Pharmacists; Pharmacy; Phaseolus; Phenotype; Phoeniceae; Phosphates; Phosphatidylinositol 3-Kinases; Phospholipid Transfer Proteins; Phospholipids; Phosphorus; Phosphorylation; Photoperiod; Photosynthesis; Phylogeny; Physical Endurance; Physicians; Pilot Projects; Piperidines; Pituitary Adenylate Cyclase-Activating Polypeptide; Plant Extracts; Plant Leaves; Plant Proteins; Plant Roots; Plaque, Atherosclerotic; Pneumonia; Pneumonia, Viral; Point-of-Care Testing; Polyethylene Glycols; Polymers; Polysorbates; Pore Forming Cytotoxic Proteins; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Postprandial Period; Poverty; Pre-Exposure Prophylaxis; Prediabetic State; Predictive Value of Tests; Pregnancy; Pregnancy Trimester, First; Pregnancy, High-Risk; Prenatal Exposure Delayed Effects; Pressure; Prevalence; Primary Graft Dysfunction; Primary Health Care; Professional Role; Professionalism; Prognosis; Progression-Free Survival; Prolactin; Promoter Regions, Genetic; Proof of Concept Study; Proportional Hazards Models; Propylene Glycol; Prospective Studies; Prostate; Protein Binding; Protein Biosynthesis; Protein Isoforms; Protein Kinase Inhibitors; Protein Phosphatase 2; Protein Processing, Post-Translational; Protein Serine-Threonine Kinases; Protein Structure, Tertiary; Protein Transport; Proteoglycans; Proteome; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins c-ret; Proto-Oncogene Proteins p21(ras); Proton Pumps; Protons; Protoporphyrins; Pseudomonas aeruginosa; Pseudomonas fluorescens; Pulmonary Artery; Pulmonary Disease, Chronic Obstructive; Pulmonary Gas Exchange; Pulmonary Veins; Pyrazoles; Pyridines; Pyrimidines; Qualitative Research; Quinoxalines; Rabbits; Random Allocation; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Histamine H3; Receptors, Immunologic; Receptors, Transferrin; Recombinant Proteins; Recurrence; Reference Values; Referral and Consultation; Regional Blood Flow; Registries; Regulon; Renal Insufficiency, Chronic; Reperfusion Injury; Repressor Proteins; Reproducibility of Results; Republic of Korea; Research Design; Resistance Training; Respiration, Artificial; Respiratory Distress Syndrome; Respiratory Insufficiency; Resuscitation; Retinal Dehydrogenase; Retreatment; Retrospective Studies; Reverse Transcriptase Inhibitors; Rhinitis, Allergic; Ribosomal Proteins; Ribosomes; Risk Assessment; Risk Factors; Ritonavir; Rivers; RNA Interference; RNA-Seq; RNA, Messenger; RNA, Ribosomal, 16S; RNA, Small Interfering; Rosuvastatin Calcium; Rural Population; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Salivary Ducts; Salivary Gland Neoplasms; San Francisco; SARS-CoV-2; Satiation; Satiety Response; Schools; Schools, Pharmacy; Seasons; Seawater; Selection, Genetic; Sequence Analysis, DNA; Serine-Threonine Kinase 3; Sewage; Sheep; Sheep, Domestic; Shock, Hemorrhagic; Signal Transduction; Silver; Silymarin; Single Photon Emission Computed Tomography Computed Tomography; Sirolimus; Sirtuin 1; Skin; Skin Neoplasms; Skin Physiological Phenomena; Sleep Initiation and Maintenance Disorders; Social Class; Social Participation; Social Support; Soil; Soil Microbiology; Solutions; Somatomedins; Soot; Specimen Handling; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectrum Analysis; Spinal Fractures; Spirometry; Staphylococcus aureus; STAT1 Transcription Factor; STAT3 Transcription Factor; Streptomyces coelicolor; Stress, Psychological; Stroke; Stroke Volume; Structure-Activity Relationship; Students, Medical; Students, Pharmacy; Substance Abuse Treatment Centers; Sulfur Dioxide; Surface Properties; Surface-Active Agents; Surveys and Questionnaires; Survival Analysis; Survival Rate; Survivin; Sweden; Swine; Swine, Miniature; Sympathetic Nervous System; T-Lymphocytes, Regulatory; Talaromyces; Tandem Mass Spectrometry; tau Proteins; Telemedicine; Telomerase; Telomere; Telomere Homeostasis; Temperature; Terminally Ill; Th1 Cells; Thiamethoxam; Thiazoles; Thiophenes; Thioredoxin Reductase 1; Thrombosis; Thulium; Thyroid Cancer, Papillary; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Time Factors; Titanium; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Transcription Factor AP-1; Transcription Factors; Transcription, Genetic; Transcriptional Activation; Transcriptome; Transforming Growth Factor beta1; Transistors, Electronic; Translational Research, Biomedical; Transplantation Tolerance; Transplantation, Homologous; Transportation; Treatment Outcome; Tretinoin; Tuberculosis, Multidrug-Resistant; Tuberculosis, Pulmonary; Tubulin Modulators; Tumor Microenvironment; Tumor Necrosis Factor Inhibitors; Tumor Necrosis Factor-alpha; Twins; Ultrasonic Therapy; Ultrasonography; Ultraviolet Rays; United States; Up-Regulation; Uranium; Urethra; Urinary Bladder; Urodynamics; Uromodulin; Uveitis; Vasoconstrictor Agents; Ventricular Function, Left; Vero Cells; Vesicular Transport Proteins; Viral Nonstructural Proteins; Visual Acuity; Vital Capacity; Vitamin D; Vitamin D Deficiency; Vitamin K 2; Vitamins; Volatilization; Voriconazole; Waiting Lists; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Whole Genome Sequencing; Wine; Wnt Signaling Pathway; Wound Healing; Wounds and Injuries; WW Domains; X-linked Nuclear Protein; X-Ray Diffraction; Xanthines; Xenograft Model Antitumor Assays; YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

Multiple cytokines and growth factors are critical for the prognosis of cancer which has been regarded as a worldwide health problem. Recently, neuropeptides, soluble factors regulating a series of functions in the central nervous system, have also been demonstrated to stimulate the proliferation and migration of tumor cells. Among these signaling peptides, the role of neurotensin (NTS) on malignancy procession has become a hot topic. The effects of NTS on tumor growth and its antiapoptosis role have already been identified. Subsequently, studies demonstrated the impact of NTS on the migration and invasion, but the molecular mechanisms involved are still unclear at present. Recently, some reports indicated that NTS could induce expression and secretion of interleukin-8 (IL-8) to promote local imflammatory response which might participate in epithelial-mesenchymal transition (EMT)-related tumor migration. In present review, we highlight the process of tumor EMT induced by NTS through stimulating IL-8 and the significance of NTS/IL-8 pathway in clinical application prospect.

Topics: Animals; Carcinogenesis; Cell Movement; Epithelial-Mesenchymal Transition; Humans; Inflammation; Interleukin-8; Neoplasm Invasiveness; Neoplasms; Neurotensin; Signal Transduction; Tumor Microenvironment

Persistent infection or chronic inflammation contributes significantly to tumourigenesis and tumour progression. C-X-C motif ligand 8 (CXCL8) is a chemokine that acts as an important multifunctional cytokine to modulate tumour proliferation, invasion and migration in an autocrine or paracrine manner. Studies have suggested that CXCL8 and its cognate receptors, C-X-C chemokine receptor 1 (CXCR1) and C-X-C chemokine receptor 2 (CXCR2), mediate the initiation and development of various cancers including breast cancer, prostate cancer, lung cancer, colorectal carcinoma and melanoma. CXCL8 also integrates with multiple intracellular signalling pathways to produce coordinated effects. Neovascularisation, which provides a basis for fostering tumour growth and metastasis, is now recognised as a critical function of CXCL8 in the tumour microenvironment. In this review, we summarize the biological functions and clinical significance of the CXCL8 signalling axis in cancer. We also propose that CXCL8 may be a potential therapeutic target for cancer treatment.

Topics: Animals; Humans; Interleukin-8; Molecular Targeted Therapy; Neoplasms; Protein Conformation; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Signal Transduction

The crucial role of the immune system in the formation and progression of tumors has been widely accepted. On one hand, the surveillance role of the immune system plays an important role in endogenous tumor prevention, but on the other hand, in some special circumstances such as in chronic inflammation, the immune system can actually contribute to the formation and progression of tumors. In recent years, there has been an explosion of novel targeted immunotherapies for advanced cancers. In the present manuscript, we explore known and potential various types of cancer prevention strategies and focus on nonvaccine-based cancer preventive strategies targeting the immune system at the early stages of tumorigenesis.

Topics: Chemoprevention; Dendritic Cells; Humans; Immunotherapy; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Interleukin-8; Monitoring, Immunologic; Neoplasms; Programmed Cell Death 1 Receptor; STAT3 Transcription Factor; T-Lymphocytes, Regulatory; Th17 Cells

Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere chronological age will contribute to treatment tolerance and outcome in the older patients with cancer. Clinical/comprehensive geriatric assessment can provide information on the general health status of individuals, but is far from perfect as a prognostic/predictive tool for individual patients. On the other hand, aging can also be assessed in terms of biological changes in certain tissues like the blood compartment which result from adaptive alterations due to past history of exposures, as well as intrinsic aging processes. There are major signs of 'aging' in lymphocytes (e.g. lymphocyte subset distribution, telomere length, p16INK4A expression), and also in (inflammatory) cytokine expression and gene expression patterns. These result from a combination of the above two processes, overlaying genetic predispositions which contribute significantly to the aging phenotype. These potential "aging biomarkers" might provide additional prognostic/predictive information supplementing clinical evaluation. The purpose of the current paper is to describe the most relevant potential "aging biomarkers" (markers that indicate the biological functional age of patients) which focus on the biological background, the (limited) available clinical data, and technical challenges. Despite their great potential interest, there is a need for much more (validated) clinical data before these biomarkers could be used in a routine clinical setting. This manuscript tries to provide a guideline on how these markers can be integrated in future research aimed at providing such data.

Topics: Aged; Aging; Biomarkers, Tumor; Evidence-Based Medicine; Gene Expression Regulation; Genes, p16; Genetic Markers; Geriatric Assessment; Guidelines as Topic; Humans; Insulin-Like Growth Factor Binding Proteins; Interleukin-6; Interleukin-8; Lymphocyte Subsets; Neoplasms; Plasminogen Activator Inhibitor 1; Predictive Value of Tests; Sensitivity and Specificity; Serine Proteinase Inhibitors; Telomere

Pro-inflammatory cytokines have been associated with chronic inflammation and inflammatory diseases. Increased levels of interleukins (ILs) have been associated with inflammatory disease exacerbation. ILs levels have been observed to be associated with advance stage cancer for several types of cancer and a poor prognostic maker for malignant disease. Moreover; increased levels of cytokines induce tumorigenesis. There are several paradigms such as the hepatocellular carcinoma induced from chronic inflammation of an underlying hepatitis. In the current review, we will focus on IL-8 and -17. These two ILs as in the case of others, induce neo-angiogenesis through activation of the vascular endothelial growth (VEGF) factor pathway. Additionally, they enhance the activity of matrix metalloproteinase-2 and -9 (MMP-2,-9) which in turn increase the metastatic activity of the underlying malignancy. Inhibition of cytokine production could be a potential treatment both for chronic inflammatory diseases and tumor modulation. Local microenvironment modulation could be applied in surgery resected patients as in the case of lung cancer in order to enhance the local immune activity.

Topics: Biomarkers, Tumor; Humans; Inflammation; Interleukin-17; Interleukin-8; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Vascular Endothelial Growth Factor A

Fever during neutropenia (FN) is a frequent and potentially life-threatening complication of the treatment of childhood cancer. The role of biomarkers in predicting morbidity and mortality associated with FN in children has been explored with varying results. This systematic review identified, critically appraised and synthesized information on the use of biomarkers for the prediction of outcome of FN in children/young adults, updating a review of initial assessment and adding further analysis of their value at reassessment.. This review was conducted in accordance with the Centre for Reviews and Dissemination Methods, using 3 different random effects meta-analysis models.. Thirty-seven studies involving over 4689 episodes of FN in children were assessed, including an additional 13 studies investigating 18 biomarkers in 1670 FN episodes since the original review. Meta-analysis was possible for admission C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 and interleukin-8 in their ability to detect significant infection. Marked heterogeneity exists, precluding clear clinical interpretation of the results. Qualitative synthesis of the role of serial biomarkers suggests their predictive ability may be more pronounced at 24 to 48 hours compared with admission. Direct comparisons of the discriminatory power of admission values of PCT and CRP showed PCT generally had a better discriminatory estimate of serious infection than CRP.. There remains a paucity of robust and reproducible data on the use of biomarkers in prediction of serious infection in children with FN. Available evidence suggests PCT has better discriminatory ability than CRP and that the role of serial biomarkers warrants further study.

Topics: Adolescent; Biomarkers, Tumor; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Febrile Neutropenia; Humans; Infant; Interleukin-8; Neoplasms; Prospective Studies; Protein Precursors; Young Adult

CXCL8 was the first chemokine shown to be secreted by thyrocytes. Experimental data suggest that CXCL8 plays a role in thyroid homeostasis but its role in thyroid diseases remains poorly investigated. Clinical studies measuring the serum levels of CXCL8 in patients with autoimmune-thyroid-diseases reported conflicting results. Solid evidences support a role of CXCL8 as a tumor-promoting agent in several human cancers. Studies in thyroid cancer are still in their initial stage, but promising. Several evidences indicate that thyroid cancer may share with other human malignancies some of the effects of CXCL8 and highlight the possibility of using CXCL8 as a marker of aggressiveness. Basic and clinical evidences in favor or against a role for CXCL8 in thyroid diseases are discussed.

Topics: Animals; Autoimmune Diseases; Humans; Interleukin-8; Neoplasms; Thyroid Diseases; Thyroid Gland

The -251T/A (rs4073), a single nucleotide polymorphism, has been identified in the promoter region of the interleukin-8 (IL-8) gene. It's presence could influence the production of IL-8 protein by regulating the transcriptional activity of the gene. A large number of studies have been performed to evaluate the role of -251T/A polymorphism on various cancers, with inconsistent results being reported. In this paper, we summarized 13,189 cases and 16,828 controls from 42 case-control studies and attempted to assess the susceptibility of -251T/A polymorphism to cancers by a comprehensive meta-analysis. Pooled odds ratios and 95% confidence intervals were calculated by using the random-effects model. Publication bias, subgroup, and sensitivity analysis were also performed. Results showed that the carriers of the -251A allele had about a 12-21% increased risk for the reviewed cancer, in total. The carriers of -251A had an elevated risk to breast cancer, gastric cancer and nasopharyngeal cancer and a reduced risk to prostate cancer, but no evidence was found to indicate that the -251A allele predisposed its carriers to colorectal and lung cancers. When stratified separately by 'racial descent' and 'study design', it was found that the carriers of the -251A allele among the African group, Asian group and hospital-based case-control study group were at a higher risk for cancer, but not in European group and population-based case-control study. These results show that -251A allele is susceptible in the development of low-penetrance cancers.

Topics: Case-Control Studies; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Interleukin-8; Models, Genetic; Neoplasms; Odds Ratio; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Factors

Interleukin-8 (IL-8, CXCL8) was originally discovered as a powerful attractor and activator of polymorphonuclear leukocytes. It was soon recognized that IL-8 also affects proliferation and migration of cancer cells, tumor angiogenesis and metastasis, and that it is expressed in many cancerous cell types. IL-8 protein expression is usually increased in serum of cancer patients, but markedly higher concentrations are found in cancer-associated non-vascular extracellular fluids, such as pleural effusion, ascites and cyst fluid. Elevated concentrations of IL-8 are indicative of malignant processes also in cerebrospinal fluid, urine, saliva, interstitial fluid and cervicovaginal secretions. Higher IL-8 levels are typically found in high-grade peritumoral fluids rather than low-grade tumors and benign conditions, with the exception of inflammatory processes. In line with recent molecular biology investigations, it appears that the local IL-8 production is related to its malignant origin and to tumor progression. Hence, IL-8 in peritumoral fluid is to be taken into consideration while assessing tumor character and monitoring the tumor progression/remission status. Besides, the data here collected justify the attempts to find an IL-8-targeted inhibitory therapy

Topics: Biomarkers, Tumor; Extracellular Fluid; Humans; Interleukin-8; Neoplasms; Prognosis

It is increasingly evident that the microenvironment of bone can influence the cancer phenotype in many ways that favor growth in bone. The ability of cancer cells to adhere to bone matrix and to promote osteoclast formation are key requirements for the establishment and growth of bone metastases. Several cytokine products of breast cancers (e.g. PTHrP, IL-11, IL-8) have been shown to act upon host cells of the bone microenvironment to promote osteoclast formation, allowing for excessive bone resorption. The increased release of matrix-derived growth factors, especially TGF-β, acts back upon the tumor to facilitate further tumor expansion and enhance cytokine production, and also upon osteoblasts to suppress bone formation. This provides a self-perpetuating cycle of bone loss and tumor growth within the skeleton. Other contributing factors favoring tumor metastasis and colonization in bone include the unique structure and stiffness of skeletal tissue, along with the diverse cellular composition of the marrow environment (e.g. bone cells, stromal fibroblasts, immune cells), any of which can contribute to the phenotypic changes that can take place in metastatic deposits that favor their survival. Additionally, it is also apparent that breast cancer cells begin to express different bone specific proteins as well as proteins important for normal breast development and lactation that allow them to grow in bone and stimulate bone destruction. Taken together, these continually emerging areas of study suggest new potential pathways important in the pathogenesis of bone metastasis and potential areas for targeting therapeutics.

Topics: Bone and Bones; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Cytokines; Female; Humans; Interleukin-11; Interleukin-8; Neoplasms; Osteoblasts; Osteoclasts; Osteogenesis; Parathyroid Hormone-Related Protein; Transforming Growth Factor beta

Metastatic, rather than primary tumours are responsible for ninety percent cancer deaths. Despite significant advances in the understanding of molecular and cellular mechanisms in tumour metastases, there are limitations in preventive treatment of metastatic tumours. Much evidence arising from laboratory and clinical studies suggests that growth factors and their receptors are implicated in cancer metastases development. We review the origin and production of growth factors and their receptors in all stages of cancer metastases including epithelial-mesenchymal transition, cancer cell invasion and migration, survival within the circulation, seeding at distant organs and metastatic tumour angiogenesis. The functions of growth factors and their receptors are also discussed. This review presents the efforts made in understanding this challenge to aid in the development of new treatment strategies for cancer metastases.

Topics: Angiopoietins; Animals; Apoptosis; Cell Movement; Epidermal Growth Factor; Epithelial-Mesenchymal Transition; ErbB Receptors; Glucose-6-Phosphate Isomerase; Hepatocyte Growth Factor; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Interleukin-8; Multienzyme Complexes; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Seeding; Neoplasms; Neoplastic Cells, Circulating; Neovascularization, Pathologic; Phosphodiesterase I; Phosphoric Diester Hydrolases; Pyrophosphatases; Receptor, IGF Type 1; Receptors, Growth Factor; Ribonuclease, Pancreatic; Smad Proteins; Snail Family Transcription Factors; Transcription Factors; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Growing evidence suggests that interleukin-8 (IL-8) play pivotal roles in the pathogenesis of cancer through the modulation of tumour immune response or enhanced angiogenesis. A single nucleotide polymorphism, -251A/T, has been identified in the promoter region of the IL-8 gene and has been shown to influence its production. Results from previous studies on the association of -251A/T polymorphism with different cancer types remained contradictory. To assess the effect of -251A/T of IL-8 on cancer susceptibility, we conducted a meta-analysis, up to May 2009, of 14,876 cases with different cancer types and 18,465 controls from 45 published case-control studies. Summary odds ratios and corresponding 95% confidence intervals (CIs) for IL-8 polymorphism and cancer were estimated using fixed- and random-effects models when appropriate. The AA/AT genotypes were associated with a significantly increased risk of nasopharyngeal carcinoma when compared with TT genotype (OR=1.48; 95% CI, 1.16-1.89). Moreover, significantly elevated risks were observed in 'other cancers', and also in African population when population is concerned. Interestingly, when stratified separately by population-based studies and hospital-based studies, significantly elevated risk was found among hospital-based studies (OR=1.21, 95% CI, 1.07-1.37), whereas significantly decreased risk was found among population-based studies (OR=0.90, 95% CI, 0.83-0.97). This meta-analysis shows that IL-8 -251A/T polymorphism may play a complex role in cancer development.

Topics: Female; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-8; Male; Neoplasms; Odds Ratio; Polymorphism, Single Nucleotide; Risk Factors

The heparan sulfate (HS) chains of heparan sulfate proteoglycans (HSPG) are "ubiquitous" components of the cell surface and the extracellular matrix (EC) and play important roles in the physiopathology of developmental and homeostatic processes. Most biological properties of HS are mediated by interactions with "heparin-binding proteins" and can be modulated by exogenous heparin species (unmodified heparin, low molecular weight heparins, shorter heparin oligosaccharides and various non-anticoagulant derivatives of different sizes). Heparin species can promote or inhibit HS activities to different extents depending, among other factors, on how closely their structure mimics the biologically active HS sequences. Heparin shares structural similarities with HS, but is richer in "fully sulfated" sequences (S domains) that are usually the strongest binders to heparin/HS-binding proteins. On the other hand, HS is usually richer in less sulfated, N-acetylated sequences (NA domains). Some of the functions of HS chains, such as that of activating proteins by favoring their dimerization, often require short S sequences separated by rather long NA sequences. The biological activities of these species cannot be simulated by heparin, unless this polysaccharide is appropriately chemically/enzymatically modified or biotechnologically engineered. This mini review covers some information and concepts concerning the interactions of HS chains with heparin-binding proteins and some of the approaches for modulating HS interactions relevant to inflammation and cancer. This is approached through a few illustrative examples, including the interaction of HS and heparin-derived species with the chemokine IL-8, the growth factors FGF1 and FGF2, and the modulation of the activity of the enzyme heparanase by these species. Progresses in sequencing HS chains and reproducing them either by chemical synthesis or semi-synthesis, and in the elucidation of the 3D structure of oligosaccharide-protein complexes, are paving the way for rational approaches to the development of HS-inspired drugs in the field of inflammation and cancer, as well in other therapeutic fields.

Topics: Animals; Anticoagulants; Antimicrobial Cationic Peptides; Blood Proteins; Carrier Proteins; Extracellular Matrix; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Glucuronidase; Heparan Sulfate Proteoglycans; Heparin; Heparitin Sulfate; Humans; Inflammation; Interleukin-8; Models, Molecular; Neoplasms; Oligosaccharides; Polysaccharides; Proteins

Senescence is an irreversible arrest triggered by stresses such as telomere shortening, DNA damage, or oncogenic signaling. Oncogene-induced senescence occurs in preneoplastic lesions, but it is absent from full-blown malignancies suggesting a tumor suppressor function. We recently found that depletion of the receptor CXCR2 [which binds to chemokines such as interleukin (IL)-8 or GROalpha] delays both replicative senescence and impairs the senescence response to oncogenic signals. Our findings suggest that signaling by IL-8 and GROalpha might limit tumor growth by reinforcing senescence early in tumorigenesis. The challenge remains in how to integrate this with the well-known tumor promoting effects of IL-8 and GROalpha.

Topics: Animals; Cellular Senescence; Chemokine CXCL1; Humans; Interleukin-8; Neoplasms; Receptors, Interleukin-8B; Signal Transduction

Chemoattractant receptors are a group of seven transmembrane, G protein coupled receptors (GPCRs). They were initially identified mainly on leukocytes to mediate cell migration in response to pathogen or host-derived chemotactic factors. During the past decade, chemoattractant GPCRs have been discovered not only to mediate leukocyte chemotaxis thus promoting innate and adaptive host immune responses, but also to play essential roles in development, homeostasis, HIV infection, angiogenesis and wound healing. A growing body of evidence further indicates that chemoattractant GPCRs contribute to tumor growth, invasion, angiogenesis/angiostasis and metastasis. The diverse properties of GPCRs in the progression of malignant tumors have attracted intense interest in their potential as novel anti-tumor pharmacological targets.

Topics: Cell Line, Tumor; Chemokine CXCL12; Disease Progression; Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Receptors, Formyl Peptide; Receptors, G-Protein-Coupled

A significant proportion of cytokines bind to glycosaminoglycans such as heparin. Glycosaminoglycans are involved in signaling, stabilization and/or storage of these cytokines. Typical examples of glycosaminoglycan-binding cytokines are basic fibroblast growth factor (bFGF), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), VEGF-C, hepatocyte growth factor (HGF), granulocyte colony-stimulating factor (G-CSF), midkine, and pleiotrophin. All are present in the tumor microenvironment and promote tumor growth, tumor invasion and/or tumor angiogenesis. Serum or plasma levels of glycosaminoglycan-binding cytokines are frequently elevated in patients with various malignant tumors. High levels of these cytokines are usually correlated with the occurrence of metastasis and a poor prognosis. The mode of elevation of individual glycosaminoglycan-binding cytokines in patients with malignant tumors is summarized here. Further studies, especially with multiple cytokines, are expected to make assays clinically useful for both early detection and prognostic prediction.

Topics: Biomarkers, Tumor; Cytokines; Fibroblast Growth Factor 2; Glycosaminoglycans; Humans; Interleukin-8; Neoplasms; Protein Binding; Vascular Endothelial Growth Factor C

Caffeine and other methylxanthines produce multiple physiologic effects throughout the human body, many of these effects could potentially modulate the activity of anticancer therapy. Caffeine may directly interfere with drug transport to tumor cells by formation of mixed stacking complexes with polyaromatic drugs. If formed in cells, these complexes may also prevent of intercalating drugs from DNA binding and, in this way, lower their antitumor activity. Since many of potent carcinogens are polyaromatic compounds, formation of stacking complexes with carcinogens could be associated with anti-genotoxic activity of caffeine and its use in cancer chemoprevention. Caffeine has also been reported to inhibit ATM and ATR kinases which leads to the disruption of multiple DNA damage-responsive cell cycle checkpoints and greatly sensitizes tumor cells to antitumor agents which induce genotoxic stress. Caffeine may inhibit repair of DNA lesions through a direct interference with DNA-PK activity and other repair enzymes. A number of in vitro and in vivo studies demonstrated that caffeine modulates both innate and adaptive immune responses via inhibition of cyclic adenosine monophosphate (cAMP)-phosphodiesterase. Finally, another group of effects induced by caffeine is mediated through its inhibitory action on adenosine receptors. This may modulate the stability of HIF1 alpha as well as VEGF and interleukin-8 expression in tumor cells, which could have a direct impact on neovascularization of human tumors. In this review, we present different molecular mechanisms by which caffeine and other methylxanthines may directly or indirectly modulate the effect of antitumor treatment in tumor cells and in cancer patients.

Topics: Animals; Antineoplastic Agents; Caffeine; Cell Cycle; DNA Repair; Humans; Interleukin-8; Molecular Structure; Neoplasms; Receptors, Purinergic P1

Both inflammation and angiogenesis are exacerbated by increased production of chemokines/cytokines, growth factors, proteolytic enzymes, proteoglycans, lipid mediators and prostaglandins. It has been reported that approximately 15-20% of all malignancies are initiated or exacerbated by inflammation. Initiation and progression of cancer are also closely linked to angiogenesis. Infiltration of macrophages is a dramatic and common feature of inflammation, angiogenesis and cancer, and has been recently highlighted in an attempt to develop novel strategies for treating cancer. The recruitment and infiltration of macrophages in the tumor microenvironment activates them to support the malignant progression of cancer cells, and these macrophages are called tumor-associated macrophages. In a model of experimental angiogenesis using mouse corneas, macrophages infiltrated tissue in response to inflammatory cytokines and produced chemokines and angiogenesis-promoting factors, such as vascular endothelial growth factor-A, interleukin-8, matrix metalloproteinases, prostanoids and reactive oxygen species. Moreover, in a cancer xenograft model, inflammatory stimuli by a representative inflammatory cytokine, interleukin-1beta, enhanced tumor growth and angiogenesis with infiltration and activation of macrophages. Co-culture of cancer cells with macrophages synergistically stimulated production of various angiogenesis-related factors when stimulated by the inflammatory cytokine. This inflammatory angiogenesis in both mouse cornea and a tumor model was mediated, in part, by activation of nuclear factor kappaB and activator protein 1 (Jun/Fos). Administration of either nuclear factor kappaB-targeting drugs or cyclooxygenase 2 inhibitors or depletion of macrophages could block both inflammatory angiogenesis and tumor angiogenesis. Thus, both inflammatory and angiogenic responses in tumor stroma could be targets for development of anticancer therapeutic drugs.

Topics: Animals; Chemokines; Cyclooxygenase 2 Inhibitors; Humans; Inflammation; Interleukin-8; Macrophages; Matrix Metalloproteinases; Mice; Neoplasms; Neovascularization, Pathologic; NF-kappa B; Prostaglandins; Reactive Oxygen Species; Transcription Factor AP-1; Vascular Endothelial Growth Factor A

Interleukin-8 (IL-8) is a proinflammatory CXC chemokine associated with the promotion of neutrophil chemotaxis and degranulation. This chemokine activates multiple intracellular signaling pathways downstream of two cell-surface, G protein-coupled receptors (CXCR1 and CXCR2). Increased expression of IL-8 and/or its receptors has been characterized in cancer cells, endothelial cells, infiltrating neutrophils, and tumor-associated macrophages, suggesting that IL-8 may function as a significant regulatory factor within the tumor microenvironment. The induction of IL-8 signaling activates multiple upstream signaling pathways that (a) impinge on gene expression via regulation of numerous transcription factor activities, (b) modulate the cellular proteome at the level of translation, and/or (c) effect the organization of the cell cytoskeleton through posttranslational regulation of regulatory proteins. As a consequence of the diversity of effectors and downstream targets, IL-8 signaling promotes angiogenic responses in endothelial cells, increases proliferation and survival of endothelial and cancer cells, and potentiates the migration of cancer cells, endothelial cells, and infiltrating neutrophils at the tumor site. Accordingly, IL-8 expression correlates with the angiogenesis, tumorigenicity, and metastasis of tumors in numerous xenograft and orthotopic in vivo models. Recently, IL-8 signaling has been implicated in regulating the transcriptional activity of the androgen receptor, underpinning the transition to an androgen-independent proliferation of prostate cancer cells. In addition, stress and drug-induced IL-8 signaling has been shown to confer chemotherapeutic resistance in cancer cells. Therefore, inhibiting the effects of IL-8 signaling may be a significant therapeutic intervention in targeting the tumor microenvironment.

Topics: Cell Movement; Cell Proliferation; Chemokines, CXC; Gene Expression Regulation; Humans; Interleukin-8; Models, Biological; Neoplasms; Neovascularization, Pathologic; Signal Transduction

The Ras family of small guanosine triphosphatases normally transmit signals from cell surface receptors to the interior of the cell. Stimulation of cell surface receptors leads to the activation of guanine exchange factors, which, in turn, convert Ras from an inactive GDP-bound state to an active GTP-bound state. However, in one third of human cancers, RAS is mutated and remains in the constitutively active GTP-bound state. In this oncogenic state, RAS activates a constellation of signaling that is known to promote tumorigenesis. One consequence of this oncogenic RAS signal in cancer cells is the upregulation of the cytokines interleukin (IL)-6, IL-8, and chemokine growth-regulated oncogene 1 (GRO-1). We review the evidence supporting a role for these cytokines in oncogenic RAS-driven solid tumors.

Topics: Animals; Chemokine CXCL1; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Interleukin-8; Neoplasms; Oncogene Protein p21(ras); Signal Transduction

Topics: Animals; Genes, ras; Humans; Interleukin-6; Interleukin-8; Mice; Models, Biological; Mutation; Neoplasms; ras Proteins; Signal Transduction

Microtubule stabilization by chemotherapy is a powerful weapon in the war against cancer. Disruption of the mitotic spindle activates a number of signaling pathways, with consequences that may protect the cell or lead to its death via apoptosis. Taxol, the first microtubule stabilizing drug to be identified, has been utilized successfully in the treatment of solid tumors for two decades. Several features, however, make this drug less than ideal, and the search for next generation stabilizing drugs with increased efficacy has been intense and fruitful. Microtubule stabilizing agents (MSAs), including the taxanes, the epothilones, discodermolide, laulimalide, and eleutherobin, form an important and expanding family of chemotherapeutic agents. A strong understanding of their molecular signaling consequences is essential to their value, particularly in regard to their potential for combinatorial chemotherapy - the use of multiple agents to enhance the efficacy of cancer treatment. Here we present a critical review of research on the signaling mechanisms induced by MSAs, their relevance to apoptosis, and their potential for exploitation by combinatorial therapy.

Topics: Alkanes; Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbamates; Cyclooxygenase 2; Diterpenes; Epothilones; Humans; Inhibitor of Apoptosis Proteins; Interleukin-1; Interleukin-8; Lactones; Macrolides; MAP Kinase Kinase 1; MAP Kinase Signaling System; Maturation-Promoting Factor; Microtubule-Associated Proteins; Microtubules; Neoplasm Proteins; Neoplasms; NF-kappa B; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Pyrones; Signal Transduction; Survivin; Taxoids; Tumor Suppressor Protein p53

This review summarises some important new findings that implicate sphingosine-1-phosphate (S1P) as a potent tumorigenic and angiogenic agent released from cancerous tumours into the tumour microenvironment. Also explored is the novel concept that bioactive lipid signalling molecules, like S1P, can themselves be targets for rational drug design, thereby opening up an entire class of lipidomic-based therapeutics for oncology and other human diseases.

Topics: Animals; Antibodies, Monoclonal; Humans; Interleukin-6; Interleukin-8; Lysophospholipids; Mice; Models, Biological; Neoplasms; Sphingosine; Vascular Endothelial Growth Factor A

Abstract Interleukin (IL)-8, a cytokine of the CXC chemokine family that was originally classified as a neutrophil chemoattractant, is now reported to play an important role in tumor progression and metastasis in a variety of human cancers, including lung cancers. IL-8 biologic activity in tumors and the tumor microenvironment may contribute to tumor progression through its potential function in the regulation of angiogenesis, cancer cell growth and survival, tumor cell motion, leukocyte infiltration and modification of immune responses. Recently, infiltrating macrophages in tumor stroma have been considered to be able to stimulate cancer growth, enhance angiogenesis and promote metastasis, and has prognostic significance in several human cancers. Accumulating evidence also shows that cancer cells and stromal cell interaction can stimulate cancer cells, as well as stromal cells in the expression of IL-8 and other growth factors. Here, we summarize current information about IL-8 biology in human lung cancers and focus on its effect on tumor angiogenesis, regulation of IL-8 expression in tumors, its prognostic significances, the role of tumor infiltrating macrophages in the production of IL-8 in cancer cells and the tumor microenvironment, gene expression profiles after cancer cell-stromal cell interaction, and the effect of a variety anti- inflammatory drugs on the modification of IL-8 and other gene expressions in cancer cells and the tumor microenvironment in lung cancers.

Topics: Anti-Inflammatory Agents; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Leukocytes; Macrophages; Microcirculation; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic

Heparan sulfate proteoglycans (HSPGs), via their interactions with numerous effector molecules such as FGF-2, IL-8, and VEGF, regulate the biological activity of cells by acting as co-receptors that promote signaling. The extent and nature of their role as co-receptors is often misregulated in cancer as manifested by alterations in HSPG structure and expression level. This misregulation of HSPGs can aid in promoting the malignant phenotype. In addition to expression-related changes in HSPGs, recent discoveries indicate that HSPGs localized within the tumor microenvironment can be attacked by enzymes that alter proteoglycan structure resulting in dramatic effects on tumor growth and metastasis. This review focuses on remodeling of HSPGs by three distinct mechanisms that occur in vivo; (i) shedding of proteoglycan extracellular domains from cell surfaces, (ii) fragmentation of heparan sulfate chains by heparanase, and (iii) removal of sulfates from the 6-O position of heparan sulfate chains by extracellular sulfatases. Assessing or monitoring the remodeling of HSPGs has important implications for tumor diagnosis and patient prognosis while therapeutic manipulation of the remodeling process represents an exciting new possibility for treating cancer.

Topics: Animals; Antineoplastic Agents; Cell Membrane; Cell Proliferation; Extracellular Matrix; Fibroblast Growth Factor 2; Gene Expression Regulation; Heparan Sulfate Proteoglycans; Humans; Interleukin-8; Membrane Glycoproteins; Models, Biological; Neoplasm Metastasis; Neoplasms; Phenotype; Protein Structure, Tertiary; Proteoglycans; Signal Transduction; Syndecans; Vascular Endothelial Growth Factor A

Interleukin (IL)-8 contributes to cancer progression through its multiple functions. Its angiogenic effects are well known, but more recently it has been found to be mitogenic for some cancer cells. Many cancer cells constitutively produce IL-8 and also express the IL-8 receptors, CXCR1 and 2 on the cell membrane. It has been established that IL-8 is an autocrine growth factor for a variety of human cancer cells. The mitogenic effects of IL-8 directly stimulate growth of cancer mass, and it may play a critical role for cancer cells to regrow in metastatic sites.

Topics: Animals; Autocrine Communication; Cell Proliferation; Humans; Interleukin-8; Neoplasms; Paracrine Communication

The Rho family of GTPases is part of the Ras superfamily. The Rho, Rac, and Cdc42 members of the family are present in mammalian cells and have been the subject of attention of researchers due to their vast spectrum of functions. Rac 1, Cdc42, and RhoA are well-known for their role in the regulation of the actin cytoskeleton in promoting the formation of lamellipodia, filopodia, and stress fibers, respectively. The Rho proteins also participate in the control of cell growth, motility, cell-cell adhesions, morphogenesis, cytoskeletal dynamics, and cellular trafficking. The mechanisms for eliciting these functions have become clearer during the last decade. Concordant with their roles in multiple processes of cellular control, the Rho proteins have been shown to be involved in tumor growth, progression, metastasis, and now angiogenesis.

Topics: Cell Adhesion; Cell Movement; Disease Progression; Fibroblast Growth Factors; Humans; Interleukin-6; Interleukin-8; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; rho GTP-Binding Proteins; Thrombospondin 1

The aggressive nature of metastatic human cancer has been shown to be related to numerous abnormalities in growth factors and their receptors. These perturbations confer a tremendous growth advantage to the malignant cells. Interleukin-8 (IL-8), originally discovered as a chemotactic factor for leukocytes, has recently been shown to contribute to human cancer progression through its potential functions as a mitogenic, angiogenic, and motogenic factor. While it is constitutively detected in human cancer tissues and established cell lines, IL-8 expression is regulated by various tumor microenvironment factors, such as hypoxia, acidosis, nitric oxide, and cell density. Understanding the mechanisms of both inducible and constitutive IL-8 expression will be helpful in designing potential therapeutic strategies of targeting IL-8 to control tumor growth and metastasis. In this review, the role and regulation of IL-8 expression in the growth and metastasis of human cancer with a focus on human pancreatic adenocarcinoma will be discussed.

Topics: Animals; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Neoplasms

Tumor and host cells frequently express interleukin-8 (IL-8). IL-8 has been shown to be motogenic, mitogenic, and angiogenic and to play important roles in human tumor progression. IL-8 expression can be induced by numerous stress factors present in the tumor environment, such as hypoxia, acidosis, hyperglycemia, hyperosmotic pressure, high cell density, hyperthermia, radiation, and chemotherapeutic agents. Understanding the mechanisms of IL-8 expression and regulation will be helpful in designing potential therapeutic modalities targeting IL-8 to control tumor growth and metastasis.

Topics: Animals; Humans; Interleukin-8; Neoplasms; Stress, Physiological

A variety of factors have been identified that regulate angiogenesis, including the CXC chemokine family. The CXC chemokines are a unique family of cytokines for their ability to behave in a disparate manner in the regulation of angiogenesis. CXC chemokines have four highly conserved cysteine amino acid residues, with the first two cysteine amino acid residues separated by one non-conserved amino acid residue (i.e., CXC). A second structural domain within this family determines their angiogenic potential. The NH2 terminus of the majority of the CXC chemokines contains three amino acid residues (Glu-Leu-Arg: the ELR motif), which precedes the first cysteine amino acid residue of the primary structure of these cytokines. Members that contain the ELR motif (ELR+) are potent promoters of angiogenesis. In contrast, members that are inducible by interferons and lack the ELR motif (ELR-) are potent inhibitors of angiogenesis. This difference in angiogenic activity may impact on the pathogenesis of a variety of disorders.

Topics: Amino Acid Motifs; Angiogenesis Inhibitors; Animals; Arthritis, Rheumatoid; Chemokine CXCL10; Chemokines, CXC; Chronic Disease; Fibrosis; Humans; Inflammation; Interleukin-8; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Pulmonary Fibrosis; Receptors, Chemokine; Structure-Activity Relationship

Topics: Angiostatins; Animals; Antineoplastic Agents; Chemokine CXCL10; Chemokines, CXC; Collagen; Endostatins; Endothelial Growth Factors; Fibroblast Growth Factor 2; Humans; Interleukin-8; Lymphokines; Macrophages; Metalloendopeptidases; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Plasminogen; Platelet Factor 4; Stromal Cells; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Topics: Animals; Apoptosis; Blindness; Blood Vessels; Endothelial Growth Factors; Extracellular Matrix Proteins; Eye Diseases; Female; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Humans; Inflammation; Integrins; Interleukin-8; Lymphokines; Male; Neoplasms; Neovascularization, Pathologic; Receptors, Vitronectin; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Inflammation is a vital consequence of tissue injury caused by various reasons including invasion of foreign particles, infection with microorganisms, autoimmune responses, ischemia-reperfusion injury, and malignant neoplasia. In 1987, a major neutrophil chemotactic and activating factor, now called interleukin 8 (IL-8), was purified and molecularly cloned. In this article, general overview of IL-8 was made describing biochemical structure, regulation of production of IL-8, properties of the receptors for IL-8 and pathophysiological roles of IL-8 in inflammation.

Topics: Amino Acid Sequence; Animals; Humans; Infections; Inflammation; Interleukin-8; Lung Neoplasms; Molecular Sequence Data; Neoplasms; Stomach Neoplasms; Tumor Cells, Cultured

During the past three years great advances have been made in the chemistry and biology of chemoattractants for human leukocytes. Two chemoattractant cytokines have been isolated, sequenced and cloned, each with distinctive leukocyte attractant specificity. Monocyte chemoattractant protein 1 (MCP-1), the subject of this review by Edward Leonard and Teizo Yoshimura, is secreted by PHA-stimulated mononuclear cells and can be identified by northern blotting in response to LPS or PHA. It attracts monocytes but not neutrophils. In contrast, neutrophil attractant/activation protein (NAP-1) (also known as interleukin 8 (IL-8)) attracts and activates human neutrophils but it is not a chemoattractant for human monocytes. Based on amino acid sequence analysis, each of these attractants has been assigned to one of two distinct families of cytokines that are thought to participate in host defense and inflammatory responses.

Topics: Amino Acid Sequence; Animals; Arteriosclerosis; Chemokine CCL2; Chemotactic Factors; Cloning, Molecular; Humans; Interleukin-8; Interleukins; Molecular Sequence Data; Monocytes; Neoplasms

Radiotherapy is a mainstay cancer therapy whose antitumor effects partially depend on T cell responses. However, the role of Natural Killer (NK) cells in radiotherapy remains unclear. Here, using a reverse translational approach, we show a central role of NK cells in the radiation-induced immune response involving a CXCL8/IL-8-dependent mechanism. In a randomized controlled pancreatic cancer trial, CXCL8 increased under radiotherapy, and NK cell positively correlated with prolonged overall survival. Accordingly, NK cells preferentially infiltrated irradiated pancreatic tumors and exhibited CD56

Topics: Adoptive Transfer; Animals; Humans; Immunity; Interleukin-8; Killer Cells, Natural; Mice; Neoplasms; Xenograft Model Antitumor Assays

HuMax-IL8 (now known as BMS-986253) is a novel, fully human monoclonal antibody that inhibits interleukin-8 (IL-8), a chemokine that promotes tumor progression, immune escape, epithelial-mesenchymal transition, and recruitment of myeloid-derived suppressor cells. Studies have demonstrated that high serum IL-8 levels correlate with poor prognosis in many malignant tumors. Preclinical studies have shown that IL-8 blockade may reduce mesenchymal features in tumor cells, making them less resistant to treatment.. Fifteen patients with metastatic or unresectable locally advanced solid tumors were enrolled in this 3 + 3 dose-escalation trial at four dose levels (4, 8, 16, or 32 mg/kg). HuMax-IL8 was given IV every 2 weeks, and patients were followed for safety and immune monitoring at defined intervals up to 52 weeks.. All enrolled patients (five chordoma, four colorectal, two prostate, and one each of ovarian, papillary thyroid, chondrosarcoma, and esophageal) received at least one dose of HuMax-IL8. Eight patients had received three or more prior lines of therapy and five patients had received prior immunotherapy. Treatment-related adverse events occurred in five patients (33%), mostly grade 1. Two patients receiving the 32 mg/kg dose had grade 2 fatigue, hypophosphatemia, and hypersomnia. No dose-limiting toxicities were observed, and maximum tolerated dose was not reached. Although no objective tumor responses were observed, 11 patients (73%) had stable disease with median treatment duration of 24 weeks (range, 4-54 weeks). Serum IL-8 was significantly reduced on day 3 of HuMax-IL8 treatment compared to baseline (p = 0.0004), with reductions in IL-8 seen at all dose levels.. HuMax-IL8 is safe and well-tolerated. Ongoing studies are evaluating the combination of IL-8 blockade and other immunotherapies.. NCTN, NCT02536469. Registered 23 August 2015, https://clinicaltrials.gov/ct2/show/NCT02536469?term=NCT02536469&rank=1 .

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Cohort Studies; Female; Follow-Up Studies; Humans; Interleukin-8; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Metastasis; Neoplasms; Prognosis; Tissue Distribution

Topics: Adult; Aged; Cell- and Tissue-Based Therapy; Cytokines; Dendritic Cells; Female; Humans; Immunotherapy; Injections, Intralesional; Interleukin-12; Interleukin-8; Male; Middle Aged; Neoplasms; Tumor Microenvironment

Middle East Respiratory Syndrome (MERS) is a novel respiratory illness firstly reported in Saudi Arabia in 2012. It is caused by a new corona virus, called MERS corona virus (MERS-CoV). Most people who have MERS-CoV infection developed severe acute respiratory illness.. This work is done to determine the clinical characteristics and the outcome of intensive care unit (ICU) admitted patients with confirmed MERS-CoV infection.. This study included 32 laboratory confirmed MERS corona virus infected patients who were admitted into ICU. It included 20 (62.50%) males and 12 (37.50%) females. The mean age was 43.99 ± 13.03 years. Diagnosis was done by real-time reverse transcription polymerase chain reaction (rRT-PCR) test for corona virus on throat swab, sputum, tracheal aspirate, or bronchoalveolar lavage specimens. Clinical characteristics, co-morbidities and outcome were reported for all subjects.. Most MERS corona patients present with fever, cough, dyspnea, sore throat, runny nose and sputum. The presence of abdominal symptoms may indicate bad prognosis. Prolonged duration of symptoms before patients' hospitalization, prolonged duration of mechanical ventilation and hospital stay, bilateral radiological pulmonary infiltrates, and hypoxemic respiratory failure were found to be strong predictors of mortality in such patients. Also, old age, current smoking, smoking severity, presence of associated co-morbidities like obesity, diabetes mellitus, chronic heart diseases, COPD, malignancy, renal failure, renal transplantation and liver cirrhosis are associated with a poor outcome of ICU admitted MERS corona virus infected patients.. Plasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (. SnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.. A Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3-4 Chronic Kidney Disease, NCT0363002 and NCT03893799.. HFNC did not significantly modify work of breathing in healthy subjects. However, a significant reduction in the minute volume was achieved, capillary [Formula: see text] remaining constant, which suggests a reduction in dead-space ventilation with flows > 20 L/min. (ClinicalTrials.gov registration NCT02495675).. 3 组患者手术时间、术中显性失血量及术后 1 周血红蛋白下降量比较差异均无统计学意义（. 对于肥胖和超重的膝关节单间室骨关节炎患者，采用 UKA 术后可获满意短中期疗效，远期疗效尚需进一步随访观察。.. Decreased muscle strength was identified at both time points in patients with hEDS/HSD. The evolution of most muscle strength parameters over time did not significantly differ between groups. Future studies should focus on the effectiveness of different types of muscle training strategies in hEDS/HSD patients.. These findings support previous adverse findings of e-cigarette exposure on neurodevelopment in a mouse model and provide substantial evidence of persistent adverse behavioral and neuroimmunological consequences to adult offspring following maternal e-cigarette exposure during pregnancy. https://doi.org/10.1289/EHP6067.. This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies.. NCT04138212, date of registration: October 24, 2019.. Results of current investigation indicated that milk type and post fermentation cooling patterns had a pronounced effect on antioxidant characteristics, fatty acid profile, lipid oxidation and textural characteristics of yoghurt. Buffalo milk based yoghurt had more fat, protein, higher antioxidant capacity and vitamin content. Antioxidant and sensory characteristics of T. If milk is exposed to excessive amounts of light, Vitamins B. The two concentration of ZnO nanoparticles in the ambient air produced two different outcomes. The lower concentration resulted in significant increases in Zn content of the liver while the higher concentration significantly increased Zn in the lungs (p < 0.05). Additionally, at the lower concentration, Zn content was found to be lower in brain tissue (p < 0.05). Using TEM/EDX we detected ZnO nanoparticles inside the cells in the lungs, kidney and liver. Inhaling ZnO NP at the higher concentration increased the levels of mRNA of the following genes in the lungs: Mt2 (2.56 fold), Slc30a1 (1.52 fold) and Slc30a5 (2.34 fold). At the lower ZnO nanoparticle concentration, only Slc30a7 mRNA levels in the lungs were up (1.74 fold). Thus the two air concentrations of ZnO nanoparticles produced distinct effects on the expression of the Zn-homeostasis related genes.. Until adverse health effects of ZnO nanoparticles deposited in organs such as lungs are further investigated and/or ruled out, the exposure to ZnO nanoparticles in aerosols should be avoided or minimised.

Topics: A549 Cells; Acetylmuramyl-Alanyl-Isoglutamine; Acinetobacter baumannii; Acute Lung Injury; Adaptor Proteins, Signal Transducing; Adenine; Adenocarcinoma; Adipogenesis; Administration, Cutaneous; Administration, Ophthalmic; Adolescent; Adsorption; Adult; Aeromonas hydrophila; Aerosols; Aged; Aged, 80 and over; Aging; Agriculture; Air Pollutants; Air Pollution; Airway Remodeling; Alanine Transaminase; Albuminuria; Aldehyde Dehydrogenase 1 Family; Algorithms; AlkB Homolog 2, Alpha-Ketoglutarate-Dependent Dioxygenase; Alzheimer Disease; Amino Acid Sequence; Ammonia; Ammonium Compounds; Anaerobiosis; Anesthetics, Dissociative; Anesthetics, Inhalation; Animals; Anti-Bacterial Agents; Anti-HIV Agents; Anti-Infective Agents; Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Antifungal Agents; Antigens, Bacterial; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antioxidants; Antitubercular Agents; Antiviral Agents; Apolipoproteins E; Apoptosis; Arabidopsis; Arabidopsis Proteins; Arsenic; Arthritis, Rheumatoid; Asthma; Atherosclerosis; ATP-Dependent Proteases; Attitude of Health Personnel; Australia; Austria; Autophagy; Axitinib; Bacteria; Bacterial Outer Membrane Proteins; Bacterial Proteins; Bacterial Toxins; Bacterial Typing Techniques; Bariatric Surgery; Base Composition; Bayes Theorem; Benzoxazoles; Benzylamines; beta Catenin; Betacoronavirus; Betula; Binding Sites; Biological Availability; Biological Oxygen Demand Analysis; Biomarkers; Biomarkers, Tumor; Biopsy; Bioreactors; Biosensing Techniques; Birth Weight; Blindness; Blood Chemical Analysis; Blood Gas Analysis; Blood Glucose; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Blood-Brain Barrier; Blotting, Western; Body Mass Index; Body Weight; Bone and Bones; Bone Density; Bone Resorption; Borates; Brain; Brain Infarction; Brain Injuries, Traumatic; Brain Neoplasms; Breakfast; Breast Milk Expression; Breast Neoplasms; Bronchi; Bronchoalveolar Lavage Fluid; Buffaloes; Cadherins; Calcification, Physiologic; Calcium Compounds; Calcium, Dietary; Cannula; Caprolactam; Carbon; Carbon Dioxide; Carboplatin; Carcinogenesis; Carcinoma, Ductal; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Carcinoma, Non-Small-Cell Lung; Carcinoma, Pancreatic Ductal; Carcinoma, Renal Cell; Cardiovascular Diseases; Carps; Carrageenan; Case-Control Studies; Catalysis; Catalytic Domain; Cattle; CD8-Positive T-Lymphocytes; Cell Adhesion; Cell Cycle Proteins; Cell Death; Cell Differentiation; Cell Line; Cell Line, Tumor; Cell Movement; Cell Nucleus; Cell Phone Use; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cell Transformation, Viral; Cells, Cultured; Cellulose; Chemical Phenomena; Chemoradiotherapy; Child; Child Development; Child, Preschool; China; Chitosan; Chlorocebus aethiops; Cholecalciferol; Chromatography, Liquid; Circadian Clocks; Circadian Rhythm; Circular Dichroism; Cisplatin; Citric Acid; Clinical Competence; Clinical Laboratory Techniques; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clostridioides difficile; Clostridium Infections; Coculture Techniques; Cohort Studies; Cold Temperature; Colitis; Collagen Type I; Collagen Type I, alpha 1 Chain; Collagen Type XI; Color; Connective Tissue Diseases; Copper; Coronary Angiography; Coronavirus 3C Proteases; Coronavirus Infections; Cost of Illness; Counselors; COVID-19; COVID-19 Testing; Creatine Kinase; Creatinine; Cross-Over Studies; Cross-Sectional Studies; Cryoelectron Microscopy; Cryosurgery; Crystallography, X-Ray; Cues; Cultural Competency; Cultural Diversity; Curriculum; Cyclic AMP Response Element-Binding Protein; Cyclin-Dependent Kinase Inhibitor p21; Cycloparaffins; Cysteine Endopeptidases; Cytokines; Cytoplasm; Cytoprotection; Databases, Factual; Denitrification; Deoxycytidine; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diagnosis, Differential; Diatoms; Diet; Diet, High-Fat; Dietary Exposure; Diffusion Magnetic Resonance Imaging; Diketopiperazines; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Disease Progression; Disease-Free Survival; DNA; DNA Damage; DNA Glycosylases; DNA Repair; DNA-Binding Proteins; DNA, Bacterial; DNA, Viral; Docetaxel; Dose Fractionation, Radiation; Dose-Response Relationship, Drug; Down-Regulation; Doxorubicin; Drosophila; Drosophila melanogaster; Drug Carriers; Drug Delivery Systems; Drug Liberation; Drug Repositioning; Drug Resistance, Bacterial; Drug Resistance, Multiple, Bacterial; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Drug Therapy, Combination; Edema; Edible Grain; Education, Graduate; Education, Medical, Graduate; Education, Pharmacy; Ehlers-Danlos Syndrome; Electron Transport Complex III; Electron Transport Complex IV; Electronic Nicotine Delivery Systems; Emergency Service, Hospital; Empathy; Emulsions; Endothelial Cells; Endurance Training; Energy Intake; Enterovirus A, Human; Environment; Environmental Monitoring; Enzyme Assays; Enzyme Inhibitors; Epithelial Cells; Epithelial-Mesenchymal Transition; Epoxide Hydrolases; Epoxy Compounds; Erythrocyte Count; Erythrocytes; Escherichia coli; Escherichia coli Infections; Escherichia coli Proteins; Esophageal Neoplasms; Esophageal Squamous Cell Carcinoma; Esophagectomy; Estrogens; Etanercept; Ethiopia; Ethnicity; Ethylenes; Exanthema; Exercise; Exercise Test; Exercise Tolerance; Extracellular Matrix; Extracorporeal Membrane Oxygenation; Eye Infections, Fungal; False Negative Reactions; Fatty Acids; Fecal Microbiota Transplantation; Feces; Female; Femur Neck; Fermentation; Ferritins; Fetal Development; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Fibroblasts; Fibroins; Fish Proteins; Flavanones; Flavonoids; Focus Groups; Follow-Up Studies; Food Handling; Food Supply; Food, Formulated; Forced Expiratory Volume; Forests; Fractures, Bone; Fruit and Vegetable Juices; Fusobacteria; G1 Phase Cell Cycle Checkpoints; G2 Phase Cell Cycle Checkpoints; Gamma Rays; Gastrectomy; Gastrointestinal Microbiome; Gastrointestinal Stromal Tumors; Gefitinib; Gels; Gemcitabine; Gene Amplification; Gene Expression; Gene Expression Regulation; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Plant; Gene Knockdown Techniques; Gene-Environment Interaction; Genotype; Germany; Glioma; Glomerular Filtration Rate; Glucagon; Glucocorticoids; Glycemic Control; Glycerol; Glycogen Synthase Kinase 3 beta; Glycolipids; Glycolysis; Goblet Cells; Gram-Negative Bacterial Infections; Granulocyte Colony-Stimulating Factor; Graphite; Greenhouse Effect; Guanidines; Haemophilus influenzae; HCT116 Cells; Health Knowledge, Attitudes, Practice; Health Personnel; Health Services Accessibility; Health Services Needs and Demand; Health Status Disparities; Healthy Volunteers; 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YAP-Signaling Proteins; Yogurt; Young Adult; Zebrafish; Zebrafish Proteins; Ziziphus

To evaluate whether the post-surgery placement of the rectus sheath block analgesia (RSB) reduces the inflammatory response following surgery. The main hypothesis of our study was to find any correlation between patients' pain experience, numeric rating scale (NRS) postoperatively and concentrations of inflammatory response biomarkers, such as interleukin-1 receptor antagonist (IL-1ra), IL-6, IL-8, IL-10, IL-1β, in patients with benign disease and cancer.. Initially, 46 patients with midline laparotomy were randomized to the placebo group (n=11) and to one of the three active groups; single-dose (n=12), repeated-dose (n=12) and continuous infusion (n=11) RSB analgesia groups. Plasma concentrations of high-sensitivity C-reactive protein (hs-CRP) and five interleukins (IL-1ra, IL-6, IL-8, IL-10, IL-1β) were measured at three time points; just before, immediately after and 24 h after operation. The primary end-point was to compare plasma concentrations of the hs-CRP and five interleukins in the placebo group and in the three different RSB analgesia groups in patients with benign disease and cancer.. The placebo group and three active groups were similar in terms of demographic variables and perioperative data. Of the anti-inflammatory cytokines, patients in the continuous infusion group had significantly higher IL-10 median values postoperatively than the three other study groups (p=0.029). In addition, patients in the three active groups combined had significantly higher IL-10 median values immediately after operation than the placebo group (p=0.028; in all patients with benign disease and cancer). There is a significant correlation between the individual values of NRS and IL-10 values postoperatively in the placebo group and the three active groups separately (r=0.40, p=0.03) and also a significant correlation between the individual values of the NRS scale and IL-1β values postoperatively in the placebo group and the three active groups separately (r=0.38, p=0.04).. Placement of RSB analgesia does not significantly reduce the inflammatory response biomarkers' concentrations in patients with benign disease or cancer patients. A new finding in the present work is a significant correlation in the NRS scale versus plasma concentrations of anti-inflammatory cytokine IL-10 and pro-inflammatory cytokine IL-1β postoperatively suggesting that inflammation and pain are related.

Topics: Adult; Aged; C-Reactive Protein; Female; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-10; Interleukin-18; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Neoplasms; Nerve Block; Pain, Postoperative

Purpose Interleukin-10 (IL-10) stimulates the expansion and cytotoxicity of tumor-infiltrating CD8+ T cells and inhibits inflammatory CD4+ T cells. Pegylation prolongs the serum concentration of IL-10 without changing the immunologic profile. This phase I study sought to determine the safety and antitumor activity of AM0010. Patients and Methods Patients with selected advanced solid tumors were treated with AM0010 in a dose-escalation study, which was followed by a renal cell cancer (RCC) dose-expansion cohort. AM0010 was self-administered subcutaneously at doses of 1 to 40 μg/kg once per day. Primary end points were safety and tolerability; clinical activity and immune activation were secondary end points. Results In the dose-escalation and -expansion cohorts, 33 and 18 patients, respectively, were treated with daily subcutaneous injection of AM0010. AM0010 was tolerated in a heavily pretreated patient population. Treatment-related adverse events (AEs) included anemia, fatigue, thrombocytopenia, fever, and injection site reactions. Grade 3 to 4 nonhematopoietic treatment-related AEs, including rash (n = 2) and transaminitis (n = 1), were observed in five of 33 patients. Grade 3 to 4 anemia or thrombocytopenia was observed in five patients. Most treatment-related AEs were transient or reversible. AM0010 led to systemic immune activation with elevated immune-stimulatory cytokines and reduced transforming growth factor beta in the serum. Partial responses were observed in one patient with uveal melanoma and four of 15 evaluable patients with RCC treated at 20 μg/kg (overall response rate, 27%). Prolonged stable disease of at least 4 months was observed in four patients, including one with colorectal cancer with disease stabilization for 20 months. Conclusion AM0010 has an acceptable toxicity profile with early evidence of antitumor activity, particularly in RCC. These data support the further evaluation of AM0010 both alone and in combination with other immune therapies and chemotherapies.

Topics: Adult; Aged; Aged, 80 and over; Anemia; Carcinoma, Renal Cell; Cytokines; Drug Eruptions; Exanthema; Fatigue; Female; Fever; Humans; Injections, Subcutaneous; Interferon-gamma; Interleukin-10; Interleukin-4; Interleukin-8; Kidney Neoplasms; Male; Melanoma; Middle Aged; Neoplasms; Polyethylene Glycols; Recombinant Proteins; Thrombocytopenia; Transforming Growth Factor beta; Uveal Neoplasms; Young Adult

Curcuminoids are bioactive polyphenolics with potent antiinflammatory properties. Although several lines of in vitro and preclinical evidence suggest potent anticancer effects of curcuminoids, clinical findings have not been conclusive. The present randomized double-blind placebo-controlled trial aimed to evaluate the efficacy of curcuminoids as adjuvant therapy in cancer patients. Eighty subjects with solid tumors who were under standard chemotherapy regimens were randomly assigned to a bioavailability-boosted curcuminoids preparation (180 mg/day; n = 40) or matched placebo (n = 40) for a period of 8 weeks. Efficacy measures were changes in the health-related quality of life (QoL) score (evaluated using the University of Washington index) and serum levels of a panel of mediators implicated in systemic inflammation including interleukins 6 (IL-6) and 8 (IL-8), TNF-α, transforming growth factor-β (TGFβ), high-sensitivity C-reactive protein (hs-CRP), calcitonin gene-related peptide (CGRP), substance P and monocyte chemotactic protein-1 (MCP-1). Curcuminoid supplementation was associated with a significantly greater improvement in QoL compared with placebo (p < 0.001). Consistently, the magnitude of reductions in TNF-α (p < 0.001), TGFβ (p < 0.001), IL-6 (p = 0.061), substance P (p = 0.005), hs-CRP (p < 0.001), CGRP (p < 0.001) and MCP-1 (p < 0.001) were all significantly greater in the curcuminoids versus placebo group. In contrast, the extent of reduction in serum IL-8 was significantly greater with placebo versus curcuminoids (p = 0.012). Quality of life variations were associated with changes in serum TGFβ levels in both correlation and regression analyses. Adjuvant therapy with a bioavailable curcuminoid preparation can significantly improve QoL and suppress systemic inflammation in patients with solid tumors who are under treatment with standard chemotherapy protocols.

Topics: Adult; Aged; Biological Availability; C-Reactive Protein; Calcitonin Gene-Related Peptide; Chemokine CCL2; Chemotherapy, Adjuvant; Curcuma; Curcumin; Double-Blind Method; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Iran; Male; Middle Aged; Neoplasms; Quality of Life; Tumor Necrosis Factor-alpha

In cancer patients, metabolic alterations, reduced immune competence and anti-cancer treatment can increase the risk of infections. A rapid-acting nutritional intervention might reduce this risk and support overall treatment. The present study investigated whether one week of intervention with a specific medical food led to fatty acid incorporation and functional immunological changes.. In a randomized, double-blind study, 38 cancer patients receiving radiotherapy consumed daily for one week 400 ml of specific medical food, which is high in protein and leucine, and enriched with fish oil and specific oligosaccharides (Active group), or iso-caloric/iso-nitrogenous product (Control group). Blood samples were taken at day 0 (baseline) and day 7.. After one week of intervention, the incorporation of EPA and DHA in white blood cells was significantly higher in the Active group (2.6% and 2.6% of total fatty acids) compared to the Control group (1.0% and 2.2% of total fatty acids) (p < 0.001 and p < 0.05). Serum PGE2 levels decreased in the Active group and increased in the Control group (p < 0.01). No differences were observed on cytokine production in LPS-stimulated whole blood cultures.. In cancer patients receiving radiotherapy, nutritional intervention with a specific medical food rapidly increased the percentage EPA and DHA in white blood cell phospholipids and reduced serum levels of the inflammatory mediator PGE2 within one week. CLINICAL REGISTRATION NUMBER: NTR2121.

Topics: Aged; Biomarkers; Dinoprostone; Docosahexaenoic Acids; Double-Blind Method; Eicosapentaenoic Acid; Female; Fish Oils; Food, Fortified; Humans; Interferon-gamma; Interleukin-10; Interleukin-1beta; Interleukin-8; Leucine; Leukocytes; Male; Middle Aged; Neoplasms; Oligosaccharides; Phospholipids; Tumor Necrosis Factor-alpha

Dasatinib has been shown preclinically to overcome resistance to gemcitabine. We evaluated the safety and biological activity of the combination of dasatinib and gemcitabine in patients with advanced solid tumors.. In a phase 1 study (3 + 3 design), patients received daily dasatinib with weekly gemcitabine on days 1, 8 and 15 of a 28-day cycle (except cycle 1 which was 8 weeks). Dose escalation began with dasatinib 70 mg orally (PO) daily and gemcitabine 800 mg/m(2) intravenously (IV) weekly.. Forty-seven patients (15 men; median age = 55 years; median number of prior systemic treatments = 4) were enrolled. Dose-limiting toxicities were grade 3 fatigue and dehydration, with the maximum tolerated dose being dasatinib 100 mg PO qd and gemcitabine 600 mg/m(2) IV weekly. The most common grade 3-4 toxicities were anemia (21.5 %), thrombocytopenia (26.2 %), leukopenia (26.2 %), and pleural effusion (10.7 %). Six of 47 patients attained stable disease (SD) ≥ 6 months or partial response including 2 of 8 patients with pancreatic cancer (SD ≥ 6 months; both gemcitabine-refractory), 2 of 3 patients with thymoma (SD for 9.8 and 15 months), 1 of 1 patient with anal squamous cancer (SD 15 months) and 1 of 5 patients with inflammatory breast cancer. No significant changes in circulating tumor cells or interleukin-8 levels were observed.. The combination was well tolerated at doses of dasatinib 100 mg PO daily and gemcitabine 600 mg/m(2) IV weekly. SD ≥ 6 months/ PR was observed in gemcitabine-refractory pancreatic cancer, thymoma, anal cancer and inflammatory breast cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cell Count; Dasatinib; Demography; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Humans; Interleukin-8; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Neoplasms; Neoplastic Cells, Circulating; Pyrimidines; Thiazoles; Young Adult

The purpose of this study is to determine the levels of procalcitonin (PCT), IL-8 (interleukin-8), MIF (macrophage migration inhibitory factor), osteoprotegerin (OPG), hs-CRP and D-dimer during fever above 38.3°C due to various causes.. Blood samples taken from a total of consecutive 65 hospitalized patients during fever were prospectively tested for hsCRP, PCT, IL-8, OPG, MIF and D-dimer. Of these patients, there were 26 patients presenting with chemotherapy-induced neutropenia who had no infectious agents found; 23 patients, who had a malignancy with a febrile episode which was neither a microbiologically documented infection nor a chemotherapy-induced neutropenia, and 16 patients who did not have a malignancy and were considered to have a clinically and microbiologically documented infection.. IL-8 and D-dimer levels were higher in patients with febrile neutropenia than in the other two groups. Although MIF and OPG were higher in patients with newly diagnosed cancers, there were no differences among the three groups regarding PCT and hs-CRP values.. High serum IL-8 and D-dimer levels can be useful markers to identify hospitalized chemotherapy-induced neutropenia patients. MIF and OPG were found to be higher in patients with newly diagnosed cancer.

Topics: Antineoplastic Agents; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Fever; Fibrin Fibrinogen Degradation Products; Humans; Infections; Interleukin-8; Intramolecular Oxidoreductases; Macrophage Migration-Inhibitory Factors; Male; Neoplasms; Neutropenia; Osteoprotegerin; Prospective Studies; Protein Precursors

Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.

Topics: Adult; Aging; Antineoplastic Agents; Cell Line, Tumor; Cells, Cultured; Cellular Senescence; Epithelial Cells; Fibroblasts; Genes, ras; Humans; Infant, Newborn; Interleukin-6; Interleukin-8; Male; Neoplasm Invasiveness; Neoplasms; Phenotype; Prostatic Neoplasms; Tumor Suppressor Protein p53

Children with cancer often develop febrile illnesses after cytotoxic chemotherapy. Determining which children have serious bacterial infections in this vulnerable period would be valuable. We evaluated the ability of a rapid and sensitive assay for the concentration of calcitonin precursors (CTpr) as a sensitive diagnostic marker for bacterial sepsis in febrile, neutropenic children and determined the utility of measuring cytokines to improve the predictive value of this approach.. Prospective cohort study.. Academic children's hospital.. Fifty-six children (aged 5 months to 17 yrs) with a known malignancy who presented with fever and neutropenia.. Serial blood samples were obtained (admission, 24 hrs, and 48 hrs), and concentrations of CTpr, interleukin-6, and interleukin-8 were determined. Demographic and laboratory data from the patients were collected from the medical record.. Sixteen (29%) of the children met the criteria for bacterial sepsis. Plasma levels of CTpr and interleukin-8, but not interleukin-6, were increased at all time points in children with sepsis compared with those without sepsis. CTpr at 24 and 48 hrs after admission were reliable markers for sepsis (area under the curve = 0.92 and 0.908, respectively). Logistic regression using CTpr at 24 hrs in addition to interleukin-8 at 48 hrs produced the best-fit models associated with sepsis. Using cutoff values of CTpr >500 pg/mL and interleukin-8 >20 pg/mL produced a screening test for sepsis with 94% sensitivity and 90% specificity.. Our data show the utility of a rapid and sensitive assay for CTpr combined with interleukin-8 as a highly sensitive and specific diagnostic marker of bacterial sepsis in febrile, neutropenic children. The use of these markers as a clinical tool may allow for better prognostication for clinicians and may eventually lead to more targeted therapies for this heterogeneous population.

Topics: Adolescent; Bacterial Infections; Calcitonin; Child; Child, Preschool; Female; Fever; Follow-Up Studies; Humans; Infant; Interleukin-6; Interleukin-8; Luminescent Measurements; Male; Neoplasms; Neutropenia; Prospective Studies; Protein Precursors; Sensitivity and Specificity; Sepsis

Recently, new experimental data suggested that, besides inhibiting osteoclasts, bisphosphonate may also have an antitumor effect. Antiangionetetic activity is one of the possible mechanisms of anticancer activity attributed to bisphosphonates. The purpose of this study was to evaluate the modifications in angiogenic cytokines levels after pamidronate infusion.. Twenty-five consecutive cancer patients with bone metastases treated monthly with disodium pamidronate infusion were evaluated prospectively for circulating levels of vascular endothelial growth factor (VEGF), gamma-IFN, interleukin (IL)-6, and IL-8 at different time points: just before and after 1, 2, and 7 days after pamidronate infusion.. Basal VEGF levels decreased significantly 1, 2, and 7 days after pamidronate infusion. gamma-IFN and IL-6 levels increased 1 day after the infusion but rapidly decreased after 2 days. Moreover, our data showed a statistically significant negative correlation between VEGF and gamma-IFN levels (P < 0.0001) and a positive correlation between VEGF and IL-8 (P = 0.04).. This study confirms that pamidronate could have antiangiogenic properties through a significant and lasting decrease of VEGF serum levels.

Topics: Aged; Angiogenesis Inducing Agents; Antineoplastic Agents; Cytokines; Diphosphonates; Endothelial Growth Factors; Female; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Linear Models; Lymphokines; Male; Middle Aged; Neoplasms; Pamidronate; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Immunotherapy with intravenous recombinant human interleukin-2 (rh IL-2) may be accompanied by hypotension and the emergence of capillary leak syndrome. Nitric oxide (NO) is supposed to be responsible for both side effects. The aim of the current investigation was to elucidate the relationship between pro- and anti-inflammatory cytokines and the production of NO in eight tumor patients receiving intravenous rh IL-2 continuously over a time period of 120 hours. Markers of systemic inflammation, as well as nitrate plasma levels, were consecutively determined. Significant changes in the levels of pro-inflammatory cytokines IL-6 and IL-8 were observed (p < 0.05). In contrast to the anti-inflammatory cytokine IL-10, which did not increase significantly, the serum concentrations of the soluble tumor necrosis factor receptors (sTNFr) I and II rose continuously and significantly during the observation period (p < 0.05). In parallel, a significant rise in nitrate plasma levels was observed (p < 0.05). Moreover, there were highly significant correlations between nitrate and IL-6 serum levels (p < 0.05), nitrate and sTNFr-I (p < 0.05), nitrate and sTNFr-II (p < 0.05), and between IL-6 and IL-10 (p < 0.05), respectively. We conclude that immunotherapy with IL-2 promotes a pro-inflammatory state, parallelled by an increased production of nitric oxide. Although anti-inflammatory responses accompany this process, they are not able to diminish the production of nitric oxide.

Topics: Adult; Antigens, CD; Biomarkers; Cytokines; Female; Humans; Immunotherapy; Inflammation; Infusions, Intravenous; Interleukin-10; Interleukin-2; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Neoplasms; Nitrates; Nitric Oxide; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Recombinant Proteins

Interfering with the endotoxin-mediated cytokine cascade is thought to be a promising approach to prevent septic complications in gram-negative infections. The synthetic lipid A analog SDZ MRL 953 has been shown to be protective against endotoxic shock and bacterial infection in preclinical in vivo models. As part of a trial of unspecific immunostimulation in cancer patients, we conducted a double-blind, randomized, vehicle-controlled phase I trial of SDZ MRL 953 to investigate, first, its biologic effects and safety of administration in humans and, second, its influence on reactions to a subsequent challenge of endotoxin (Salmonella abortus equi). Twenty patients were treated intravenously with escalating doses of SDZ MRL 953 or vehicle control, followed by an intravenous application of endotoxin (2 ng/kg of body weight [BW]). Administration of SDZ MRL 953 was safe and well-tolerated. SDZ MRL 953 itself increased granulocyte counts and serum levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but not of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), IL-1beta, and IL-8. Compared with vehicle control, pretreatment with SDZ MRL 953 markedly reduced the release of TNF-alpha, IL-1beta, IL-8, IL-6, and G-CSF, but augmented the increase in granulocyte counts to endotoxin. Induction of tolerance to the endotoxin-mediated cascade of proinflammatory cytokines by pretreatment with SDZ MRL 953 in patients at risk may help to prevent complications of gram-negative sepsis.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Toxins; Cytokines; Double-Blind Method; Down-Regulation; Endotoxins; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Lipid A; Lipopolysaccharides; Middle Aged; Neoplasms; Neutrophils; Prospective Studies; Salmonella; Tumor Necrosis Factor-alpha

Interleukin-8 (IL-8) has been recently shown to bind to human erythrocytes with high affinity and is therefore potentially difficult to detect in serum or plasma. IL-8 is transiently elevated in the serum of baboons after the administration of interleukin-1 alpha (IL-1 alpha). The objective of this study was to investigate whether IL-8 can be detected in the plasma or in detergent-lysed erythrocytes from cancer patients undergoing treatment with IL-1 alpha. Using a specific radioimmunoassay (RIA), plasma IL-8 was detected within 1-2 h after the first IL-1 alpha infusion. Thereafter, the levels declined rapidly and after 4-8 h were undetectable. Erythrocyte-bound IL-8 was detectable 1-2 h after the increase in plasma levels. The erythrocyte-bound IL-8 levels were higher than those measured in plasma and remained elevated long after the plasma levels had become undetectable. Erythrocyte membranes accounted for all of the erythrocyte-associated IL-8, as IL-8 was undetectable in the cytosol after erythrocyte lysis. The assay used in these studies detects IL-8 in erythrocyte lysates when it cannot be measured in plasma and may therefore be useful in monitoring IL-8 production in vivo.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Separation; Cyclophosphamide; Detergents; Edetic Acid; Erythrocytes; Humans; Interleukin-1; Interleukin-8; Neoplasms; Octoxynol; Polyethylene Glycols; Radioimmunoassay

Most studies on melatonin have focused on tumor cells but have ignored the tumor microenvironment (TME), especially one of its important components, the cancer-associated fibroblasts (CAFs). Therefore, we attempted to explore the role of melatonin in TME.. We investigated the regulatory role of melatonin in the tumor-promoting effect of CAFs and its underlying mechanism by using cell and animal models.. CAFs promoted tumor progression, but melatonin weakened the tumor-promoting effect of CAFs. Compared with tumor cells, IL-8 was mainly expressed in CAFs. CAFs-overexpressing IL-8 induced the epithelial-mesenchymal transition (EMT) of tumor cells, and a positive crosstalk was observed between CAFs and tumor cells undergoing EMT, thereby further promoting the IL-8 expression. Melatonin suppressed this crosstalk by inhibiting the NF-κB pathway, thereby impeding the IL-8 expression from CAFs. Importantly, melatonin reversed CAFs-derived IL-8-mediated EMT by inhibiting the AKT pathway. Melatonin was found to directly and indirectly inhibit tumor progression.. Our research reveals the potential action mechanism of melatonin in regulating the CAF-tumor cell interaction and suggests the potential of melatonin as an adjuvant of tumor therapy.

Topics: Animals; Cancer-Associated Fibroblasts; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Fibroblasts; Interleukin-8; Melatonin; Neoplasms; Tumor Microenvironment

Epidemiological studies show that having a history of cancer protects from the development of Alzheimer's Disease (AD), and vice versa, AD protects from cancer. The mechanism of this mutual protection is unknown. We have reported that the peripheral blood mononuclear cells (PBMC) of amnestic cognitive impairment (aMCI) and Alzheimer's Disease (AD) patients have increased susceptibility to oxidative cell death compared to control subjects, and from the opposite standpoint a cancer history is associated with increased resistance to oxidative stress cell death in PBMCs, even in those subjects who have cancer history and aMCI (Ca + aMCI). Cellular senescence is a regulator of susceptibility to cell death and has been related to the pathophysiology of AD and cancer. Recently, we showed that cellular senescence markers can be tracked in PBMCs of aMCI patients, so we here investigated whether these senescence markers are dependent on having a history of cancer. Senescence-associated βeta-galactosidase (SA-β-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry; phosphorylated H2A histone family member X (γH2AX) by immunofluorescence; IL-6 and IL-8 mRNA by qPCR; and plasmatic levels by ELISA. Senescence markers that were elevated in PBMCs of aMCI patients, such as SA-β-Gal, Go-G1 arrested cells, IL-6 and IL-8 mRNA expression, and IL-8 plasmatic levels, were decreased in PBMCs of Ca + aMCI patients to levels similar to those of controls or of cancer survivors without cognitive impairment, suggesting that cancer in the past leaves a fingerprint that can be peripherally traceable in PBMC samples. These results support the hypothesis that the senescence process might be involved in the inverse association between cancer and AD.

Topics: Alzheimer Disease; Cognition; Cognitive Dysfunction; Humans; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Neoplasms; Neuropsychological Tests; RNA, Messenger

Tumor vascular normalization prevents tumor cells from breaking through the basement membrane and entering the vasculature, thereby inhibiting metastasis initiation. In this study, we report that the antitumor peptide JP1 regulated mitochondrial metabolic reprogramming through AMPK/FOXO3a/UQCRC2 signaling, which improved the tumor microenvironment hypoxia. The oxygen-rich tumor microenvironment inhibited the secretion of IL-8 by tumor cells, thereby promoting tumor vascular normalization. The normalized vasculature resulted in mature and regular blood vessels, which made the tumor microenvironment form a benign feedback loop consisting of vascular normalization, sufficient perfusion, and an oxygen-rich microenvironment, prevented tumor cells from entering the vasculature, and inhibited metastasis initiation. Moreover, the combined therapy of JP1 and paclitaxel maintained a certain vascular density in the tumor and promoted tumor vascular normalization, increasing the delivery of oxygen and drugs and enhancing the antitumor effect. Collectively, our work highlights the antitumor peptide JP1 as an inhibitor of metastasis initiation and its mechanism of action.

Topics: Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Oxygen; Paclitaxel; Tumor Microenvironment

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic landscape of cancer therapy. This study aimed to develop novel risk classifiers to predict the risk of immune-related adverse events (irAEs) and the probability of clinical benefits. Patients with cancer who received ICIs from the First Affiliated Hospital of Xi 'an Jiaotong University from November 2020 to October 2022 were recruited and followed up. Logistic regression analyses were performed to identify independent predictive factors for irAEs and clinical response. Two nomograms were developed to predict the irAEs and clinical responses of these individuals, with a receiver operating characteristic curve to assess their predictive ability. Decision curve analysis was performed to estimate the clinical utility of the nomogram. This study included 583 patients with cancer. Among them, 111 (19.0%) developed irAEs. Duration of treatment (DOT)>3 cycles, hepatic-metastases, IL2>2.225 pg/mL, and IL8>7.39 pg/mL were correlated with higher irAEs risk. A total of 347 patients were included in the final efficacy analysis, with an overall clinical benefit rate of 39.7%. DOT>3 cycles, nonhepatic-metastases, and irAEs and IL8>7.39 pg/mL were independent predictive factors of clinical benefit. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and their clinical benefits. Ultimately, 2 nomograms were successfully established to predict the probability of irAEs and clinical benefits. The receiver operating characteristic curves yielded acceptable nomogram performance. Calibration curves and decision curve analysis supported the hypothesis that nomograms could provide more significant net clinical benefits to these patients. Specific baseline plasma cytokines were closely correlated with irAEs and clinical responses in these individuals.

Topics: Cytokines; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Interleukin-8; Models, Statistical; Neoplasms; Prognosis; Retrospective Studies

High-intensity focused ultrasound (HIFU) represents an emerging noninvasive modality for tumor treatment. While biological responses and immunological change associated with incomplete ablation have not been thoroughly investigated. This study aims to evaluate the damage effect of HIFU incomplete ablation. The rabbit VX2 breast cancer model was established and received HIFU treatment with complete ablation (100% tumor volume) and incomplete ablation (about 80% tumor volume) under real-time B-ultrasound monitoring. Histopathological alterations, dynamics of tumor cell apoptosis and proliferation, expression levels of VEGF, MMP-9, IL-2R, TGF-β1, HSP-70, IL-6, IL-8, and INF-γ, and the presence of circulating tumor cells (CTCs) were evaluated post-HIFU incomplete ablation.. For HIFU 80% ablation group, there was an 85.85% reduction in tumor volume 21 days post-intervention. A marked increase in tumor cell apoptosis and a concomitant decrease in proliferation were observed. Notably, distant tumor metastasis rates, CTC counts, and expression levels of VEGF, MMP-9, IL-2R, TGF-β1, IL-6, and IL-8 were significantly reduced. In contrast, INF-γ and HSP-70 expressions were notably elevated, aligning with findings from the 100% ablation group.. HIFU incomplete ablation, with an 80% tumor ablation rate, induces substantial tumor damage, augments tumor cell apoptosis, and triggers an anti-tumor immune response, curtailing metastasis. These insights may underpin further investigations into the therapeutic implications of HIFU incomplete ablation.

Topics: Animals; HSP70 Heat-Shock Proteins; Interleukin-6; Interleukin-8; Matrix Metalloproteinase 9; Neoplasms; Prognosis; Rabbits; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Arsenic exposure is associated with lung cancer. Angiogenesis is essential for tumor development. However, the role and mechanism of human vascular endothelial cells in tumor growth and angiogenesis induced by arsenic-transformed bronchial epithelial (As-T) cells remain to be elucidated. In this study, we found that endothelial cells significantly increased As-T cell-induced tumor growth compared to those induced by As-T cells alone. To understand the molecular mechanism, we found that endothelial cells co-cultured with As-T cells or cultured in conditioned medium (CM) prepared from As-T cells showed much higher cell migration, proliferation, and tube formation compared to those co-cultured with BEAS-2B (B2B) cells or cultured in CM from B2B. We identified that higher levels of intracellular interleukin 8 (IL-8) were secreted by As-T cells, which activated IL-8/IL-8R signaling to promote endothelial cells migration and tube formation. IL-8 silencing and knockout (KO) in As-T cells, or IL-8 neutralizing antibody dramatically suppressed endothelial cell proliferation, migration, tube formation

Topics: Arsenic; Bronchi; Cell Movement; Cell Proliferation; Culture Media, Conditioned; Endothelial Cells; Epithelial Cells; Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Receptors, Interleukin-8A

Children who experience early life stress demonstrate changes to their stress responses, which may modulate long-term health. Childhood cancer presents significant stress during diagnosis, treatment, and survivorship. We hypothesized that children who have completed chemotherapy treatment for ALL will demonstrate altered hormone patterns in response to a stressor compared with healthy controls. Twelve pediatric ALL survivors and 12 healthy controls completed the Trier Social Stress Test. Salivary samples, heart rate, and self-report ratings of stress were collected at baseline, pretest, and posttest. Between group comparison showed baseline (interleukin [IL]-8) was significantly higher in the survivor group versus controls (survivors: 89.9, 40.1-544.9 pg ml

Topics: Cancer Survivors; Child; Humans; Hydrocortisone; Interleukin-8; Neoplasms; Saliva; Salivary alpha-Amylases; Stress, Physiological; Stress, Psychological; Survivors; Tumor Necrosis Factor-alpha

THP-1-differentiated macrophages are useful for investigating the physiological significance of tumor-associated macrophages (TAMs). In the tumor microenvironment (TME), TAMs with the M

Topics: Down-Regulation; Humans; Interleukin-10; Interleukin-8; Intermediate-Conductance Calcium-Activated Potassium Channels; Macrophages; Neoplasms; Tumor Microenvironment

(1) Phytic acid (PA) is a component of cereal seeds and legumes, therefore its consumption is much higher in a vegan and vegetarian diet compared to a conventional diet. The diet is the main driver of metabolic activity of gut microbiota, therefore, the ability to degrade phytates by the microbiota of vegans significantly exceeds that of the gut microbiota of omnivores. The aim of the study was to investigate the early phase of the immune response of colonocytes treated with an enzymatic hydrolysate of phytic acid (hPA120) and gut bacteria. (2) Cell lines derived from healthy (NCM460D) and cancer (HCT116) colonic tissue and fecal bacteria from vegan (V) and omnivorous (O) donors were investigated. Fecal bacteria were grown in mucin and phytic acid supplemented medium. Cultured bacteria (BM) were loaded onto colonocytes alone (V BM and O BM) or in combination with the phytate hydrolysate (V BM + hPA120 and O BM + hPA120). After a treatment of 2 h, bacterial adhesion, secretion of cytokines, and the expression of genes and proteins important for immune response were determined. (3) All bacteria-treated colonocytes increased the expression of IL8 compared to controls. The significant increase of the secreted IL-8 (p < 0.01) in both cell lines was observed for O BM and O BM + hPA120. The increase of TNF, IL-1β, and IL-10 secretion in healthy colonocytes (V BM alone and with hPA120 treatments; p < 0.05) and for TNF and IL-10 in cancer cells (treatments except O BM + hPA120 and V BM, respectively; p > 0.05) were stated. A comparison of solely the effect of hPA120 on bacteria-treated colonocytes (BM vs. BM + hPA120) showed that hPA120 decreased expression of NFkB1 and TNFR (p < 0.001) in healthy colonocytes. In cancer colonocytes, the expression of TLR4 and IL1R increased after BM + hPA120 treatment, whereas the secretion of IL-8 and MYD88 and TNFR expression decreased (p < 0.01). (4) The investigated hPA120 showed a differentiated modulatory activity on the immune response of healthy and cancer human colonocytes. Especially when analyzed independently on the gut bacteria origin, it reduced the proinflammatory response of HCT116 cells to gut bacteria, while being neutral for the bacteria-treated healthy colonocytes.

Topics: Bacteria; Cytokines; Humans; Immunity; Interleukin-10; Interleukin-8; Mucins; Myeloid Differentiation Factor 88; Neoplasms; Phytic Acid; Toll-Like Receptor 4

Patients with malignancy have higher risk of developing venous thromboembolism. The incidence among different groups of cancer patients varies considerably depending on clinical factors, the most important being tumor entity and stage. The study was approved by the local ethics committee on human research, and written informed consent was obtained from all the study participants. After written informed consent was obtained, a precise medical history was taken, with particular attention to questions about the presence of thrombotic risk factors at the onset of VTE. We retrospectively enrolled 50 patients with Venous Thromboembolism (DVT and PTE) having malignancy and 50 healthy controls from January 2020 to December 2020. DVT were diagnosed using peripheral vascular duplex ultrasonography while PTE was confirmed in all cases by computed tomography. Patients having treatment with anticoagulant therapy, recent surgery less than 8 days previously, refusal or inability to give informed consent, and inability for ascending contrast venography or inadequate results of the venographic examination were excluded from the study. Biomarkers have been specifically investigated for their capacity of predicting venous thromboembolism (VTE) during the course of disease. The relationships between inflammation markers e.g., IL-6, IL-8 and CRP as indicators of the inflammatory process and clinical venous thromboembolism need to be investigated. We investigated IL-6, IL-8 and CRP in 50 patients with venous thromboembolism having malignancy and reported that patients having venous thromboembolism have increased levels of IL-6, IL-8 and CRP (p value < 0.05). Our study concluded that in cancer patients, inflammatory biomarkers play significant role in developing venous thromboembolism. This supports the hypothesis that, markers of systemic inflammatory response are involved in development of thromboembolism in patients with malignancy.

Topics: Biomarkers; Humans; Incidence; Interleukin-6; Interleukin-8; Neoplasms; Pulmonary Embolism; Retrospective Studies; Risk Factors; Systemic Inflammatory Response Syndrome; Thrombosis; Venous Thromboembolism

Topics: Adolescent; Biomarkers; Child; Female; Fever; Humans; Infant; Inflammation; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Prospective Studies; Sepsis

Cancer immunotherapy is associated with several immune-related adverse events, but the relationship between immunotherapy and venous thromboembolism has not been thoroughly studied.. We conducted a retrospective cohort study of 1,686 patients who received immunotherapy for a variety of malignancies to determine the incidence of venous thromboembolism and the impact of venous thromboembolism on survival. To examine the potential role of inflammation in venous thromboembolism, we also profiled immune cells and plasma cytokines in blood samples obtained prior to initiation of immunotherapy in a sub-cohort of patients treated on clinical trials who subsequently did (N = 15), or did not (N = 10) develop venous thromboembolism.. Venous thromboembolism occurred while on immunotherapy in 404/1686 patients (24%) and was associated with decreased overall survival [HR=1.22 (95% CI 1.06-1.41), p<0.008]. Patients that developed venous thromboembolism had significantly higher pretreatment levels of myeloid-derived suppressor cells (5.382 ± 0.873 vs. 3.341 ± 0.3402, mean ± SEM; p=0.0045), interleukin 8 (221.2 ± 37.53 vs. 111.6 ± 25.36, mean ± SEM; p=0.016), and soluble vascular cell adhesion protein 1 (1210 ± 120.6 vs. 895.5 ± 53.34, mean ± SEM; p=0.0385).. These findings demonstrate that venous thromboembolism is an underappreciated and important immune-related adverse event associated with cancer immunotherapy, and may implicate an interleukin 8 and myeloid-derived suppressor cell-driven pathway in pathogenesis.

Topics: Humans; Immunotherapy; Incidence; Interleukin-8; Neoplasms; Retrospective Studies; Venous Thromboembolism

Topics: Capsaicin; Cell Line; Cyclodextrins; Interleukin-8; Liposomes; Neoplasms; Polyethylene Glycols; Solubility

Neutrophil extracellular traps (NETs) are webs of extracellular nuclear DNA extruded by dying neutrophils infiltrating tissue. NETs constitute a defence mechanism to entrap and kill fungi and bacteria. Tumours induce the formation of NETs to the advantage of the malignancy via a variety of mechanisms shown in mouse models. Here, we investigated the presence of NETs in a variety of human solid tumours and their association with IL-8 (CXCL8) protein expression and CD8

Topics: CD8-Positive T-Lymphocytes; Extracellular Traps; Humans; Interleukin-8; Lymphocytes, Tumor-Infiltrating; Neoplasms; Tumor Microenvironment

The bile acid component of gastric refluxate has been implicated in inflammation of the oesophagus including conditions such as gastro-oesophageal reflux disease (GORD) and Barrett's Oesophagus (BO). Here we demonstrate that the hydrophobic bile acid, deoxycholic acid (DCA), stimulated the production of IL-6 and IL-8 mRNA and protein in Het-1A, a model of normal oesophageal cells. DCA-induced production of IL-6 and IL-8 was attenuated by pharmacologic inhibition of the Protein Kinase C (PKC), MAP kinase, tyrosine kinase pathways, by the cholesterol sequestering agent, methyl-beta-cyclodextrin (MCD) and by the hydrophilic bile acid, ursodeoxycholic acid (UDCA). The cholesterol-interacting agent, nystatin, which binds cholesterol without removing it from the membrane, synergized with DCA to induce IL-6 and IL-8. This was inhibited by the tyrosine kinase inhibitor genistein. DCA stimulated the phosphorylation of lipid raft component Src tyrosine kinase (Src). while knockdown of caveolin-1 expression using siRNA resulted in a decreased level of IL-8 production in response to DCA. Taken together, these results demonstrate that DCA stimulates IL-6 and IL-8 production in oesophageal cells via lipid raft-associated signaling. Inhibition of this process using cyclodextrins represents a novel therapeutic approach to the treatment of inflammatory diseases of the oesophagus including GORD and BO.

Topics: Barrett Esophagus; beta-Cyclodextrins; Bile Acids and Salts; Caveolin 1; Cell Line, Tumor; Cholesterol; Cytokines; Deoxycholic Acid; Esophagus; Gastroesophageal Reflux; Gene Expression; Humans; Inflammation; Interleukin-6; Interleukin-8; Lipids; Membrane Microdomains; Neoplasms; NF-kappa B; Phosphorylation; Signal Transduction; src-Family Kinases

Tumors and neutrophils undergo an unexpected interaction, in which products released by tumor cells interact to support neutrophils that in turn support cancer growth, angiogenesis, and metastasis. A key protein that is highly expressed by cancer cells in tumors is the a2 isoform V-ATPase (a2V). A peptide from a2V (a2NTD) is secreted specifically by cancer cells, but not normal cells, into the tumor microenvironment. This peptide reprograms neutrophils to promote angiogenesis, cancer cell invasiveness, and neutrophil recruitment. Here, we provide evidence that cancer-associated a2V regulates the life span of protumorigenic neutrophils by influencing the intrinsic pathway of apoptosis. Immunohistochemical analysis of human cancer tissue sections collected from four different organs shows that levels of a2NTD and neutrophil counts are increased in cancer compared with normal tissues. Significant increases in neutrophil counts were present in both poorly and moderately differentiated tumors. In addition, there is a positive correlation between the number of neutrophils and a2NTD expression. Human neutrophils treated with recombinant a2NTD show significantly delayed apoptosis, and such prolonged survival was dependent on NF-κB activation and ROS generation. Induction of antiapoptotic protein expression (Bcl-xL and Bcl-2A1) and decreased expression of proapoptotic proteins (Bax, Apaf-1, caspase-3, caspase-6, and caspase-7) were a hallmark of these treated neutrophils. Autocrine secretion of prosurvival cytokines of TNF-α and IL-8 by treated neutrophils prolongs their survival. Our findings highlight the important role of cancer-associated a2V in regulating protumorigenic innate immunity, identifying a2V as a potential important target for cancer therapy.

Topics: Adenosine Triphosphatases; Apoptosis; Apoptosis Regulatory Proteins; Cell Line, Tumor; Endometrial Neoplasms; Female; Gene Expression; Humans; Immunohistochemistry; Interleukin-8; Kidney Neoplasms; Lung Neoplasms; Mitochondria; Neoplasms; Neutrophils; NF-kappa B; Reactive Oxygen Species; Recombinant Proteins; Signal Transduction; Toll-Like Receptor 2; Tumor Microenvironment; Tumor Necrosis Factor-alpha; Urinary Bladder Neoplasms

Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4, which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.

Topics: Activating Transcription Factor 4; Antimetabolites; Cell Death; Deoxyglucose; Epithelial Cells; Gene Expression Regulation; Glucose; Glutamine; HeLa Cells; Humans; Inflammation; Interleukin-6; Interleukin-8; Macrophages; Metformin; Neoplasms; NF-kappa B; Promoter Regions, Genetic; Starvation; Stress, Physiological

Topics: Humans; Immunologic Factors; Immunotherapy; Interleukin-8; Neoplasms; Neutrophils

Serum interleukin-8 (IL-8) levels and tumor neutrophil infiltration are associated with worse prognosis in advanced cancers. Here, using a large-scale retrospective analysis, we show that elevated baseline serum IL-8 levels are associated with poor outcome in patients (n = 1,344) with advanced cancers treated with nivolumab and/or ipilimumab, everolimus or docetaxel in phase 3 clinical trials, revealing the importance of assessing serum IL-8 levels in identifying unfavorable tumor immunobiology and as an independent biomarker in patients receiving immune-checkpoint inhibitors.

Topics: Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Biomarkers, Pharmacological; Biomarkers, Tumor; Cell Cycle Checkpoints; Cohort Studies; Female; Humans; Interleukin-8; Male; Neoplasms; Neutrophil Infiltration; Neutrophils; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Analysis; Treatment Failure; Tumor Microenvironment; Up-Regulation

Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade

Topics: Adult; Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; B7-H1 Antigen; Biomarkers, Pharmacological; Biomarkers, Tumor; Carcinoma, Renal Cell; Carcinoma, Transitional Cell; Drug Resistance, Neoplasm; Female; Humans; Interleukin-8; Kidney Neoplasms; Male; Neoplasms; Prognosis; Survival Analysis; Treatment Failure; Urologic Neoplasms

The aim was to investigate the systemic levels of cytokines and the expression of the chemokine receptor CXCR2 in circulating neutrophils in patients with non-neoplastic ovarian lesions, benign neoplasia or malignant neoplasia.. Controls and patients with ovarian tumours were pre-operatively compared for the production of cytokines (IL-2, IL-5, IL-6, IL-8, IL-10 and TNF-α) by ELISA, and for the expression of the chemokine receptor, CXCR2, in neutrophils, by flow cytometry. Randomly selected patients within the malignant group were re-evaluated for the inflammatory parameters at 30 days after surgery.. The serum concentrations of IL-6, IL-8 and IL-10 were significantly higher in the benign and malignant neoplasia than in the control group, and their levels were significantly higher in ovarian cancer patients than in patients with non-neoplastic tumours or benign neoplasia. Treatment reduced IL-8 serum levels but did not affect CXCR2 expression in neutrophils. Cut-off values for IL-6, IL-8, and IL-10 comparing malignant vs. benign neoplasia were 11.3, 71.7, 14.8, and comparing malignant neoplasm vs. non-neoplastic lesions were 7.2, 43.5, 12.3, respectively.. Serum IL-6, IL-8, and IL-10 levels, and expression of CXCR2 in circulating neutrophils seem promising for distinguishing ovarian cancer patients from patients with benign tumours.

Topics: Adult; Aged; Biomarkers, Tumor; Cytokines; Female; Gene Expression Regulation, Neoplastic; Humans; Interleukin-10; Interleukin-2; Interleukin-5; Interleukin-6; Interleukin-8; Middle Aged; Neoplasms; Ovarian Neoplasms; Receptors, Interleukin-8B; Tumor Necrosis Factor-alpha

Studies have shown a relationship between endometriosis and ovarian cancer. Our aims were to evaluate and compare the dosages of cytokines IL-2, IL-5, IL-6, IL-8, IL-10, and TNF-α in serum, intracystic fluid, and peritoneal fluid of patients with ovarian endometrioma, malignant and benign ovarian neoplasms, and non-neoplastic ovarian tumors; to verify if there is a correlation between the values of these cytokines between ovarian endometrioma and ovarian malignancy; and to determine the best cut-off point for serum cytokines that can be used to differentiate patients with ovarian malignancy and endometrioma.. The concentrations of cytokines were quantified by enzyme-linked immunosorbent assay (ELISA), analyzed by Kruskal-Wallis test with the Dunn post-test. Receiver operating feature (ROC) curve was used to obtain the area under the curve (AUC) and to determine the best cut-off values that could be used in the diagnosis of ovarian malignancy. Correlations of cytokine concentrations were performed by the Spearman test.. IL-6, IL-8, and IL-10 concentrations were higher in patients with malignant neoplasia. When evaluating the area under the curve (AUC) of serum cytokine levels comparing patients with malignant neoplasia and endometriomas, there was statistical significance for IL-6, IL-8, and IL-10.. Our results showed utility in serum concentrations of IL-6, IL-10, and IL-8 as parameters that differentiate endometriomas from ovarian malignancies.

Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Child; Diagnosis, Differential; Endometriosis; Female; Humans; Interleukin-10; Interleukin-6; Interleukin-8; Middle Aged; Neoplasms; Ovarian Neoplasms; ROC Curve; Young Adult

This investigation evaluates the pro-apoptotic and anti-inflammatory effects of β-D-mannuronic acid [M2000] compared to diclofenac, based on gene expression involved in apoptosis and inflammation process [including Bcl2, NFκB, IL-8 and Cd49d] in Peripheral Blood Mononuclear Cells [PBMCs] of healthy donors under exvivo conditions.. The venous blood samples of twelve healthy volunteers with aged 25-60 years were collected in heparinized tubes. The healthy volunteers were selected from no smoking group and without using illicit drugs and suffering from diabetes. The PBMCs were separated and divided into untreated and treated groups.. The PBMCs of each sample were cultured in 5 wells of culture plate, so that the first well consisted of 2×106 cells exposed by LPS-EB [1μg/ml] to stimulate PBMCs and absence of M2000 [untreated well]. The second, third, fourth and fifth wells containing 2×106 cells/well and LPS-EB, after 4 hours incubation at 37ºC, received 5, 25 and 50 μg/well of M2000 and 5 μg/well of diclofenac, respectively as treated group.. The PBMCs were separated and RNAs were then extracted and cDNAs synthesized and gene expression levels were assessed by qRT-PCR. Furthermore, we studied whether M2000 is able to facilitate apoptosis in PBMCs. Our findings represent that the high dose of M2000 could significantly decrease the expression level of NFκB gene compared to untreated group (p < 0.0002). On the other hand, no significant change was observed in treated cells with diclofenac. All doses of M2000 could significantly augment apoptosis compared to untreated group [p < 0.0001]. Additionally, we observed the same apoptotic effects between the medium dose of M2000 and diclofenac. Besides, no significant reduction was shown in expression levels of IL8, Bcl2 and Cd49d genes in all doses of M2000 and diclofenac compared to untreated group. This experiment demonstrates M2000 as a new effective NSAID with immunosuppressive characteristics capable of stimulating apoptosis through lowering expression levels of NFκB gene, which might be probably considered as an appropriate drug for reducing the risk of developing inflammatory diseases and cancer.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Diclofenac; Gene Expression Profiling; Gene Expression Regulation; Healthy Volunteers; Hexuronic Acids; Humans; Immunosuppressive Agents; Inflammation; Integrin alpha4; Interleukin-8; Leukocytes, Mononuclear; Middle Aged; Neoplasms; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Young Adult

Interleukin-8 (IL-8) and heat shock protein 60 (Hsp60) play crucial roles in cell survival and maintenance of cellular homoeostasis. However, cross talks between these two proteins are not defined.. IL-8 expression in tumour tissue sections was analysed by immunohistochemistry. IL-8 expression and release in cancer cells was quantified using enzyme-linked immunosorbent assay (ELISA). Apoptosis was quantified using caspase activity and Annexin-V/PI staining.. We observed IL-8 release from cancer cells in response to histone deacetylase inhibitor, apicidin (Api), and non-competitive inhibitor of the sarco/endoplasmic reticulum Ca. This study describes the underlying mechanism associated with apoptosis resistance mediated via Hsp60-IL-8 axis in cancer.

Topics: Animals; Apoptosis; Caspase 8; Caspase 9; Chaperonin 60; Gene Knockdown Techniques; HCT116 Cells; Heterografts; Humans; Interleukin-8; Male; Mice; Mice, SCID; Mitochondrial Proteins; Neoplasms; PC-3 Cells; Peptides, Cyclic; Signal Transduction; Thapsigargin

Tumor cell repopulation after radiotherapy is a major cause for the tumor radioresistance and recurrence. This study aims to investigate the underlying mechanism of tumor repopulation after radiotherapy, with focus on whether and how necroptosis takes part in this process.. Necroptosis after irradiation were examined in vitro and in vivo. And the growth-promoting effect of necroptotic cells was investigated by chemical inhibitors or shRNA against necroptosis associated proteins and genes in in vitro and in vivo tumor repopulation models. Downstream relevance factors of necroptosis were identified by western blot and chemiluminescent immunoassays. Finally, the immunohistochemistry staining of identified necroptosis association growth stimulation factor was conducted in human colorectal tumor specimens to verify the relationship with clinical outcome.. Radiation-induced necroptosis depended on activation of RIP1/RIP3/MLKL pathway, and the evidence in vitro and in vivo demonstrated that the inhibition of necroptosis attenuated growth-stimulating effects of irradiated tumor cells on living tumor reporter cells. The JNK/IL-8 were identified as downstream molecules of pMLKL during necroptosis, and inhibition of JNK, IL-8 or IL-8 receptor significantly reduced tumor repopulation after radiotherapy. Moreover, the high expression of IL-8 was associated with poor clinical prognosis in colorectal cancer patients.. Necroptosis associated tumor repopulation after radiotherapy depended on activation of RIP1/RIP3/MLKL/JNK/IL-8 pathway. This novel pathway provided new insight into understanding the mechanism of tumor radioresistance and repopulation, and MLKL/JNK/IL-8 could be developed as promising targets for blocking tumor repopulation to enhance the efficacy of colorectal cancer radiotherapy.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Humans; Immunohistochemistry; Interleukin-8; Luminescent Measurements; Mice; Molecular Imaging; Necroptosis; Neoplasms; Nuclear Pore Complex Proteins; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases; RNA-Binding Proteins; Signal Transduction

A new synergistic treatment that combines photothermal therapy (PTT) and inflammation-mediated active targeting (IMAT) chemotherapy based on cytopharmaceuticals is developed. During PTT, the photothermal tumor ablation is accompanied by an inflammatory effect and upregulation of inflammatory factors at the tumor site, which may accelerate tumor regeneration. Moreover, PTT-induced inflammation can also recruit neutrophils (NEs) to the tumor site. To convert the disadvantages of PTT-induced inflammation into strengths, NEs are investigated as cytopharmaceuticals for IMAT chemotherapy to further inhibit the tumor recurrence after PTT due to the chemotaxis of NEs to the inflammatory sites. In this study, PEGylated gold nanorods (PEG-GNRs) are explored as the photothermal agent and paclitaxel-loaded cytopharmaceuticals of NEs as the IMAT chemotherapeutic agent. PTT is conducted at 72 h postinjection of PEG-GNRs, followed by cytopharmaceuticals for IMAT chemotherapy. It is demonstrated that the cytopharmaceuticals effectively accumulate in the tumor sites after PTT, which leads to a significant enhancement of antitumor efficacy and a reduction in systemic toxicity. These studies suggest that PTT-induced inflammation further enhances the chemotherapy of cytopharmaceuticals, and the combination of PTT and IMAT chemotherapy may be a promising synergistic strategy for targeted cancer therapy.

Topics: Animals; Cell Line, Tumor; Combined Modality Therapy; Gold; Humans; Hyperthermia, Induced; Infrared Rays; Interleukin-8; Liver; Mice; Nanotubes; Neoplasms; Neutrophils; Optical Imaging; Paclitaxel; Phototherapy; Polyethylene Glycols; Tumor Necrosis Factor-alpha

Topics: Allergy and Immunology; Animals; Carcinogenesis; History, 20th Century; History, 21st Century; Humans; Immune System Diseases; Interleukin-1; Interleukin-8; Leukocyte Disorders; Neoplasms; Signal Transduction; Tumor Necrosis Factor-alpha

Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3' splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.

Topics: Cell Line, Tumor; Cytoplasm; Disease Progression; Gene Expression Regulation, Neoplastic; HEK293 Cells; Humans; Interleukin-8; MCF-7 Cells; Mutation; Neoplasms; Protein Binding; RNA, Messenger; Splicing Factor U2AF

Due to their ability to preferentially induce cell death in tumor cells, while sparing healthy cells, TNF-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL-R1 or anti-TRAIL-R2-specific antibodies are under clinical investigations for cancer-treatment. However, TRAIL-Rs may also induce signaling pathways, which result in malignant progression. TRAIL receptors are transcriptionally upregulated via wild-type p53 following radio- or chemotherapy. Nevertheless, the impact of p53 status on the expression and signaling of TRAIL-Rs is not fully understood. Therefore, we analyzed side by side apoptotic and non-apoptotic signaling induced by TRAIL or the agonistic TRAIL-R-specific antibodies Mapatumumab (anti-TRAIL-R1) and Lexatumumab (anti-TRAIL-R2) in the two isogenic colon carcinoma cell lines HCT116 p53+/+ and p53-/-. We found that HCT116 p53+/+ cells were significantly more sensitive to TRAIL-R-triggering than p53-/- cells. Similarly, A549 lung cancer cells expressing wild-type p53 were more sensitive to TRAIL-R-mediated cell death than their derivatives with knockdown of p53. Our data demonstrate that the contribution of p53 in regulating TRAIL-R-induced apoptosis does not correlate to the levels of TRAIL-Rs at the plasma membrane, but rather to p53-mediated upregulation of Bax, favouring the mitochondrial amplification loop. Consistently, stronger caspase-9 and caspase-3 activation as well as PARP-cleavage was observed following TRAIL-R-triggering in HCT116 p53+/+ compared to HCT116 p53-/- cells. Interestingly, HCT116 p53+/+ cells showed also a more potent activation of non-canonical TRAIL-R-induced signal transduction pathways like JNK, p38 and ERK1/ERK2 than p53-/- cells. Likewise, these cells induced IL-8 expression in response to TRAIL, Mapatumumab or Lexatumumab significantly stronger than p53-/- cells. We obtained similar results in A549 cells with or without p53-knockdown and in the two isogenic colon cancer cell lines RKO p53+/+ and p53-/-. In both cellular systems, we could clearly demonstrate the potentiating effects of p53 on TRAIL-R-mediated IL-8 induction. In conclusion, we found that wild-type p53 increases TRAIL-R-mediated apoptosis but simultaneously augments non-apoptotic signaling.

Topics: A549 Cells; Apoptosis; bcl-2-Associated X Protein; Cell Membrane; Gene Knockdown Techniques; Genes, p53; HCT116 Cells; Humans; Interleukin-8; Neoplasms; Receptor Activator of Nuclear Factor-kappa B; Receptors, TNF-Related Apoptosis-Inducing Ligand; Signal Transduction; TNF-Related Apoptosis-Inducing Ligand; Tumor Suppressor Protein p53

BACKGROUND Senescence is a natural barrier for the body to resist the malignant transformation of its own cells. This work investigated the senescence characteristics of cancer cells in vitro. MATERIAL AND METHODS Human cervical cancer HeLa cells were treated with different concentrations of doxorubicin for 3 days, with or without subsequent extended culture in drug-free medium for 6 days. Senescent cell ratios between these 2 culture schemes were calculated. Expression of 2 senescence-associated secretory factors, IL-6 and IL-8, were detected by RT-PCR and ELISA. Doxorubicin treatment induced epithelial-mesenchymal transition in cancer cells. The proportions of senescent cells in epithelial-like and mesenchymal-like sub-groups were calculated. Doxorubicin-treated HeLa cells were stained with Vimentin antibody and sorted by flow cytometry. Senescent cell marker p16ᴵᴺᴷ⁴ᵃ and IL-8 expression in Vimentin-high and Vimentin-low cells were detected by Western blot. RESULTS We found that less than 1% of HeLa cells showed senescence phenotype after treatment with doxorubicin for 3 days. However, the proportion of senescent cells was significantly increased when the doxorubicin-treated cells were subsequently cultured in drug-free medium for another 6d. RT-PCR and ELISA results showed that this prolonged culture method could further improve the expression of IL-6 and IL-8. We also found that the senescent cells were mainly epithelial-like type and few presented mesenchymal-like shape. p16ᴵᴺᴷ⁴ᵃ and IL-8 expression were decreased in cell fraction with higher Vimentin expression. CONCLUSIONS Our results suggested the existence of time delay effect in doxorubicin-induced senescence of HeLa cells, and epithelial- mesenchymal transition may resist doxorubicin-induced cell senescence.

Topics: Cell Line, Tumor; Cell Transformation, Neoplastic; Cellular Senescence; Doxorubicin; Epithelial-Mesenchymal Transition; HeLa Cells; Humans; Interleukin-6; Interleukin-8; Neoplasms; Time Factors; Vimentin

CagL is an essential pilus surface component of the virulence-associated type IV secretion system (T4SS) employed by Helicobacter pylori to translocate the oncogenic effector protein CagA into human gastric epithelial cells. CagL contains an RGD motif and integrin α

Topics: Antigens, Bacterial; Antigens, Neoplasm; Bacterial Proteins; Helicobacter Infections; Helicobacter pylori; Host-Pathogen Interactions; Humans; Integrins; Interleukin-8; Neoplasms; Oligopeptides; Protein Binding; Protein Transport; Tumor Cells, Cultured; Type IV Secretion Systems

Citrullinated histone H3 (H3Cit) is a central player in the neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs). NETs have been shown to elicit harmful effects on the host, and were recently proposed to promote tumor progression and spread. Here we report significant elevations of plasma H3Cit in patients with advanced cancer compared with age-matched healthy individuals. These elevations were specific to cancer patients as no increase was observed in severely ill and hospitalized patients with a higher non-malignant comorbidity. The analysis of neutrophils from cancer patients showed a higher proportion of neutrophils positive for intracellular H3Cit compared to severely ill patients. Moreover, the presence of plasma H3Cit in cancer patients strongly correlated with neutrophil activation markers neutrophil elastase (NE) and myeloperoxidase (MPO), and the inflammatory cytokines interleukin-6 and -8, known to induce NETosis. In addition, we show that high levels of circulating H3Cit strongly predicted poor clinical outcome in our cohort of cancer patients with a 2-fold increased risk for short-term mortality. Our results also corroborate the association of NE, interleukin-6 and -8 with poor clinical outcome. Taken together, our results are the first to unveil H3Cit as a potential diagnostic and prognostic blood marker associated with an exacerbated inflammatory response in patients with advanced cancer.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Case-Control Studies; Citrullination; Extracellular Traps; Female; Histones; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Neoplasms; Neutrophil Activation; Neutrophils; Prognosis

Acellular tumor extracellular matrices (ECMs) have limitations when employed as three-dimensional (3D) scaffolds for tumor engineering. In this work, methylene blue-mediated photooxidation was used to crosslink acellular tumor ECMs. Photooxidative crosslinking greatly increased the stiffness of acellular tumor ECM scaffolds but barely altered the Amide III band of the secondary structure of polypeptides and proteins. MCF-7, HepG2 and A549 cells cultured on photooxidatively crosslinked acellular tumor ECM scaffolds exhibited greater cell number per scaffold, more IL-8 and VEGF secretion, and increase migration and invasion abilities than cells cultured on uncrosslinked acellular tumor ECM scaffolds. The three tumor cell lines cultured on the stiffer photooxidatively crosslinked acellular matrices acquire mesenchymal properties (mesenchymal shift) and dedifferentiated phenotypes. Furthermore, the malignant phenotypes induced in vitro when cultured on the crosslinked scaffold promoted the in vivo tumor growth of BALB/c nude mice. Finally, the dedifferentiated cancer cells, including MCF-7, HepG2 and A549 cells, were less sensitive to chemotherapeutics. Thus, photooxidatively crosslinked acellular tumor ECMs have potentials as 3D tumor engineering scaffolds for cancer research.. Natural material scaffolds have been successfully used as 3D matrices to study the in vitro tumor cell growth and mimic the in vivo tumor microenvironment. Acellular tumor ECMs are developed as 3D scaffolds for tumor engineering but have limitations in terms of elastic modulus and cell spheroid formation. Here we use methylene blue-mediated photooxidation to crosslink acellular tumor ECMs and investigate the influence of photooxidative crosslinking on structural, mechanical and biological characteristics of acellular tumor ECM scaffolds. It is the first study to evaluate the feasibility of photooxidatively crosslinked acellular tumor ECMs as 3D scaffolds for cancer research and the results are encouraging. Moreover, this study provides new research areas in regard to photodynamic therapy (PDT) for Cancer.

Topics: A549 Cells; Animals; Extracellular Matrix; Hep G2 Cells; Heterografts; Humans; Interleukin-8; MCF-7 Cells; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins; Neoplasm Transplantation; Neoplasms; Oxidants, Photochemical; Tissue Engineering; Tissue Scaffolds; Vascular Endothelial Growth Factor A

Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate-limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP-induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling.

Topics: Cell Line, Tumor; Dihydrotestosterone; Gene Knockout Techniques; Glucosephosphate Dehydrogenase; Humans; Interleukin-8; Metabolism; NADPH Oxidases; Neoplasms; Pentose Phosphate Pathway; Reactive Oxygen Species; RNA, Small Interfering; Thymidine; Thymidine Phosphorylase

Systemic inflammation occurring around the course of tumor progression and treatment are often correlated with adverse oncological outcomes. As such, it is suspected that neutrophils, the first line of defense against infection, may play important roles in linking inflammation and metastatic seeding. To decipher the dynamic roles of inflamed neutrophils during hematogenous dissemination, we employ a multiplexed microfluidic model of the human microvasculature enabling physiologically relevant transport of circulating cells combined with real-time, high spatial resolution observation of heterotypic cell-cell interactions. LPS-stimulated neutrophils (PMNs) and tumor cells (TCs) form heterotypic aggregates under flow, and arrest due to both mechanical trapping and neutrophil-endothelial adhesions. Surprisingly, PMNs are not static following aggregation, but exhibit a confined migration pattern near TC-PMN clusters. We discover that PMNs are chemotactically confined by self-secreted IL-8 and tumor-derived CXCL-1, which are immobilized by the endothelial glycocalyx. This results in significant neutrophil sequestration with arrested tumor cells, leading to the spatial localization of neutrophil-derived IL-8, which also contributes to increasing the extravasation potential of adjacent tumor cells through modulation of the endothelial barrier. Strikingly similar migration patterns and extravasation behaviors were also observed in an in vivo zebrafish model upon PMN-tumor cell coinjection into the embryo vasculature. These insights into the temporal dynamics of intravascular tumor-PMN interactions elucidate the mechanisms through which inflamed neutrophils can exert proextravasation effects at the distant metastatic site.

Topics: Animals; Animals, Genetically Modified; Cell Line, Tumor; Chemokine CXCL1; Chemotaxis; Humans; Interleukin-8; Lipopolysaccharides; Microfluidic Analytical Techniques; Neoplasm Proteins; Neoplasms; Neutrophils; Zebrafish

Classic ataxia telangiectasia (A-T) is an autosomal recessive disease characterized by early onset ataxia, immune deficiency, sino-pulmonary disease, lymphoid/solid malignancies and telangiectasias. Prior studies have suggested that chronic inflammation and premature aging may contribute to the development of malignancy and pulmonary disease in people with A-T. To further examine the link between A-T and inflammation, we hypothesized that subjects with classic A-T would have greater enrichment of inflammatory pathways in peripheral blood mononuclear cells (PBMCs) compared to non A-T age-matched controls. To test this hypothesis we used RNAseq as an unsupervised approach to identify biological processes altered in people with classic A-T.. PBMCs were isolated from subjects with classic A-T and compared to non-A-T age-matched healthy controls. RNAseq with differential gene expression analyses was then performed. Selected genes were validated by RT-qPCR using cohorts of subjects consisting of classic A-T, mild A-T or non-A-T controls. Subjects with mild A-T were characterized by later onset/mild neurologic features and normal/near normal immune status.. RNAseq revealed 310 differentially expressed genes (DEGs) including genes involved in inflammation, immune regulation, and cancer. Using gene set enrichment analysis, A-T subjects were found to have biological processes enriched for inflammatory and malignancy pathways. In examining a cohort of A-T subjects in which baseline serum IL8 and IL6 levels were measured previously, an association was found between higher serum IL8 levels and higher likelihood of developing malignancy and/or death in a subsequent 4-6 year period.. RNAseq using PBMCs from subjects with classic A-T uncovered differential expression of immune response genes and biological processes associated with inflammation, immune regulation, and cancer. Follow-up of A-T subjects over a 4-6 year period revealed an association between higher baseline serum IL8 levels and malignancy/death. These findings support a role for inflammation as a contributing factor in A-T phenotypes.

Topics: Adolescent; Adult; Ataxia Telangiectasia; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Gene Expression Profiling; Gene Expression Regulation; Healthy Volunteers; Humans; Inflammation; Interleukin-8; Leukocytes, Mononuclear; Male; Neoplasms; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, RNA; Young Adult

Carcinomas develop in complex environments that include a diverse spectrum of cell types that influence tumor cell behavior. These microenvironments represent dynamic systems that contribute to pathologic processes. Damage to DNA is a notable inducer of both transient and permanent alterations in cellular phenotypes. Induction of a DNA damage secretory program is known to promote adverse tumor cell behaviors such as proliferation, invasion, metastasis, and treatment resistance. However, prior studies designed to identify genotoxic stress-induced factors evaluated actively proliferating

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; DNA Damage; Fibroblasts; Humans; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 3; Mitoxantrone; Neoplasms; Prostate; Signal Transduction; Tumor Microenvironment

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Cells, Cultured; Cytotoxicity, Immunologic; Drug Synergism; Humans; Immunization; Immunotherapy, Adoptive; Interferon-gamma; Interleukin-12; Interleukin-18; Interleukin-8; Killer Cells, Natural; Neoplasms; Tumor Necrosis Factor-alpha

Immunoparalysis was observed in both patients with cancer and sepsis. In cancer patients, Cytotoxic T lymphocyte antigen-4 and programmed cell death protein 1/programmed death-ligand 1 axis are two key components of immunoparalysis. Several emerging therapies against these two axes gained significant clinical benefit. In severe sepsis patients, immunoparalysis was known as compensatory anti-inflammatory response syndrome and this has been suggested as an important cause of death in patients with sepsis. It would be interesting to see if immune status was different in severe sepsis patients with or without active cancer. The aim of this study was to assess the differences in immune profiles, and clinical outcomes between severe sepsis patients with or without cancer admitted to ICU.. A combined retrospective and prospective observational study from a cohort of adult sepsis patients admitted to three medical ICUs at Kaohsiung Chang Gung Memorial Hospital in Taiwan between August 2013 and June 2016.. Of the 2744 patients admitted to the ICU, 532 patients with sepsis were included. Patients were divided into those with or without active cancer according to their medical history. Of the 532 patients, 95 (17.9%) patients had active cancer, and 437 (82.1%) patients had no active cancer history. Patients with active cancer were younger (p = 0.001) and were less likely to have diabetes mellitus (p < 0.001), hypertension (p < 0.001), coronary artery disease (p = 0.004), chronic obstructive pulmonary disease (p = 0.002) or stroke (p = 0.002) compared to patients without active cancer. Patients with active cancer also exhibited higher baseline lactate levels (p = 0.038), and higher baseline plasma interleukin (IL)-10 levels (p = 0.040), higher trend of granulocyte colony-stimulating factor (G-CSF) (p = 0.004) compared to patients without active cancer. The 14-day, 28-day and 90-day mortality rates were higher for patients with active cancer than those without active cancer (P < 0.001 for all intervals).. Among patients admitted to the ICU with sepsis, those with underling active cancer had higher baseline levels of plasma IL-10, higher trend of G-CSF and higher mortality rate than those without active cancer.

Topics: Aged; Female; Hospitalization; Humans; Intensive Care Units; Interleukin-10; Interleukin-8; Male; Middle Aged; Neoplasms; Prognosis; ROC Curve; Sepsis; Treatment Outcome

Human chorionic gonadotropin (hCG), a hormone essential for pregnancy, is also ectopically expressed by a variety of cancers and is associated with poor prognosis; molecular mechanisms which may contribute to tumor progression remain ill-defined. Exogenous hCG enhanced the viability of human colorectal and lung cancer cells and promoted the growth of syngeneic tumors in mice. It induced the synthesis of VEGF, IL-8, matrix metalloprotease (MMP)-2 and MMP-9, and increased invasiveness in an MMP-dependent manner. While inducing the secretion of the tumor-associated extra-cellular matrix proteoglycan versican from tumor cells, hCG consequently caused the TLR-2-mediated generation of the inflammatory, tumor-associated cytokines TNF-α and IL-6 from peripheral blood adherent cells. The molecule up-modulated the Treg-associated transcription factor FOXP3 in tumor cells and increased the secretion of TGFβ and IL-10, thereby inhibiting T cell proliferation and inducing the differentiation FOXP3

Topics: Animals; Antibodies; Cancer Vaccines; Carcinogenesis; Cell Line, Tumor; Chorionic Gonadotropin; Cytokines; Female; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Inflammation Mediators; Interleukin-8; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice, Inbred C57BL; Mice, Nude; Neoplasm Invasiveness; Neoplasms; Tumor Necrosis Factor-alpha; Versicans

mTOR inhibitor treatment of solid cancers is associated with mTOR inhibitor-associated stomatitis (mIAS) a common, significant, dose-limiting toxicity, with aphthous-like lesions. Our objective was to assess the utility of a new organotypic model in defining mIAS' pathogenesis.. The effect of everolimus on organotypic human oral mucosa was studied. Sterile specimens were assessed 24 and 48 h after exposure to varying concentrations of everolimus. Morphologic changes and measures of apoptosis, proliferation, and levels of six Th1 and Th2 cytokines were studied.. Following a 24-h incubation, concentrations of 500 ng ml. Everolimus elicited epithelial damage manifest by morphologic changes, increased apoptosis, and decreased proliferation with concurrent release of keratinocyte-derived pro-inflammatory cytokines in the absence of bacteria. The extent of the effect was concentration and time dependent. These results suggest that mIAS is likely initiated by direct epithelial injury, independent of the microbiome. Keratinocyte cytokine release could likely play a role in accelerating an inflammatory infiltrate.

Topics: Antineoplastic Agents; Apoptosis; Cell Proliferation; Dose-Response Relationship, Drug; Everolimus; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Models, Biological; Mouth Mucosa; Neoplasms; Stomatitis; Tissue Culture Techniques; TOR Serine-Threonine Kinases

Peroxisome proliferator-activated receptor-δ (PPARD) is upregulated in many major human cancers, but the role that its expression in cancer cells has in metastasis remains poorly understood. Here, we show that specific PPARD downregulation or genetic deletion of PPARD in cancer cells significantly repressed metastasis in various cancer models in vivo. Mechanistically, PPARD promoted angiogenesis via interleukin 8 in vivo and in vitro. Analysis of transcriptome profiling of HCT116 colon cancer cells with or without genetic deletion of PPARD and gene expression patterns in The Cancer Genome Atlas colorectal adenocarcinoma database identified novel pro-metastatic genes (GJA1, VIM, SPARC, STC1, SNCG) as PPARD targets. PPARD expression in cancer cells drastically affected epithelial-mesenchymal transition, migration, and invasion, further underscoring its necessity for metastasis. Clinically, high PPARD expression in various major human cancers (e.g., colorectal, lung, breast) was associated with significantly reduced metastasis-free survival. Our results demonstrate that PPARD, a druggable protein, is an important molecular target in metastatic cancer.

Topics: Angiogenesis Inducing Agents; Animals; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Gene Deletion; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Interleukin-8; Lung Neoplasms; Mice; Molecular Targeted Therapy; Neoplasm Metastasis; Neoplasms; PPAR delta

The epithelial-mesenchymal transition (EMT) is a process through which epithelial cells trans-differentiate and acquire an aggressive mesenchymal phenotype. In tumor cells, EMT is a vital step of tumor progression and metastasis. Amid the increasing interest in tumor EMT, only a few studies focused on the soluble mediators secreted by tumor cells passing through this phenotypic switch. In this review, we focus on the essential role of interleukin-8 (IL-8) signaling for the acquisition and maintenance of tumor EMT via direct and indirect mechanisms. Besides the autocrine loop between IL-8 and tumor cells that have gone through EMT, IL-8 could potentiate adjacent epithelial tumor cells into a mesenchymal phenotype via a paracrine mode. Moreover, understanding the role of IL-8 in EMT will provide insight into the pathogenesis of tumor progression and may facilitate the development of an effective strategy for the prevention and treatment of metastatic cancer.

Topics: Autocrine Communication; Cell Differentiation; Epithelial Cells; Epithelial-Mesenchymal Transition; Humans; Inflammation; Interleukin-8; Neoplasms; Paracrine Communication; Signal Transduction

The angiogenic switch is an important oncogenic step that determines whether microtumors remain dormant or progresses further. It has been generally perceived that the primary function of this tumorgenic event is to supply oxygen and nutrients through blood circulation. Using in vivo imaging of zebrafish and mouse tumor models, we showed that endothelial cords aggressively penetrated into microtumors and remained non-circulatory for several days before undergoing vascular blood perfusion. Unexpectedly, we found that initial tumor growth in both models was significantly reduced if endothelial cords were removed by blocking VEGF-VEGFR2 signaling or using a vascular deficient zebrafish mutant. It was further shown that soluble factors including IL-8, secreted by endothelial cells (ECs) were responsible for stimulating tumor cells proliferation. These findings establish that tumor angiogenesis play a much earlier and broader role in promoting tumor growth, which is independent of vascular circulation. Understanding this novel mechanism of angiogenic tumor progression offers new entry points for cancer therapeutics.

Topics: Animals; Cell Proliferation; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Heterografts; Interleukin-8; Lung Neoplasms; Melanoma, Experimental; Mice; Neoplasms; Neovascularization, Pathologic; Paracrine Communication; Tumor Burden; Tumor Microenvironment; Zebrafish

Oncolytic viruses are able to specifically replicate, infect, and kill only cancer cells. Their combination with chemotherapeutic drugs has shown promising results due to the synergistic action of virus and drugs; the combinatorial therapy is considered a potential clinically relevant approach for cancer. In this study, we optimized a strategy to absorb peptides on the viral capsid, based on electrostatic interaction, and used this strategy to deliver an active antitumor drug. We used L-carnosine, a naturally occurring histidine dipeptide with a significant antiproliferative activity. An ad hoc modified, positively charged L-carnosine was combined with the capsid of an oncolytic adenovirus to generate an electrostatic virus-carnosine complex. This complex showed enhanced antitumor efficacy in vitro and in vivo in different tumor models. In HCT-116 colorectal and A549 lung cancer cell lines, the complex showed higher transduction ratio and infectious titer compared with an uncoated oncolytic adenovirus. The in vivo efficacy of the complex was tested in lung and colon cancer xenograft models, showing a significant reduction in tumor growth. Importantly, we investigated the molecular mechanisms underlying the effects of complex on tumor growth reduction. We found that complex induces apoptosis in both cell lines, by using two different mechanisms, enhancing viral replication and affecting the expression of Hsp27. Our system could be used in future studies also for delivery of other bioactive drugs. Mol Cancer Ther; 15(4); 651-60. ©2016 AACR.

Topics: Adenoviridae; Animals; Apoptosis; Autophagy; Carnosine; Cell Line, Tumor; Cell Survival; Disease Models, Animal; Gene Expression; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; HSP27 Heat-Shock Proteins; Humans; Interleukin-8; Mice; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Transduction, Genetic; Tumor Burden; Virus Replication; Xenograft Model Antitumor Assays

Myeloid-derived suppressor cells (MDSC) are considered an important T-cell immunosuppressive component in cancer-bearing hosts. The factors that attract these cells to the tumor microenvironment are poorly understood. IL8 (CXCL8) is a potent chemotactic factor for neutrophils and monocytes.. MDSC were characterized and sorted by multicolor flow cytometry on ficoll-gradient isolated blood leucokytes from healthy volunteers (n = 10) and advanced cancer patients (n = 28). In chemotaxis assays, sorted granulocytic and monocytic MDSC were tested in response to recombinant IL8, IL8 derived from cancer cell lines, and patient sera. Neutrophil extracellular traps (NETs) formation was assessed by confocal microscopy, fluorimetry, and time-lapse fluorescence confocal microscopy on short-term MDSC cultures.. IL8 chemoattracts both granulocytic (GrMDSC) and monocytic (MoMDSC) human MDSC. Monocytic but not granulocytic MDSC exerted a suppressor activity on the proliferation of autologous T cells isolated from the circulation of cancer patients. IL8 did not modify the T-cell suppressor activity of human MDSC. However, IL8 induced the formation of NETs in the GrMDSC subset.. IL8 derived from tumors contributes to the chemotactic recruitment of MDSC and to their functional control. Clin Cancer Res; 22(15); 3924-36. ©2016 AACR.

Topics: Animals; Biomarkers; Cell Line, Tumor; Chemotaxis, Leukocyte; Disease Models, Animal; Extracellular Traps; Humans; Interleukin-8; Mice; Mice, Knockout; Myeloid-Derived Suppressor Cells; Neoplasms; Neutrophils; Sulfonamides; T-Lymphocyte Subsets

The innate immune response molecules and their use as a predictor of mortality in cancer patients with severe sepsis and septic shock are poorly investigated.. To analyze the value of interleukin (IL)-1ß, IL-6, IL-8, IL-10, IL-12, tumor necrosis factor α (TNF-α), soluble triggering receptor expressed on myeloid cells 1 (sTREM-1), and high-mobility group box 1 (HMGB-1) as predictors of mortality in cancer patients with severe sepsis and septic shock compared with septic patients without malignancies.. Prospective, observational cohort study.. Tertiary level adult intensive care unit (ICU).. Seventy-five patients with severe sepsis or septic shock, 40 with cancer and 35 without.. Laboratory data were collected at ICU admission, 24 and 48 hours after. Plasma concentrations of HMGB-1 and sTREM-1 were measured by enzyme-linked immunosorbent assay, whereas cytokines were measured by cytometric bead array.. Intensive care unit mortality in cancer and noncancer patients was 40% and 28.6% (P = .29), and 28-day mortality was 45% and 34.3% (P = .34). Proinflammatory cytokines IL-1ß, IL-6, IL-8, IL-12, and TNF-α showed significantly higher values in the cancer group. Interleukin-10 at 48 hours (P = .01), sTREM-1 in all measurements (P < .01) and HMGB-1 at 24 hours (P < .01) showed significantly lower values in the cancer group. In addition, for the cancer group, sTREM-1 at 24 hours (P = .02) and 48 hours (P = .01) showed higher levels in nonsurvivors patients. The area under the receiver operating characteristic curve for predicting ICU mortality for sTREM-1 was 0.73 (95% confidence interval, 0.57-0.89; P = .01). Multivariate logistic analysis showed that the days spent in mechanical ventilation and levels of sTREM-1 and IL-1ß at 48 hours were independent predictors of ICU mortality; corticosteroids requirement and levels of sTREM-1 and TNF-α at 24 hours were independent predictors of 28-day mortality.. Patients with cancer have different immune profile in sepsis when compared with patients without cancer, as demonstrated for levels of cytokines, sTREM-1 and HMGB-1. sTREM-1 and days spent in mechanical ventilation proved to be good predictors of ICU and 28-day mortality in cancer patients.

Topics: Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Cohort Studies; Cytokines; Enzyme-Linked Immunosorbent Assay; Female; HMGB1 Protein; Humans; Intensive Care Units; Interleukin-10; Interleukin-6; Interleukin-8; Male; Membrane Glycoproteins; Middle Aged; Neoplasms; Prognosis; Prospective Studies; Receptors, Immunologic; Respiration, Artificial; ROC Curve; Sepsis; Shock, Septic; Triggering Receptor Expressed on Myeloid Cells-1; Tumor Necrosis Factor-alpha

Oxygen status and tissue dimensionality are critical determinants of tumor angiogenesis, a hallmark of cancer and an enduring target for therapeutic intervention. However, it is unclear how these microenvironmental conditions interact to promote neovascularization, due in part to a lack of comprehensive, unbiased data sets describing tumor cell gene expression as a function of oxygen levels within three-dimensional (3D) culture. Here, we utilized alginate-based, oxygen-controlled 3D tumor models to study the interdependence of culture context and the hypoxia response. Microarray gene expression analysis of tumor cells cultured in 2D versus 3D under ambient or hypoxic conditions revealed striking interdependence between culture dimensionality and hypoxia response, which was mediated in part by pro-inflammatory signaling pathways. In particular, interleukin-8 (IL-8) emerged as a major player in the microenvironmental regulation of the hypoxia program. Notably, this interaction between dimensionality and oxygen status via IL-8 increased angiogenic sprouting in a 3D endothelial invasion assay. Taken together, our data suggest that pro-inflammatory pathways are critical regulators of tumor hypoxia response within 3D environments that ultimately impact tumor angiogenesis, potentially providing important therapeutic targets. Furthermore, these results highlight the importance of pathologically relevant tissue culture models to study the complex physical and chemical processes by which the cancer microenvironment mediates new vessel formation.

Topics: Alginates; Biocompatible Materials; Cell Culture Techniques; Cell Hypoxia; Endothelium, Vascular; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glucuronic Acid; Hexuronic Acids; Human Umbilical Vein Endothelial Cells; Humans; Hydrogels; Inflammation; Interleukin-8; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Oxygen; Signal Transduction; Tissue Engineering; Tumor Cells, Cultured

Development of RNA-based antagonists (antimiRs) for disease-associated miRNAs in specific cell types or tissues has recently become a promising approach for treating several pathological conditions, including cancer. In order to explore the use of RNA-aptamers as carriers for cell-targeted delivery of antimiRs, here we designed two different conjugates using as carrier two aptamers that bind and antagonize cancer-associated receptor tyrosine kinases, Axl and PDGFRβ. We conjugated the tumor suppressor antimiR-222 to each aptamer demonstrating: 1) effective and selective delivery to receptor-expressing tumor cells, 2) increased expression of miR-222 target mRNAs, and 3) functional synergy between the kinase inhibitory aptamer and the antimiR antagonizing functions. Furthermore, we generated modular molecules in which two different antimiR sequences connected in tandem are conjugated to a unique carrier aptamer. We proved this strategy to be effective to deplete multiple microRNAs simultaneously, thus combining the effects of different antimiRs without losing the cell targeting specificity.

Topics: 2',5'-Oligoadenylate Synthetase; Animals; Aptamers, Nucleotide; Axl Receptor Tyrosine Kinase; Cell Line, Tumor; Humans; Interleukin-6; Interleukin-8; Liver; Mice, Nude; MicroRNAs; Neoplasms; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Receptor, Platelet-Derived Growth Factor beta; Spleen; Tumor Burden

The aim of this study was to investigate the role of cytokine genes in the susceptibility to Candida infection. A total of 275 consecutive patients diagnosed with Candida infection were selected between May 2010 and May 2011, along with 305 uninfected controls. Genotyping of the IL-1β gene polymorphisms (IL1β) rs1143634, IL1βrs16944, IL8 rs4073, IL10 rs1800872, and IL10 rs1800896 was carried out using a 384-well plate format on the Sequenom MassARRAY platform. Patients with invasive Candida infections were more likely to have had an immunocompromised state, hematopoietic stem cell transplantation, solid organ transplant, solid tumor, chemotherapy within the past three months, neutropenia, surgery within the past 30 days, acute renal failure, liver failure, and/or median baseline serum creatinine. Conditional logistic regression analyses found that individuals with the rs1800896 GG genotype were associated with a higher risk of invasive Candida infections than those carrying the AA genotype (odds ratio = 0.61, 95% confidence interval = 0.37-0.94). From the results of this case-control study, we suggest that the cytokine IL-10 gene rs1800896 polymorphism might play a role in the etiology of invasive Candida infections.

Topics: Acute Kidney Injury; Adult; Aged; Alleles; Candida; Candidiasis, Invasive; Case-Control Studies; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Immunocompromised Host; Interleukin-10; Interleukin-1beta; Interleukin-8; Liver Failure; Logistic Models; Male; Middle Aged; Neoplasms; Polymorphism, Single Nucleotide

Salmonella Typhimurium employs an array of type III secretion system effectors that facilitate intracellular survival and replication during infection. The Salmonella effector SseK3 was originally identified due to amino acid sequence similarity with NleB; an effector secreted by EPEC/EHEC that possesses N-acetylglucoasmine (GlcNAc) transferase activity and modifies death domain containing proteins to block extrinsic apoptosis. In this study, immunoprecipitation of SseK3 defined a novel molecular interaction between SseK3 and the host protein, TRIM32, an E3 ubiquitin ligase. The conserved DxD motif within SseK3, which is essential for the GlcNAc transferase activity of NleB, was required for TRIM32 binding and for the capacity of SseK3 to suppress TNF-stimulated activation of NF-κB pathway. However, we did not detect GlcNAc modification of TRIM32 by SseK3, nor did the SseK3-TRIM32 interaction impact on TRIM32 ubiquitination that is associated with its activation. In addition, lack of sseK3 in Salmonella had no effect on production of the NF-κB dependent cytokine, IL-8, in HeLa cells even though TRIM32 knockdown suppressed TNF-induced NF-κB activity. Ectopically expressed SseK3 partially co-localises with TRIM32 at the trans-Golgi network, but SseK3 is not recruited to Salmonella induced vacuoles or Salmonella induced filaments during Salmonella infection. Our study has identified a novel effector-host protein interaction and suggests that SseK3 may influence NF-κB activity. However, the lack of GlcNAc modification of TRIM32 suggests that SseK3 has further, as yet unidentified, host targets.

Topics: Bacterial Proteins; Cell Line, Tumor; Green Fluorescent Proteins; HEK293 Cells; HeLa Cells; Host-Pathogen Interactions; Humans; Immunoblotting; Interleukin-8; Microscopy, Confocal; Mutation; Neoplasms; NF-kappa B; Protein Binding; RNA Interference; Salmonella typhimurium; Signal Transduction; trans-Golgi Network; Transcription Factors; Tripartite Motif Proteins; Ubiquitin-Protein Ligases

The exposure of calreticulin (CRT) on the surface of stressed and dying cancer cells facilitates their uptake by dendritic cells and the subsequent presentation of tumor-associated antigens to T lymphocytes, hence stimulating an anticancer immune response. The chemotherapeutic agent mitoxantrone (MTX) can stimulate the peripheral relocation of CRT in both human and yeast cells, suggesting that the CRT exposure pathway is phylogenetically conserved. Here, we show that pheromones can act as physiological inducers of CRT exposure in yeast cells, thereby facilitating the formation of mating conjugates, and that a large-spectrum inhibitor of G protein-coupled receptors (which resemble the yeast pheromone receptor) prevents CRT exposure in human cancer cells exposed to MTX. An RNA interference screen as well as transcriptome analyses revealed that chemokines, in particular human CXCL8 (best known as interleukin-8) and its mouse ortholog Cxcl2, are involved in the immunogenic translocation of CRT to the outer leaflet of the plasma membrane. MTX stimulated the production of CXCL8 by human cancer cells in vitro and that of Cxcl2 by murine tumors in vivo. The knockdown of CXCL8/Cxcl2 receptors (CXCR1/Cxcr1 and Cxcr2) reduced MTX-induced CRT exposure in both human and murine cancer cells, as well as the capacity of the latter-on exposure to MTX-to elicit an anticancer immune response in vivo. Conversely, the addition of exogenous Cxcl2 increased the immunogenicity of dying cells in a CRT-dependent manner. Altogether, these results identify autocrine and paracrine chemokine signaling circuitries that modulate CRT exposure and the immunogenicity of cell death.

Topics: Animals; Antineoplastic Agents; Apoptosis; Calreticulin; Cell Line, Tumor; Chemokine CXCL2; Dendritic Cells; HCT116 Cells; HeLa Cells; Humans; Interleukin-8; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mitoxantrone; Neoplasms; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Transcriptome

Total phenolic content, antioxidant activity and phenolic profiles of six herbal infusions - namely rosemary, Cretan dittany, St. John's Wort, sage, marjoram and thyme were assayed. Additionally, the infusion anticarcinogenic effect as to their ability to (a) scavenge free radicals, (b) inhibit cell growth, (c) decrease IL-8 levels and (d) regulate p65 subunit in epithelial colon cancer (HT29) and prostate (PC3) cancer cells was investigated. LC-DAD-MS and GC-MS analyses showed major qualitative and quantitative differences in phenolic profiles of the infusions. All herbal infusions exhibited antiradical activity which correlated strongly with their total phenolic content. Infusions exhibited the potential to inhibit cell growth and to reduce IL-8 levels in HT29 colon and PC3 prostate cancer cells. The regulation reported in p65 subunit in HT29 treated with St John's Wort and in PC3 treated with thyme might point to the NF-κB as the molecular target underlying the effect of these infusions.

Topics: Animals; Antineoplastic Agents, Phytogenic; Antioxidants; Cell Line, Tumor; Cell Proliferation; Chemoprevention; Herbal Medicine; Humans; Interleukin-8; Neoplasms; NF-kappa B; Phenols; Plant Extracts; Plants, Medicinal

Having unique architectural features, cationic polymeric nanocapsules (NCs) with well-defined covalently stabilized biodegradable structures were generated as potentially universal and safe therapeutic nanocarriers. These NCs were synthesized from allyl-functionalized cationic polylactide (CPLA) by highly efficient UV-induced thiol-ene interfacial cross-linking in transparent miniemulsions. With tunable nanoscopic sizes, negligible cytotoxicity and remarkable degradability, they are able to encapsulate doxorubicin (Dox) with inner cavities and bind interleukin-8 (IL-8) small interfering RNA (siRNA) with cationic shells. The Dox-encapsulated NCs can effectively bypass the P-glycoprotein (Pgp)-mediated multidrug resistance of MCF7/ADR cancer cells, thereby resulting in increased intracellular drug concentration and reduced cell viability. In vitro studies also showed that the NCs loaded with Dox, IL-8 siRNA and both agents can be readily taken up by PC3 prostate cancer cells, resulting in a significant chemotherapeutic effect and/or IL-8 gene silencing.

Topics: Biocompatible Materials; Cations; Cell Line, Tumor; Cross-Linking Reagents; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Gene Silencing; Gene Transfer Techniques; Genetic Therapy; Humans; Interleukin-8; Magnetic Resonance Spectroscopy; Male; MCF-7 Cells; Nanocapsules; Nanoparticles; Nanotechnology; Neoplasms; Polyesters; RNA, Small Interfering; Ultraviolet Rays

The induction of angiogenesis and the promotion of tumor growth and invasiveness are processes critical to metastasis, and are dependent on reciprocal interactions between tumor cells and their microenvironment. The formation of a clinically relevant tumor requires support from the surrounding stroma, and it is hypothesized that three-dimensional (3D) tumor coculture models offer a microenvironment that more closely resembles the physiological tumor microenvironment. In this study, we investigated the effects of tissue-engineered 3D architecture and tumor-stroma interaction on the angiogenic factor secretion profiles of U2OS osteosarcoma cells by coculturing the tumor cells with immortalized fibroblasts or human umbilical vein endothelial cells (HUVECs). We also carried out Transwell migration assays for U2OS cells grown in monoculture or fibroblast coculture systems to study the physiological effect of upregulated angiogenic factors on endothelial cell migration. Anti-IL-8 and anti-vascular endothelial growth factor (VEGF)-A therapies were tested out on these models to investigate the role of 3D culture and the coculture of tumor cells with immortalized fibroblasts on the efficacy of antiangiogenic treatments. The coculture of U2OS cells with immortalized fibroblasts led to the upregulation of IL-8 and VEGF-A, especially in 3D culture. Conversely, coculture with endothelial cells resulted in the downregulation of VEGF-A for cells seeded in 3D scaffolds. The migration of HUVECs through the Transwell polycarbonate inserts increased for the 3D and immortalized fibroblast coculture models, and the targeted inhibition of IL-8 greatly reduced HUVEC migration despite the presence of VEGF-A. A similar effect was not observed when anti-VEGF-A neutralizing antibody was used instead, suggesting that IL-8 plays a more critical role in endothelial cell migration than VEGF-A, with significant implications on the clinical utility of antiangiogenic therapy targeting VEGF-A.

Topics: Angiogenesis Inducing Agents; Antineoplastic Agents; Cell Line, Transformed; Cell Movement; Coculture Techniques; Female; Green Fluorescent Proteins; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Tissue Engineering; Up-Regulation

In the present study we determined the relative contribution of two processes to breast cancer progression: (1) Intrinsic events, such as activation of the Ras pathway and down-regulation of p53; (2) The inflammatory cytokines TNFα and IL-1β, shown in our published studies to be highly expressed in tumors of >80% of breast cancer patients with recurrent disease.. Using MCF-7 human breast tumor cells originally expressing WT-Ras and WT-p53, we determined the impact of the above-mentioned elements and cooperativity between them on the expression of CXCL8 (ELISA, qRT-PCR), a member of a "cancer-related chemokine cluster" that we have previously identified. Then, we determined the mechanisms involved (Ras-binding-domain assays, Western blot, luciferase), and tested the impact of Ras + TNFα on angiogenicity (chorioallantoic membrane assays) and on tumor growth at the mammary fat pad of mice and on metastasis, in vivo.. Using RasG12V that recapitulates multiple stimulations induced by receptor tyrosine kinases, we found that RasG12V alone induced CXCL8 expression at the mRNA and protein levels, whereas down-regulation of p53 did not. TNFα and IL-1β potently induced CXCL8 expression and synergized with RasG12V, together leading to amplified CXCL8 expression. Testing the impact of WT-Ras, which is the common form in breast cancer patients, we found that WT-Ras was not active in promoting CXCL8; however, TNFα has induced the activation of WT-Ras: joining these two elements has led to cooperative induction of CXCL8 expression, via the activation of MEK, NF-κB and AP-1. Importantly, TNFα has led to increased expression of WT-Ras in an active GTP-bound form, with properties similar to those of RasG12V. Jointly, TNFα + Ras activities have given rise to increased angiogenesis and to elevated tumor cell dissemination to lymph nodes.. TNFα cooperates with Ras in promoting the metastatic phenotype of MCF-7 breast tumor cells, and turns WT-Ras into a tumor-supporting entity. Thus, in breast cancer patients the cytokine may rescue the pro-cancerous potential of WT-Ras, and together these two elements may lead to a more aggressive disease. These findings have clinical relevance, suggesting that we need to consider new therapeutic regimens that inhibit Ras and TNFα, in breast cancer patients.

Topics: Animals; Cell Line, Tumor; Chick Embryo; Female; Gene Expression Regulation, Neoplastic; Guanosine Triphosphate; Humans; Interleukin-1beta; Interleukin-8; MAP Kinase Signaling System; MCF-7 Cells; Mice; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; NF-kappa B; Protein Binding; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins p21(ras); Signal Transduction; Transcription Factor AP-1; Transcription, Genetic; Tumor Necrosis Factor-alpha; Tumor Suppressor Protein p53

Epidermal growth factor receptor inhibitor (EGFRI) induced skin toxicity has a prognostic value suggesting skin toxicity can be a useful surrogate marker for successful epidermal growth factor receptor (EGFR) inhibition, improved response and survival. But the pathophysiology of EGFRI induced skin toxicity remains elusive. However the involvement of immunological mechanisms has been speculated. This study investigates the possible underlying mechanism of EGFR inhibition associated cytokine production in keratinocytes as well as in patients after treatment with epidermal growth factor receptor inhibitors (EGFRIs).. Normal human epidermal keratinocytes (NHEK) were incubated for 2 and 24h with different concentrations of EGFRI (erlotinib) for Western blot analysis and cytokine expression analysis, respectively. Inhibition of EGFR, extracellular-signal-regulated kinase 1/2 (Erk 1/2) and c-Jun was examined by Western blot analysis. Cytokine concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in the NHEK cell supernatant and also in the serum of 186 cancer patients who are followed up for EGFRI induced skin rash.. A significant inhibitory effect of EGFRI was seen on EGFR (Y845), Erk 1/2 and c-Jun in a dose dependent manner. Further downstream, increased CC-chemokine ligand 2 (CCL2), CC-chemokine ligand 5 (CCL5) and decreased interleukin-8 (IL-8) or CXCL8 expression was observed in keratinocytes. In EGFRI treated patients, low levels of serum CXCL8 corresponding to stronger EGFR inhibition were associated with a higher grade of skin toxicity (p=0.0016) and a prolonged overall survival (p=0.018).. The results obtained in this study indicate that EGFRI can regulate cytokines by modulating EGFR signalling pathway in keratinocytes. Moreover, serum levels of CXCL8 in EGFRI treated patients may be important for individual EGFRI induced skin toxicity and patient's survival.

Topics: Adult; Aged; Aged, 80 and over; Cells, Cultured; Cytokines; Disease-Free Survival; ErbB Receptors; Female; Humans; Interleukin-8; Keratinocytes; Male; Middle Aged; Neoplasms; Prospective Studies; Protein Kinase Inhibitors; Signal Transduction; Skin Diseases

Targeting the endothelial-to-mesenchymal transition (EndoMT) may be a novel therapeutic strategy for cancer and various diseases induced by fibrosis. We aimed to identify a small chemical molecule as an inducer of EndoMT and find a new signal pathway by using the inducer. Safrole oxide (SFO), 50 µg/ml, could most effectively induce EndoMT within 12 h. To understand the underlying molecular mechanism, we performed microarray, quantitative real-time PCR and western blot analysis to find key factors involved in SFO-induced EndoMT and demonstrated the involvement of the factors by RNAi. The expression of activating transcription factor 4 (ATF4), p75 neurotrophin receptor (p75NTR), and interleukin 8 (IL-8) was greatly increased in SFO-induced EndoMT. Knockdown of ATF4 inhibited the SFO-induced EndoMT completely, and knockdown of p75NTR or IL-8 partially inhibited the EndoMT, which suggests that all three factors were involved in the process. Furthermore, knockdown of p75NTR inhibited the SFO-increased IL-8 expression and secretion, and knockdown of ATF4 inhibited SFO-increased p75NTR level significantly. The ATF4/p75NTR/IL-8 signal pathway may have an important role in EndoMT induced by SFO. Our findings support potential novel targets for the therapeutics of cancer and fibrosis disease.

Topics: Activating Transcription Factor 4; Fibrosis; Gene Expression Regulation; Gene Knockdown Techniques; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-8; Neoplasms; Nerve Tissue Proteins; Receptors, Nerve Growth Factor; Safrole; Signal Transduction

Serum levels of sRANKL, RANK, OPG, IL-8, IL-6, IL-16, MMP-2, and calcitonin were measured by ELISA in patients with malignant, borderline, and benign bone tumors and in healthy individuals (control). Serum levels of RANK, OPG, IL-8, IL-6, and the OPG/sRANKL ratio were significantly higher, while the level of MMP-2 was significantly lower in patients with bone tumors than in controls. Serum concentration of IL-16 in osteosarcoma patients was significantly lower than in chondrosarcoma patients. No significant differences between bone sarcomas of different differentiation were detected for any of the studied markers. Calcitonin level depended on the tumor location and type.

Topics: Adolescent; Adult; Aged; Bone Neoplasms; Calcitonin; Case-Control Studies; Chondrosarcoma; Chordoma; Female; Gene Expression; Humans; Interleukin-16; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 2; Middle Aged; Neoplasms; Osteoprotegerin; Osteosarcoma; RANK Ligand; Receptor Activator of Nuclear Factor-kappa B

To observe the influence of propofol, isoflurane and enflurance on interleukin-8 (IL-8) and IL-10 levels in cancer patients.. Ninety cancer patients with selective operation from March 2011 to May 2014 were randomly divided into group A (34 cases), group B (28 cases) and group C (28 cases). Intramuscular injections of scopine hydrochloride and phenobarbital sodium were routinely conducted to 3 groups. After general anesthesia was induced, tracheal intubations were given. During the maintenance of anesthesia, 0.5~1.0 mg/ kg propofol was intravenously injected to group A discontinuously, while continuous suctions of isoflurane and enflurance were subsequently performed to group B and C correspondingly. Clinical outcomes, postoperative complications as well as serum IL-8 and IL-10 levels before operation (T0), at the time of skin incision (T1), 3 h after the beginning of the operation (T2) and 24 h (T3) and 72 h (T4) after the operation were observed among 3 groups.. Operations in all groups were successfully completed. The rates of surgery associated complications were 8.82% (3/34), 7.14% (2/28) and 7.14% (2/28) in group A, B and C, respectively, and there were no significant differences (P>0.05). Serum IL-8 and IL-10 levels increased gradually from the beginning of the operation and reached the peak at T3, and were evidently higher at each time point than at T0 (P<0.01). At T1, serum IL-8 and IL-10 levels had no significant differences among 3 groups (P<0.05), but the differences were significant at T2, T3 and T4 (P<0.05). Moreover, correlation analysis suggested that serum IL-8 level was in positive relation with IL-10 level (r=0.952, P<0.01).. Propofol, which is better in inhibiting serum IL-8 secretion and improving IL-10 secretion than isoflurane and enflurance, can be regarded as a preferable anesthetic agent in inhibiting traumatic inflammatory responses.

Topics: Adult; Aged; Anesthetics, Inhalation; Anesthetics, Intravenous; Enflurane; Female; Humans; Inflammation; Interleukin-10; Interleukin-8; Isoflurane; Male; Middle Aged; Neoplasms; Phenobarbital; Postoperative Complications; Propofol

Interleukin-8 (IL8) is a chemokine produced by malignant cells of multiple cancer types. It exerts various functions in shaping protumoral vascularization and inflammation/immunity. We evaluated sequential levels of serum IL8 in preclinical tumor models and in patients to assess its ability to estimate tumor burden.. IL8 levels were monitored by sandwich ELISAs in cultured tumor cells supernatants, tumor-xenografted mice serum, and in samples from 126 patients with cancer. We correlated IL8 serum levels with baseline tumor burden and with treatment-induced changes in tumor burden, as well as with prognosis.. IL8 concentrations correlated with the number of IL8-producing tumor cells in culture. In xenografted neoplasms, IL8 serum levels rapidly dropped after surgical excision, indicating an accurate correlation with tumor burden. In patients with melanoma (n = 16), renal cell carcinoma (RCC; n = 23), non-small cell lung cancer (NSCLC; n = 21), or hepatocellular carcinoma (HCC; n = 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n = 16; RCC, n = 23; HCC, n = 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n = 16) and immunomodulatory monoclonal antibodies (melanoma, n = 8). IL8 concentrations in urine (n = 18) were mainly elevated in tumors with direct contact with the urinary tract.. IL8 levels correlate with tumor burden in preclinical models and in patients with cancer. IL8 is a potentially useful biomarker to monitor changes in tumor burden following anticancer therapy, and has prognostic significance.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Disease Models, Animal; Humans; Interleukin-8; Mice, Knockout; Neoplasms; Treatment Outcome; Tumor Burden; Xenograft Model Antitumor Assays

Despite a low bacteremia rate, pediatric oncology patients are frequently admitted for febrile neutropenia. A pediatric risk prediction model with high sensitivity to identify patients at low risk for bacteremia is not available. We performed a single-institution prospective cohort study of pediatric oncology patients with febrile neutropenia to create a risk prediction model using clinical factors, respiratory viral infection, and cytokine expression.. Pediatric oncology patients with febrile neutropenia were enrolled between March 30, 2010 and April 1, 2011 and managed per institutional protocol. Blood samples for C-reactive protein and cytokine expression and nasopharyngeal swabs for respiratory viral testing were obtained. Medical records were reviewed for clinical data. Statistical analysis utilized mixed multiple logistic regression modeling.. During the 12-month period, 195 febrile neutropenia episodes were enrolled. There were 24 (12%) episodes of bacteremia. Univariate analysis revealed several factors predictive for bacteremia, and interleukin (IL)-8 was the most predictive variable in the multivariate stepwise logistic regression. Low serum IL-8 predicted patients at low risk for bacteremia with a sensitivity of 0.9 and negative predictive value of 0.98.. IL-8 is a highly sensitive predictor for patients at low risk for bacteremia. IL-8 should be utilized in a multi-institution prospective trial to assign risk stratification to pediatric patients admitted with febrile neutropenia.

Topics: Adolescent; Adult; Bacteremia; Bacteria; Biomarkers, Tumor; Child; Child, Preschool; Female; Humans; Infant; Interleukin-8; Male; Neoplasms; Neutropenia; Prognosis; Prospective Studies; Risk Factors; ROC Curve; Young Adult

Despite great efforts to develop a more effective oncolytic adenovirus (Ad) for eradicating tumors, in vivo application via systemic administration is strictly limited to local injection due to host immune responses by Ad surface proteins and liver accumulation by the inherent nature of the Ad. In the last decade, numerous techniques using synthetic polymers have widely emerged to shield the exterior of therapeutic Ad vectors for systemic delivery. We developed a cationic polymer linked with polyethylene glycol for systemically delivering oncolytic Ad. The increased transduction efficiency and oncolytic effect of the Ad vectors physically coated with the polymer were evaluated, showing the optimal size (130 nm) of the Ad/polymer complex for systemic administration and prolonged stability of the Ad/polymer complex. Marked tumor growth suppression of the oncolytic Ad delivered by the polymer through systemic injection was observed in HT1080 and A549 xenograft models. The masking effect of the Ad surface by the polymer elicited evasion of innate adaptive immune responses and the tumor-to-liver ratio of the complex was significantly elevated 1229-fold greater than that of a naked Ad. These results demonstrate that the potential system of oncolytic Ad complexed with the biodegradable polymer may be useful for developing therapeutic vector systems via systemic delivery.

Topics: Adaptive Immunity; Adenoviridae; Animals; Cell Line; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Genetic Therapy; Genetic Vectors; Humans; Immunity, Innate; Interleukin-8; Mice; Mice, Nude; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Polymers; Transduction, Genetic; Vascular Endothelial Growth Factor A

No predictive factors are currently available to establish patient-specific GVHD risk. A panel of six serum cytokines (TNF receptor 1, IL-2 receptor alfa (IL-2Rα), hepatocyte growth factor (HGF), monocyte chemo-attractant protein-2, IL-8, IL-12p70) were monitored at established time points (days -1, +1, +7, +14, +21, +28 and +60) in 170 paediatric hematopoietic SCT (HSCT) recipients. We found that higher concentrations of IL-2Rα on days +14 and +21 together with HGF on days +14 and +21 were significantly associated at a higher probability of both grade II-IV GVHD (on day +14 it was: 60% vs 28%, P=0.007) and grade III-IV (on day +14 it was: 40% vs 15%, P=0.001). The higher IL-8 serum concentration on day +28 was associated with a lower probability of chronic GVHD being 4% vs 29% (P=0.01) for patients with higher vs lower IL-8 serum concentration. These findings were confirmed when the analysis was restricted to the the matched unrelated donor group. In conclusion, even if the serum cytokine levels were related to several variables associated with HSCT, we identified two cytokines as predictors of GVHD II-IV and III-IV, translating into a higher TRM risk (17% vs 3%, P=0.004).

Topics: Adolescent; Adult; Biomarkers, Tumor; Child; Child, Preschool; Cytokines; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hepatocyte Growth Factor; Humans; Infant; Infant, Newborn; Interleukin-12; Interleukin-2 Receptor alpha Subunit; Interleukin-8; Male; Neoplasms; Prognosis; Receptors, Tumor Necrosis Factor, Type I; Transplantation Conditioning; Transplantation, Homologous; Young Adult

The miR-200 family is well known to inhibit the epithelial-mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent.

Topics: Angiogenesis Inhibitors; Breast Neoplasms; Cell Movement; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Interleukin-8; Lung Neoplasms; MicroRNAs; Models, Biological; Nanoparticles; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Oligonucleotides; Pericytes; Treatment Outcome

Nature has been a provenance of medicinal agents for thousands of years. Resveratrol (RESL) is a naturally occurring polyphenolic compound in food stuffs such as peanuts, seeds, berries, grapes, and beverages (red wine). RESL has received significant attention due to a plethora of in vitro and in vivo reports on its cancer chemopreventive and therapeutic properties. In the present study, diacetate RESL derivative (RESL43) was synthesized. The RESL43 displayed potent cytotoxicity and triggered apoptosis in U937 cells as evidenced by poly (ADP-ribose) polymerase (PARP) cleavage, DNA fragmentation, morphological changes, and activation of FasR and FasL genes. The electrophoretic mobility shift assay revealed the suppression NFkB activity in U937 cells after treatment with RESL43 in corroboration with the deactivation of NFkB dependent genes such as IL-8, TNFR, and TNFα. Furthermore, molecular docking and dynamics studies have shown that RESL and RESL43 might exert their inhibitory activity on NFkB by altering the intramolecular binding abilities between DNA and NFkB. Taken together, RESL43 can have greater putative activity than parental RESL in a context of cancer chemoprevention and therapeutics. We suggest that the diacetate resveratrol derivative RESL43 warrants further evaluation in preclinical and clinical bridging studies in the near future.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Binding Sites; Cell Line, Tumor; DNA; DNA Fragmentation; Fas Ligand Protein; Gene Expression Regulation, Neoplastic; Humans; Interleukin-8; Molecular Docking Simulation; Neoplasms; NF-kappa B; Poly(ADP-ribose) Polymerases; Protein Binding; Receptors, Tumor Necrosis Factor; Resveratrol; Stereoisomerism; Stilbenes; Tumor Necrosis Factor-alpha

Senescent cells accumulate in aged tissue and are causally linked to age-associated tissue degeneration. These non-dividing, metabolically active cells are highly secretory and alter tissue homeostasis, creating an environment conducive to metastatic disease progression. IL-1α is a key senescence-associated (SA) proinflammatory cytokine that acts as a critical upstream regulator of the SA secretory phenotype (SASP). We established that SA shifts in steady-state H2O2 and intracellular Ca(2+) levels caused an increase in IL-1α expression and processing. The increase in intracellular Ca(2+) promoted calpain activation and increased the proteolytic cleavage of IL-1α. Antioxidants and low oxygen tension prevented SA IL-1α expression and restricted expression of SASP components IL-6 and IL-8. Ca(2+) chelation or calpain inhibition prevented SA processing of IL-1α and its ability to induce downstream cytokine expression. Conditioned medium from senescent cells treated with antioxidants or Ca(2+) chelators or cultured in low oxygen markedly reduced the invasive capacity of proximal metastatic cancer cells. In this paracrine fashion, senescent cells promoted invasion by inducing an epithelial-mesenchymal transition, actin reorganization, and cellular polarization of neighboring cancer cells. Collectively, these findings demonstrate how SA alterations in the redox state and Ca(2+) homeostasis modulate the inflammatory phenotype through the regulation of the SASP initiator IL-1α, creating a microenvironment permissive to tumor invasion.

Topics: Calcium; Calcium Signaling; Calpain; Cell Line, Tumor; Cellular Senescence; Enzyme Activation; Epithelial-Mesenchymal Transition; Humans; Hydrogen Peroxide; Interleukin-1alpha; Interleukin-6; Interleukin-8; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Neoplasms; Oxidants; Oxidation-Reduction; Paracrine Communication; Proteolysis; Tumor Microenvironment

We previously created a risk prediction model for severe sepsis not clinically apparent during the first 24 hours of hospitalization in children with high-risk febrile neutropenia (HRFN), which identified 3 variables, age ≥ 12 years, serum C-reactive protein (CRP) ≥ 90 mg/L and interleukin-8 ≥ 300 pg/mL, evaluated at the time of admission and at 24 hours of hospitalization. The combination of these 3 variables identified a risk for severe sepsis ranging from 8% to 73% with a relative risk of 3.15 (95% confidence interval: 1.1-9.06). The aim of this study was to validate prospectively our risk prediction model for severe sepsis in a new cohort of children with cancer and HRFN.. Predictors of severe sepsis identified in our previous model (age, CRP and interleukin-8) were evaluated at admission and at 24 hours of hospitalization in a new cohort of children with HRFN between April 2009 and July 2011. Diagnosis of severe sepsis, not clinically apparent during the first 24 hours of hospitalization, was made after discharge by a blind evaluator.. A total of 447 HRFN episodes were studied, of which 76 (17%) had a diagnosis of severe sepsis. The combination of age ≥ 12 years, CRP ≥ 90 mg/L and interleukin-8 ≥ 300 pg/mL at admission and/or at 24 hours in the new cohort identified a risk for severe sepsis ranging from 7% to 46% with an RR of 6.7 (95% CI: 2.3-19.5).. We validated a risk prediction model for severe sepsis applicable to children with HRFN episodes within the first 24 hours of admission. We propose to incorporate this model in the initial patient assessment to offer a more selective management for children at risk for severe sepsis.

Topics: Adolescent; C-Reactive Protein; Chemotherapy-Induced Febrile Neutropenia; Child; Child, Preschool; Female; Humans; Interleukin-8; Male; Models, Statistical; Neoplasms; Risk; Sepsis

Despite the descriptive presence of cancer cachexia (CC) in clinical practice, the underlying mechanisms and diagnostic definition have not been clearly identified. Recent work, attempting to establish diagnostic and staging criteria for CC, has identified IL-6 as a biomarker. This study aimed to investigate the clinical relevance of plasma levels of four pro-inflammatory cytokines (IL-6, IL-1β, IL-8 and TNF-α) in advanced cancer patients (ACP) to further establish their potential in the diagnostic definition of CC.. Blood was obtained from 83 ACP (47 male and 36 female, aged 34-85 years) and analyzed for white blood cells, lymphocytes, C-reactive protein, albumin and cytokines. Subjects completed questionnaires to establish weakness, loss of appetite, fatigue, quality of life and weight loss; completed tests to determine strength, body composition and sarcopenia; and consented to chart review to calculate survival and total days admitted to hospital.. This study shows that, in ACP, IL-1β is better associated with clinical features of the cachectic condition, such as weakness, loss of appetite, weight loss and sarcopenia, than IL-6.. IL-6 may not best represent the clinical correlates of CC in ACP. Additional cytokines should be considered in the definition of this condition.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Appetite; Biomarkers; C-Reactive Protein; Cachexia; Female; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Lymphocytes; Male; Middle Aged; Neoplasms; Quality of Life; Sarcopenia; Surveys and Questionnaires; Tumor Necrosis Factor-alpha; Weight Loss

Topics: Angiogenesis Inhibitors; Animals; Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Neutrophils; Receptors, Interleukin-8A; Receptors, Interleukin-8B

Early diagnosis of sepsis in children with febrile neutropenia and cancer still remains a challenge for modern medicine because of lack of specific laboratory markers and clinical signs especially at the beginning of the infection. The objective of this study was to evaluate the ability of interleukin-6 and interleukin-8 to predict bacteremia and sepsis during the first 2 days in oncohematologic patients with febrile neutropenia.. A total of 61 febrile neutropenic episodes in 37 children were studied. Serum samples were collected on day 1 and day 2 from the onset of fever and analyzed using an automated random access analyzer.. Neutropenic children with febrile episodes were classified into the following 2 groups: (1) fever of unknown origin group--patients with a negative blood culture--and (2) bacteremia/sepsis group--patients with a positive blood culture or clinical sepsis. High negative predictive values were found on day 1 for interleukin-6 and interleukin-8 (89% and 82%, respectively) for exclusion of bacteremia/sepsis.. These interleukins could be used as a screening tool for the rejection of sepsis or bacteremia on the first day of fever in neutropenic children with cancer.

Topics: Adolescent; Bacteremia; Biomarkers; Child; Child, Preschool; Diagnosis, Differential; Female; Fever; Humans; Infant; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Sepsis

The receptor tyrosine kinase MET contributes to a wide range of biological activities, including survival, proliferation, and metastasis, which play an important role in cancer progression. MET is frequently overexpressed or amplified in a range of malignancies. Therefore, MET is an attractive therapeutic target for treatment of cancer. BAY-853474 is a novel specific MET inhibitor highly effective in preclinical tumor models.. For response monitoring in clinical studies, soluble plasma biomarkers are the most convenient and least invasive choice. Therefore, we sought to identify such biomarkers in xenograft models.. We show that BAY-853474 reduces the tumor burden in U87MG glioblastoma, NCI-H1993 nonsmall cell lung cancer, and HS746T gastric cancer xenograft models. We demonstrate that the dose dependence is reflected by inhibition of MET phosphorylation and that the soluble plasma biomarkers hepatocyte growth factor, vascular endothelial growth factor, and interleukin-8 as well as the MET-ectodomain can be used to monitor the tumor size and response to treatment. Clinical samples, however, show only moderately elevated levels of these biomarker candidates in cancer patients even with MET amplification. We, therefore, established an immunohistochemistry (IHC) protocol to detect MET phosphorylation that is suitable to monitor the effect of BAY-853474 in tumor biopsies.. IHC-based analysis of target phosphorylation in tumor biopsies is recommended in addition to testing plasma biomarkers for response monitoring.

Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Case-Control Studies; Cell Line, Tumor; Enzyme Activation; Female; Hepatocyte Growth Factor; Humans; Interleukin-8; Mice; Mice, Nude; Neoplasms; Phosphorylation; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-met; Tumor Burden; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Patients receiving myelosuppressive chemotherapy remain at increased risk for developing febrile neutropenia (FN). For this heterogeneous population, a biomarker based risk stratification of FN patients may be a useful clinical tool. We hypothesized that serum biomarkers during initial presentation of an FN event could be predictive of subsequent clinical outcome.. Eighty-nine FN events from 36 non-consecutive subjects were analyzed. "High-risk" FN criteria included prolonged hospitalization (≥ 7 days), admission to pediatric intensive care unit (PICU) or a microbiology confirmed bacteremia. Patients with "low risk" FN had none of the above. Biomarkers measured during the first 2 days of FN hospitalization were analyzed and correlated with respective clinical outcome.. Of the 89 FN events, 44 (49%) fulfilled pre-defined high-risk criteria and 45 (51%) were low-risk. Procalcitonin level (>0.11 ng/ml) was found to be associated with the high-risk FN outcome with sensitivity of 97%. With an increase in log scale by 1, the odds of being high-risk FN increased twofold. Hs-CRP >100 mg/L had sensitivity of 88% in predicting high-risk FN. The odds of a high-risk FN event increased by approximately 1.8-fold with an increase in the log scale of hs-CRP by 1 (10-fold). In univariate analysis, IL-6, IL-8, and IL-10 were statistically significant and associated with high-risk FN. However, no statistically significant difference was found for IL-1α, sIL-2Ra, IL-3, or TNF-α.. Biomarkers with appropriate critical threshold values may be a useful clinical tool for appropriate risk stratification of children with FN.

Topics: Adolescent; Adult; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Female; Hospitalization; Humans; Infant; Intensive Care Units; Interleukin-10; Interleukin-3; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Pilot Projects; Prognosis; Prospective Studies; Protein Precursors; Risk Factors; ROC Curve; Tumor Necrosis Factor-alpha; Young Adult

The armamentarium of therapeutics used to treat cancer patients relies heavily on ionizing radiation and chemotherapeutic drugs that severely damage DNA. Tumor cells' responses to such treatments are heavily influenced by their environment: Physical contacts with structural elements such as the extracellular matrix, associations with resident and transitory benign cells such as fibroblasts and leukocytes, and interactions with numerous soluble endocrine and paracrine-acting factors all modulate tumor-cell behavior. Of importance, this complex tumor microenvironment is not static and dynamically responds to a variety of stimuli. Here, we describe emerging data indicating that genotoxic cancer treatments activate highly conserved damage response programs in benign constituents of the tumor microenvironment. These damage signals, transmitted via master regulators such as NF-κB, culminate in a powerful and diverse secretory program that generates a proangiogenic, proinflammatory microenvironment. Constituents of this program include interleukin (IL)-6, IL-8, hepatocyte growth factor, amphiregulin, matrix metalloproteinases, and other factors that have been shown to promote adverse tumor-cell phenotypes, such as enhanced resistance to treatment and rapid tumor repopulation. A detailed understanding of these survival signals induced in the context of genotoxic stress provides a platform for developing combinatorial treatment strategies that take into account malignant cells, the tumor microenvironment, and the dynamics exerted by the treatment itself.

Topics: Amphiregulin; Cell Survival; Chemoradiotherapy; DNA Damage; EGF Family of Proteins; Glycoproteins; Hepatocyte Growth Factor; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-6; Interleukin-8; Matrix Metalloproteinases; Models, Biological; Neoplasms; NF-kappa B; Signal Transduction; Tumor Microenvironment

The energy deposition characteristics of proton radiation have attracted considerable attention in light of its implications for carcinogenesis risk in space travel, as well for application to cancer treatment. In space, it is the principle component of the galactic cosmic radiation to which astronauts will be exposed. For treatment, an increasing number of proton facilities are being established to exploit the physical advantages of this radiation type. However, the possibility that there may also be biologically based advantages to proton exposure has not been considered in either context. We demonstrate here that high-energy proton irradiation can inhibit expression of major pro-angiogenic factors and multiple angiogenesis-associated processes, including invasion and endothelial cell proliferation, which is prominent in cancer progression. Dose-dependent suppression of angiogenic signaling was demonstrated for both cancer and nontransformed cells. Pan-genomic microarray analysis and RT-PCR revealed that post-irradiation (0.5, 1.0 and 2.0 Gy), critical pro-angiogenic signaling factors including: vascular endothelial growth factor (VEGF), interleukin 6 and 8 (IL-6, IL-8) and hypoxia-inducible factor-1 alpha (HIF-1A), were significantly downregulated. Co-culture studies demonstrated that endothelial cell proliferation and invasion were inhibited by culturing with irradiated cancer or fibroblast cells, which suggests that proton irradiation may, in addition to direct action, contribute to angiogenesis suppression through modulation of paracrine signalings from targeted cells. Addition of recombinant IL-8 or VEGF partially restored these functions in vitro, while in vivo, an attenuated tumor growth rate was demonstrated for proton-irradiated human lung cancer cells. Taken together, these findings provide novel pre-clinical evidence that proton irradiation may, in addition to its physical targeting advantages, have important biological ramifications that should be a consideration in the optimization of proton therapy.

Topics: Cell Movement; Cell Proliferation; Cell Survival; Cells, Cultured; Gene Expression; Humans; Interleukin-8; Neoplasm Invasiveness; Neoplasms; Neovascularization, Pathologic; Neovascularization, Physiologic; Proton Therapy; Vascular Endothelial Growth Factor A

Inflammation may underlie cancer-related fatigue; however, there are no studies that assess the relation between fatigue and cytokines in patients with advanced disease versus patients without disease activity. Furthermore, the relation between cytokines and the separate dimensions of fatigue is unknown. Here, association of plasma levels of inflammatory markers with physical fatigue and mental fatigue was explored in advanced cancer patients and cancer survivors.. A total of 45 advanced cancer patients and 47 cancer survivors completed the subscales Physical Fatigue and Mental Fatigue of the Multidimensional Fatigue Inventory. Plasma concentrations of C-reactive protein (CRP), interleukin-1 receptor antagonist (IL-1-ra), interleukin-6 (IL-6), interleukin-8 (IL-8), and neopterin were measured. Nonparametric tests were used to assess differences in fatigue intensity and levels of inflammatory markers and to determine correlation coefficients between the fatigue dimensions and inflammatory markers.. Compared with cancer survivors, patients with advanced cancer had higher levels of physical fatigue (median 16 vs 9, P < .001) and mental fatigue (median 11 vs 6, P = .01). They also had higher levels of all cytokines (P < .01). In advanced cancer, CRP (r = 0.49, P = .001), IL-6 (r = 0.43, P = .003), IL-1-ra (r = 0.32, P = .03), and neopterin (r = 0.25, P = .10) were correlated with physical but not with mental fatigue. In cancer survivors, only IL-1-ra was related to both physical fatigue (r = 0.24, P = .10) and mental fatigue (r = 0.35, P = .02).. In advanced cancer, inflammation seems to be associated with physical fatigue, but not to mental fatigue. In cancer survivors, there was no convincing evidence that inflammation plays a major role in fatigue.

Topics: Adult; Aged; Aged, 80 and over; C-Reactive Protein; Fatigue; Female; Humans; Inflammation; Interleukin 1 Receptor Antagonist Protein; Interleukin-6; Interleukin-8; Male; Middle Aged; Neoplasms; Survivors

This study aimed to investigate the association of biomarkers among circulating pro-inflammatory cytokines with all-cause mortality in elderly community dwellings of the MEMO study, Germany. All-cause mortality (cancer, cardiovascular diseases (CVD), and other causes of death) was assessed in a general population sample (N = 385) of the elderly (age 65-83 years) 9 years after baseline assessment in 1998. As markers of inflammation, a variety of cytokines (IL-1beta, IL-4sR, IL-6, IL-8, IL-10, IL-12, TNF-alpha) were assessed in serum. Cox proportional Hazard model was used to estimate the association of cytokines with all-cause mortality over 9 years. In total, 110 deaths had occurred during follow-up (cancer N = 36; CVD N = 56; other = 18). Deaths were more frequent in male (N  = 76, 37.4%) as compared to females (N = 40, 21.9%; p  = 0.001). Among individual cytokines, IL-1 beta, IL-6, IL-8, IL-10, and TNF-alpha were associated with all-cause mortality, of which IL-6, IL-8, and IL-10 remained significant after adjusting for confounders. When the upper tertiles of these cytokines were compared to the lower tertiles, only IL-6 was consistently related to all-cause mortality independently of the level of adjustment and showing a dose-response relationship between IL-6 tertiles and risk of death. This effect originated in the male population. The study shows that IL-6 is a powerful predictor of all-cause mortality in male elderly community dwellings. Higher levels of IL-6 may reflect a chronic low-level systemic inflammation prospectively increasing the risk of death in the elderly.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cause of Death; Cytokines; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Male; Mortality; Neoplasms; Proportional Hazards Models

In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis.. Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24-48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26).. At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24-48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels.. IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8.

Topics: Adolescent; Antineoplastic Agents; Bacterial Infections; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Child; Female; Fever; Gastrointestinal Tract; Humans; Interleukin-8; Male; Membrane Glycoproteins; Mucositis; Neoplasms; Neutropenia; Prospective Studies; Protein Precursors; Receptors, Immunologic; Sensitivity and Specificity; Triggering Receptor Expressed on Myeloid Cells-1

ABT-737, a small molecule cell-permeable Bcl-2 antagonist that acts by mimicking BH3 proteins, induces apoptotic cell death in multiple cancer types. However, when incubated with this agent many solid tumor cell lines do not undergo apoptosis. The current study reveals a novel mechanism whereby ABT-737 when added to apoptosis-resistant cancer cells has profound biologic effects. In PV-10 cells, a renal cell carcinoma that does not die after ABT-737 treatment, this agent induces a two-fold change in the transcription of nearly 430 genes. Many of these induced mRNA changes are in secreted proteins, IL-6, IL-8, and IL-11 and chemokines CXCL2 and CXCL5, or genes associated with an "inflammatory" phenotype. Strikingly, these gene changes are highly similar to those changes previously identified in cellular senescence. Brief exposure of apoptosis-resistant renal, lung and prostate cancer cell lines to ABT-737, although not capable of inducing cell death, causes the induction of senescence-associated β-galactosidase and inhibition of cell growth consistent with the induction of cellular senescence. Evidence indicates that the induction of senescence occurs as a result of reactive oxygen species elevation followed by low-level activation of the caspase cascade, insufficient to induce apoptosis, but sufficient to lead to minor DNA damage and increases in p53, p21, IL-6 and 8 proteins. By overexpression of a dominant-negative p53 protein, we show that ABT-737-induced cellular senescence is p53-dependent. Thus, in multiple cancer types in which ABT-737 is incapable of causing cell death, ABT-737 may have additional cellular activities that make its use as an anticancer agent highly attractive.

Topics: Biomimetic Materials; Biphenyl Compounds; Caspase 3; Cell Cycle; Cell Growth Processes; Cell Line, Tumor; Cellular Senescence; Chemokine CXCL2; Chemokine CXCL5; Cyclin-Dependent Kinase Inhibitor p21; DNA Damage; Humans; Interleukin-6; Interleukin-8; Neoplasms; Nitrophenols; Peptide Fragments; Piperazines; Proto-Oncogene Proteins; Sulfonamides; Transcriptional Activation; Tumor Suppressor Protein p53

Heightened DJ-1 (Park7) expression is associated with a reduction in chemotherapeutic-induced cell death and poor prognosis in several cancers, whereas the loss of DJ-1 function is found in a subgroup of Parkinson disease associated with neuronal death. This study describes a novel pathway by which DJ-1 modulates cell survival. Mass spectrometry shows that DJ-1 interacts with BBS1, CLCF1, MTREF, and Cezanne/OTUD7B/Za20d1. Among these, Cezanne is a known deubiquitination enzyme that inhibits NF-κB activity. DJ-1/Cezanne interaction is confirmed by co-immunoprecipitation of overexpressed and endogenous proteins, maps to the amino-terminal 70 residues of DJ-1, and leads to the inhibition of the deubiquitinating activity of Cezanne. Microarray profiling of shRNA-transduced cells shows that DJ-1 and Cezanne regulate IL-8 and ICAM-1 expression in opposing directions. Similarly, DJ-1 enhances NF-κB nuclear translocation and cell survival, whereas Cezanne reduces these outcomes. Analysis of mouse Park7(-/-) primary cells confirms the regulation of ICAM-1 by DJ-1 and Cezanne. As NF-κB is important in cellular survival and transformation, IL-8 functions as an angiogenic factor and pro-survival signal, and ICAM-1 has been implicated in tumor progression, invasion, and metastasis; these data provide an additional modality by which DJ-1 controls cell survival and possibly tumor progression via interaction with Cezanne.

Topics: Active Transport, Cell Nucleus; Animals; Cell Nucleus; Cell Survival; Endopeptidases; Gene Expression Profiling; Gene Expression Regulation; HEK293 Cells; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Intracellular Signaling Peptides and Proteins; Mice; Microtubule-Associated Proteins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; NF-kappa B; Oligonucleotide Array Sequence Analysis; Oncogene Proteins; Peroxiredoxins; Protein Deglycase DJ-1; Proteins; Ubiquitination

Interest continues to build around the early application of patient selection markers to prospectively identify patients likely to show clinical benefit from cancer therapies. Hypothesis generation and clinical strategies often begin at the preclinical stage where responder and nonresponder tumor cell lines are first identified and characterized. In the present study, we investigate the drivers of in vivo resistance to the γ-secretase inhibitor RO4929097. Beginning at the tissue culture level, we identified apparent IL6 and IL8 expression differences that characterized tumor cell line response to RO4929097. We validated this molecular signature at the preclinical efficacy level identifying additional xenograft models resistant to the in vivo effects of RO4929097. Our data suggest that for IL6 and IL8 overexpressing tumors, RO4929097 no longer impacts angiogenesis or the infiltration of tumor associated fibroblasts. These preclinical data provide a rationale for preselecting patients possessing low levels of IL6 and IL8 prior to RO4929097 dosing. Extending this hypothesis into the clinic, we monitored patient IL6 and IL8 serum levels prior to dosing with RO4929097 during Phase I. Interestingly, the small group of patients deriving some type of clinical benefit from RO4929097 presented with low baseline levels of IL6 and IL8. Our data support the continued investigation of this patient selection marker for RO4929097 and other types of Notch inhibitors undergoing early clinical evaluation.

Topics: Amyloid Precursor Protein Secretases; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Benzazepines; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Interleukin-6; Interleukin-8; Mice; Neoplasms; Treatment Outcome; Xenograft Model Antitumor Assays

Thymidine phosphorylase (TP) is often overexpressed in tumours and has a role in tumour aggressiveness and angiogenesis. Here, we determined whether TP increased tumour invasion and whether TP-expressing cancer cells stimulated angiogenesis.. Angiogenesis was studied by exposing endothelial cells (HUVECs) to conditioned medium (CM) derived from cancer cells with high (Colo320TP1=CT-CM, RT112/TP=RT-CM) and no TP expression after which migration (wound-healing-assay) and invasion (transwell-assay) were determined. The involvement of several angiogenic factors were examined by RT-PCR, ELISA and blocking antibodies.. Tumour invasion was not dependent on intrinsic TP expression. The CT-CM and RT-CM stimulated HUVEC-migration and invasion by about 15 and 40%, respectively. Inhibition by 10 μM TPI and 100 μM L-dR, blocked migration and reduced the invasion by 50-70%. Thymidine phosphorylase activity in HUVECs was increased by CT-CM. Reverse transcription-polymerase chain reaction revealed a higher mRNA expression of bFGF (Colo320TP1), IL-8 (RT112/TP) and TNF-α, but not VEGF. Blocking antibodies targeting these factors decreased the migration and invasion that was induced by the CT-CM and RT-CM, except for IL-8 in CT-CM and bFGF in RT-CM.. In our cell line panels, TP did not increase the tumour invasion, but stimulated the migration and invasion of HUVECs by two different mechanisms. Hence, TP targeting seems to provide a potential additional strategy in the field of anti-angiogenic therapy.

Topics: Angiogenesis Inducing Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Endothelial Cells; Fibroblast Growth Factor 2; Focal Adhesion Kinase 1; Humans; Interleukin-8; Neoplasm Invasiveness; Neoplasms; Ribosomal Protein S6 Kinases, 70-kDa; Thymidine Phosphorylase; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Interleukin-8 (IL-8, CXCL8) is readily produced by human malignant cells. Dendritic cells (DC) both produce IL-8 and express the IL-8 functional receptors CXCR1 and CXCR2. Most human colon carcinomas produce IL-8. IL-8 importance in malignancies has been ascribed to angiogenesis promotion.. IL-8 effects on human monocyte-derived DC biology were explored upon DC exposure to recombinant IL-8 and with the help of an IL-8 neutralizing mAb. In vivo experiments were performed in immunodeficient mice xenografted with IL-8-producing human colon carcinomas and comparatively with cell lines that do not produce IL-8. Allogenic T lymphocyte stimulation by DC was explored under the influence of IL-8. DC and neutrophil chemotaxis were measured by transwell-migration assays. Sera from tumor-xenografted mice contained increasing concentrations of IL-8 as the tumors progress. IL-8 production by carcinoma cells can be modulated by low doses of cyclophosphamide at the transcription level. If human DC are injected into HT29 or CaCo2 xenografted tumors, DC are retained intratumorally in an IL-8-dependent fashion. However, IL-8 did not modify the ability of DC to stimulate T cells. Interestingly, pre-exposure of DC to IL-8 desensitizes such cells for IL-8-mediated in vitro or in vivo chemoattraction. Thereby DC become disoriented to subsequently follow IL-8 chemotactic gradients towards malignant or inflamed tissue.. IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation.

Topics: Animals; Cell Adhesion; Cell Line, Tumor; Cell Movement; Cell Proliferation; Chemotactic Factors; Dendritic Cells; Humans; Injections; Interleukin-8; Lymphocyte Activation; Mice; Mice, SCID; Neoplasms; Neutrophils; T-Lymphocytes; Tumor Microenvironment; Xenograft Model Antitumor Assays

Tumour-derived microvesicles (TMVs) may interact with cells of the immune system. Our previous observations indicated that TMVs modulate production of cytokines and reactive oxygen species (ROS) by monocytes. This study was designed to determine the role of TMVs in stimulation of chemokine production by human monocytes.. Chemokines at the mRNA and protein level were detected by real-time PCR and by Western blot, respecively. Chemokine release and chemotaxis of blood leukocytes were analysed by flow cytometry. Matrigel assay was used to determine angiogenesis in a NOD-SCID mice model.. TMVs induced secretion of interleukin-8 (CXCL8), monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein-1α (CCL3) and MIP-1β (CCL4), and regulated on activation normal T-cells expressed and secreted (CCL5) chemokines and accumulation of their mRNA in monocytes. Moreover, TMVs enhanced angiogenesis in NOD-SCID mice by delivering chemokines and via stimulation of monocytes. In addition, TMVs may be storage for chemokines thus inducing chemotaxis of blood leukocytes.. These results further support the role of TMVs in modulation of monocyte biological activity.

Topics: Animals; Cells, Cultured; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Humans; Interleukin-8; Macrophages; Mice; Mice, Inbred NOD; Mice, SCID; Microvessels; Monocytes; Neoplasms; Neovascularization, Pathologic; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Even though oncolytic adenovirus (Ad) has been highlighted in the field of cancer gene therapy, transductional targeting and immune privilege still remain difficult challenges. The recent reports have noted the increasing tendency of adenoviral surface shielding with polymer to overcome the limits of its practical application. We previously reported the potential of the biodegradable polymer, poly(CBA-DAH) (CD) as a promising candidate for efficient gene delivery. To endow the selective-targeting moiety of tumor vasculature to CD, cRGDfC well-known as a ligand for cell-surface integrins on tumor endothelium was conjugated to CD using hetero-bifunctional cross-linker SM (PEG)(n). The cytopathic effects of oncolytic Ad coated with the polymers were much more enhanced dose-dependently when compared with that of naked Ad in cancer cells selectively. Above all, the most potent oncolytic effect was assessed with the treatment of Ad/CD-PEG(500)-RGD in all cancer cells. The enhanced cytopathic effect of Ad/RGD-conjugated polymer was specifically inhibited by blocking antibodies to integrins, but not by blocking antibody to CAR. HT1080 cells treated with Ad/CD-PEG(500)-RGD showed strong induction of apoptosis and suppression of IL-8 and VEGF expression as well. These results suggest that RGD-conjugated bioreducible polymer might be used to deliver oncolytic Ad safely and efficiently for tumor therapy.

Topics: Adenoviridae; Apoptosis; Cell Line, Tumor; Coxsackie and Adenovirus Receptor-Like Membrane Protein; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Humans; Integrins; Interleukin-8; Materials Testing; Molecular Structure; Neoplasms; Oligopeptides; Oncolytic Viruses; Particle Size; Polymers; Receptors, Virus; RNA, Small Interfering; Vascular Endothelial Growth Factor A

There is substantial evidence that many human cancers are driven by a subpopulation of cells that display stem cell properties. These cancer stem cells (CSC) may also contribute to metastasis and treatment resistance. Furthermore, just as normal stem cells are regulated by their microenvironment, or niche, CSCs interact with and in turn are regulated by cells in the tumor microenvironment. These interactions involve inflammatory cytokines, such as interleukin (IL)-1, IL-6, and IL-8, which in turn activate Stat3/NF-κB pathways in both tumor and stromal cells. Activation of these pathways stimulates further cytokine production, generating positive feedback loops that in turn drive CSC self-renewal. These cytokine loops and the pathways they regulate resemble those activated during chronic inflammation and wound healing, and may contribute to the known link between inflammation and cancer. Inhibitors of these cytokines and their receptors have been developed as anti-inflammatory agents. By blocking signals from the tumor microenvironment, these agents have the potential to target CSCs. Future clinical trials using these compounds will be needed to determine whether targeting the CSC population has clinical benefit.

Topics: Anti-Inflammatory Agents; Cytokines; Humans; Inflammation; Interleukin-8; Neoplasms; Neoplastic Stem Cells; NF-kappa B; Signal Transduction; Tumor Microenvironment

A short, 4-step route to the scaffold of frondosin A and B is reported. The [1-methoxycarbonyl-5-(2',5'-dimethoxyphenyl)pentadienyl]Fe(CO)(3)(+) cation was prepared in two steps from (methyl 6-oxo-2,4-hexadienoate)Fe(CO)(3). Reaction of this cation with isopropenyl Grignard or cyclohexenyllithium reagents affords (2-alkenyl-5-aryl-1-methoxycarbonyl-3-pentene-1,5-diyl)Fe(CO)(3) along with other addition products. Oxidative decomplexation of these (pentenediyl)iron complexes, utilizing CuCl(2), affords 6-aryl-3-methoxycarbonyl-1,4-cycloheptadienes via the presumed intermediacy of a cis-divinylcyclopropane.

Topics: Alkadienes; Animals; Aquatic Organisms; Autoimmune Diseases; Bridged Bicyclo Compounds; Cations; Chemistry, Pharmaceutical; Ferric Compounds; Humans; Interleukin-8; Iron; Magnetic Resonance Spectroscopy; Models, Molecular; Neoplasms; Oxidation-Reduction; Porifera; Receptors, Interleukin-8

Bacteremia is one of the most important causes of morbidity and mortality in cancer patients. The aim of this study was to evaluate the diagnostic usefulness of procalcitonin (PCT), interleukin 8 (IL-8), interleukin 6 (IL-6), and C-reactive protein (CRP) in the detection of bacteremia in cancer patients.. PCT, IL-8, IL-6, and CPR levels were measured in 2 groups of cancer patients who had fever: one group with true bacteremia and another without bacteremia.. Seventy-nine febrile episodes were analyzed in 79 patients, 43 men and 36 women. Forty-four patients were in the true bacteremia group. Significant differences in PCT (P<0.001), IL-8 (P<0.001), and IL-6 (P=0.002) values were found between patients with and without true bacteremia. CPR results were not significantly different between the groups (P=0.23). The cut-off point for PCT was 0.5 ng/mL and this parameter yielded the best specificity at 91.4%, with a sensitivity of 59.1%.. Among the infection markers studied, PCT provided the most information for diagnosing bacteremia in cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Bacteremia; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Fungemia; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Neoplasms; Prospective Studies; Protein Precursors

To detect the role of activated protein C(APC) on proliferation of endothelial cell and investigate the expression of endothelial protein C receptor( EPCR) in variety of tumor cell lines.. The effect of APC on endotheliocyte proliferation was determined by MTT colorimetry. IL-6 and IL-8 in supernatant were measured by ELISA. Expression of EPCR were measured by semi-quantitative RT-PCR.. APC can increase the proliferation of EC significantly. EPCR gene was found in 91.7% of solid tumors and 66.7% of hematopoietic malignancies.. APC can stimulate the proliferation of endothelial cell. High expression of EPCR in tumor cell lines provides a potential biological marker for malignancies.

Topics: Antigens, CD; Cell Line, Tumor; Cell Proliferation; Endothelial Protein C Receptor; Endothelium, Vascular; Gene Expression; Humans; Interleukin-6; Interleukin-8; Neoplasms; Protein C; Receptors, Cell Surface

Three-dimensional culture alters cancer cell signaling; however, the underlying mechanisms and importance of these changes on tumor vascularization remain unclear. A hydrogel system was used to examine the role of the transition from 2D to 3D culture, with and without integrin engagement, on cancer cell angiogenic capability. Three-dimensional culture recreated tumor microenvironmental cues and led to enhanced interleukin 8 (IL-8) secretion that depended on integrin engagement with adhesion peptides coupled to the polymer. In contrast, vascular endothelial growth factor (VEGF) secretion was unaffected by 3D culture with or without substrate adhesion. IL-8 diffused greater distances and was present in higher concentrations in the systemic circulation, relative to VEGF. Implantation of a polymeric IL-8 delivery system into GFP bone marrow-transplanted mice revealed that localized IL-8 up-regulation was critical to both the local and systemic control of tumor vascularization in vivo. In summary, 3D integrin engagement within tumor microenvironments regulates cancer cell angiogenic signaling, and controlled local and systemic blockade of both IL-8 and VEGF signaling may improve antiangiogenic therapies.

Topics: Animals; Bone Marrow Transplantation; Cell Culture Techniques; Diffusion; Humans; Hydrogels; Integrins; Interleukin-8; Mice; Models, Biological; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Vascular Endothelial Growth Factor A

Angiostatin, an endogenous angiogenesis inhibitor, is a fragment of plasminogen. Its anti-angiogenic activity was discovered with functional assays in vivo, however, its direct action on endothelial cells is moderate and identification of definitive mechanisms of action has been elusive to date. We had previously demonstrated that innate immune cells are key targets of angiostatin, however the pathway involved in this immune-related angiogenesis inhibition was not known. Here we present evidence that IL-12, a principal TH1 cytokine with potent anti-angiogenic activity, is the mediator of angiostatin's activity.. Function blocking antibodies and gene-targeted animals were employed or in vivo studies using the subcutaneous matrigel model of angiogenesis. Quantitative real-time PCR were used to assess modulation of cytokine production in vitro.. Angiostatin inhibts angiogenesis induced by VEGF-TNFalpha or supernatants of Kaposi's Sarcoma cells (a highly angiogenic and inflammation-associated tumor). We found that function-blocking antibodies to IL-12 reverted angiostatin induced angiogenesis inhibition. The use of KO animal models revealed that angiostatin is unable to exert angiogenesis inhibition in mice with gene-targeted deletions of either the IL-12 specific receptor subunit IL-12Rbeta2 or the IL-12 p40 subunit. Angiostatin induces IL-12 mRNA synthesis by human macrophages in vitro, suggesting that these innate immunity cells produce IL-12 upon angiostatin stimulation and could be a major cellular mediator.. Our data demonstrate that an endogenous angiogenesis inhibitor such as angiostatin act on innate immune cells as key targets in inflammatory angiogenesis. Angiostatin proves to be anti-angiogenic as an immune modulator rather than a direct anti-vascular agent. This article is dedicated to the memory of Prof Judah Folkman for his leadership and for encouragement of these studies.

Topics: Angiogenesis Inhibitors; Angiostatins; Animals; Cell Line, Tumor; Chemokine CCL2; Humans; Immune System; Immunity, Innate; Interleukin-12; Interleukin-8; Macrophages; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Polymorphonuclear neutrophils (PMNs) are potent effectors of inflammation and their attempts to respond to cancer are suggested by their systemic, regional and intratumoral activation. We previously reported on the recruitment of CD11b+ leukocytes due to tumor site-specific enrichment of TNF activity after intravenous administration of a dimeric TNF immunokine with specificity for fibroblast activation protein (FAP). However, TNF-induced chemo-attraction and extravasation of PMNs from blood into the tumor is a multistep process essentially mediated by interleukin 8. With the aim to amplify the TNF-induced and IL-8-mediated chemotactic response, we generated immunocytokines by N-terminal fusion of a human anti-FAP scFv fragment with human IL-8 (IL-8(72)) and its N-terminally truncated form IL-8(3-72). Due to the dramatic difference in chemotaxis induction in vitro, we favored the mature chemokine fused to the anti-FAP scFv for further investigation in vivo. BALB/c nu/nu mice were simultaneously xenografted with FAP-positive or -negative tumors and extended chemo-attraction of PMNs was only detectable in FAP-expressing tissue after intravenous administration of the anti-FAP scFv-IL-8(72) construct. As TNF-activated PMNs are likewise producers and primary targets for IL-8, we investigated the therapeutic efficacy of co-administration of both effectors: Sequential application of scFv-IL-8(72) and dimeric IgG1-TNF fusion proteins significantly enhanced anti-tumor activity when compared either to a single effector treatment regimen or sequential application of non-targeted cytokines, indicating that the tumor-restricted sequential application of IL-8(72) and TNF is a promising approach for cancer therapy.

Topics: Animals; Antigens; Antigens, Neoplasm; Biomarkers, Tumor; Chemotaxis; Endopeptidases; Gelatinases; Humans; Immunotherapy; Interleukin-8; Kinetics; Leukocytes, Mononuclear; Membrane Proteins; Mice; Neoplasms; Protein Multimerization; Recombinant Fusion Proteins; Serine Endopeptidases; Transfection; Treatment Outcome; Tumor Necrosis Factor-alpha; Xenograft Model Antitumor Assays

Monoclonal antibodies (mAbs) and tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR), which is often pathogenetically overexpressed or mutated in epithelial malignancies and glioma, have been modestly successful, with some approved for human use. MAb 806 was raised against de2-7EGFR (or EGFRvIII), a constitutively active mutation expressed in gliomas, but also recognizes a subset (<10%) of wild-type (wt) EGFR when it is activated by autocrine loop, overexpression or mutation. It does not bind inactive EGFR in normal tissues like liver. Glioma xenografts expressing the de2-7EGFR treated with mAb 806 show reduced receptor autophosphorylation, increased p27(KIP1) and reduced cell proliferation. Xenografts expressing the wtEGFR activated by overexpression or autocrine ligand are also inhibited by mAb 806, but the mechanism of inhibition has been difficult to elucidate, especially because mAb 806 does not prevent wtEGFR phosphorylation or downstream signalling in vitro. Thus, we examined the effects of mAb 806 on A431 xenograft angiogenesis. MAb 806 increases vascular endothelial growth factor (VEGF) and interleukin-8 production by activating NF-kappaB and normalizes tumour vasculature. Pharmacological inhibition of NF-kappaB completely abrogated mAb 806 activity, demonstrating that NF-kappaB activation is necessary for its anti-tumour function in xenografts. Given the increase in VEGF, we combined mAb 806 with bevacizumab in vivo, resulting in additive activity.

Topics: Animals; Antibodies, Monoclonal; Cell Line, Tumor; Epitopes; ErbB Receptors; Female; Humans; Interleukin-8; Mice; Mice, Nude; Mutation; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; NF-kappa B; Vascular Endothelial Growth Factor A

To determine the mechanisms of Signal Transducer and Activator of Transcription 1 (Stat1)-associated radioresistance developed by nu61 tumour selected in vivo by fractionated irradiation of the parental radiosensitive tumour SCC61.. Radioresistence of nu61 and SCC61 in vitro was measured by clonogenic assay. Apoptotic response of nu61 and SCC61 cells to genotoxic stress was examined using caspase-based apoptotic assays. Co-cultivation of carboxyfluorescein diacetate, succinimidyl ester (CFDE-SE)-labeled nu61 with un-labeled SCC61 was performed at 1:1 ratio. Production of interleukin-6, interleukin-8 and soluble receptor of interleukin 6 (IL6, IL8 and sIL6R) was measured using Enzyme-Linked Immunosorbent Assay (ELISA).. Radioresistant nu61 was also resistant to interferon-gamma (IFNgamma) and the death ligands of tumour necrosis factor alpha receptor (TNFR) family when compared to SCC61. This combined resistance is due to an impaired apoptotic response in nu61. Relative to SCC61, nu61 produced more IL6, IL8 and sIL6R. Using Stat1 knock-downs we demonstrated that IL6 and IL8 production is Stat1-dependent. Treatment with neutralising antibodies to IL6 and IL8, but not to either cytokine alone sensitised nu61 to genotoxic stress induced apoptosis.. Nu61, which over-expresses Stat1 pathway, is deficient in apoptotic response to ionising radiation and cytotoxic ligands. This resistance to apoptosis is associated with Stat1-dependent production of IL6 and IL8 and suppression of caspases 8, 9 and 3.

Topics: Animals; Apoptosis; Caspases; Cell Line, Tumor; Cell Survival; Coculture Techniques; Cytokines; Cytotoxins; DNA Damage; Gene Expression Regulation, Neoplastic; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Interleukins; Neoplasms; Radiation Tolerance; Radiation, Ionizing; Receptors, Tumor Necrosis Factor; Signal Transduction; STAT1 Transcription Factor

The mitotic checkpoint gene CHFR (checkpoint with forkhead and ring finger domains) is silenced in various human cancers by promoter hypermethylation, suggesting that CHFR is a tumor suppressor. Here, we show that CHFR functions as a negative regulator of the nuclear factor-kappaB (NF-kappaB) pathway. Expression of CHFR inhibited NF-kappaB reporter activity, whereas knockdown of CHFR activated reporter activity. These activities are independent of its RING finger domain. Furthermore, we found that CHFR physically interacts with p65 in cells. Electrophoretic mobility shift assays (EMSAs) and ELISA-based NF-kappaB-binding assays showed that CHFR negatively regulated transcriptional activity of p65. In addition, our data show that interleukin (IL)-8 is significantly downregulated by CHFR, and that the migration of human endothelial cells is suppressed in culture medium conditioned from CHFR-expressing cancer cells. Using a xenograft model, we show that neovascularization is suppressed by adenovirus-mediated transfer of CHFR. These results indicate that expression of CHFR markedly reduces the expression of IL-8 through the inhibition of NF-kappaB. As the NF-kappaB signaling pathway plays a critical role in the development and progression of cancer, our findings show the functional relationship between epigenetic alteration and inflammation/angiogenesis in human cancer cells, thereby showing several potential targets for therapeutic intervention.

Topics: Animals; Cell Cycle Proteins; Cell Line, Tumor; Cell Nucleus; DNA; Down-Regulation; Electrophoretic Mobility Shift Assay; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Interleukin-8; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Poly-ADP-Ribose Binding Proteins; Transcription Factor RelA; Transcription, Genetic; Ubiquitin-Protein Ligases; Xenograft Model Antitumor Assays

Topics: Animals; Cellular Senescence; Humans; Inflammation; Interleukin-6; Interleukin-8; MicroRNAs; Neoplasms

To construct the sense or antisense IL-8 eukaryotic expression vectors.. Sense or antisense IL-8 full length gene were amplified by RT-PCR and cloned into eukaryotic expression vector pcDNA3.1(+). After the identification by PCR, restriction endonuclease digestion and the nucleotide sequencing, the recombinant vectors were transfected into human ovarian carcinoma A2780 and SKOV3 cell lines transiently by lipofectamine mediation. The expression of IL-8 gene and protein were detected by RT-PCR and ELISA.. The sense or antisense IL-8 eukaryotic expression vectors were constructed and verified. The expression of IL-8 gene and protein in A2780 cells transfected with pcDNA3.1(+)-ssIL-8 were increased, whereas the expression of IL-8 protein in SKOV3 cells transfected with pcDNA3.1(+)-asIL-8 was decreased.. The eukaryotic expression vectors pcDNA3.1(+)-ssIL-8 or pcDNA3.1(+)-asIL-8 have been constructed successfully, which lays a base for further study on roles of IL-8 in ovarian cancer and other tumors.

Topics: Cell Line, Tumor; DNA, Antisense; Gene Expression; Genetic Vectors; Humans; Interleukin-8; Neoplasms

IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKbeta degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKbeta ubiquitination may contribute to tumorigenesis.

Topics: Animals; Breast Neoplasms; Carrier Proteins; Cell Line; Cell Line, Tumor; Cullin Proteins; DNA Copy Number Variations; Female; Gene Expression; Humans; I-kappa B Kinase; Interleukin-8; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Kelch-Like ECH-Associated Protein 1; Mice; Mutation; Neoplasms; Neovascularization, Physiologic; NF-kappa B; Protein Binding; Protein Interaction Domains and Motifs; RNA, Small Interfering; Signal Transduction; Transcription Factor RelA; Transfection; Tumor Necrosis Factor-alpha; Ubiquitination

There is evidence that polymorphonuclear neutrophils (PMNs) can exert severe antineoplastic effects. Cross-talk between tumour cells and endothelial cells (ECs) is necessary for the accumulation of PMN around a tumour. This work reports the ability of two PMN-sensitive, human, permanent cell lines-colorectal adenocarcinoma (HT-29) and pharyngeal squamous-cell carcinoma (FaDu) cells-to act as inflammatory foci. PMNs were cytotoxic to both lines, the adhesion of the PMNs to the tumour cells being important in this effect. The tumour cells released appreciable amounts of IL-8 and GROalpha, and induced the transmigration of PMN through human microvascular-EC monolayers. Conditioning media associated with both lines induced the adhesion of PMN and the surface expression of ICAM-1 in microvascular-EC. In addition, FaDu-conditioning-medium strongly induced the production of proinflammatory cytokines by microvascular-EC. These results support the idea that tumour cells might normally induce a potent acute inflammatory response, leading to their own destruction.

Topics: beta 2-Glycoprotein I; Blotting, Western; Cell Adhesion; Cell Line; Cell Line, Tumor; Cell Movement; Chemokine CXCL1; Cytokines; Flow Cytometry; HT29 Cells; Humans; Intercellular Adhesion Molecule-1; Interleukin-8; Neoplasms; Neutrophils

Tank-Binding-Kinase 1 (TBK-1) has been proposed as a putative mediator in tumor angiogenesis. It was the aim of our study to gain insight into TBK-1s role in tumor angiogenesis and tumor-associated microvascular inflammation. TBK-1 overexpressing KB 3-1 cells were generated and their growth characteristics were analyzed. Expression of TBK-1, VEGF, RANTES and Il-8 were quantified using qPCR and western blot analysis. Intravital microscopy using the dorsal skinfold chamber model in nude mice addressed total (TIVD) and functional intratumoral vascular density (FIVD), perfusion index, vessel diameter and leukocyte sticking. Transfection of KB-3 cells resulted in significantly increased TBK-1, RANTES and IL-8 expression without affecting cellular growth. Supernatants from TBK-1 overexpressing clones induced HUVEC proliferation. Intravital microscopy identified an increase in leukocyte sticking paralleled by significantly increased TIVD and FIVD as a result of increased VEGF expression. Therefore, TBK-1 represents a novel mediator of tumor angiogenesis and exerts proinflammatory effects via upregulation of inflammatory cytokines. The TBK-1 pathway might be an important cross-link between angiogenesis and inflammation representing a possible target for anti-tumor therapy.

Topics: Animals; Antineoplastic Agents; Chemokine CCL5; Clone Cells; Humans; Inflammation; Interleukin-8; KB Cells; Male; Mice; Mice, Nude; Microcirculation; Neoplasms; Neovascularization, Pathologic; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Vascular Endothelial Growth Factor A

Topics: Animals; Apoptosis; CCAAT-Enhancer-Binding Proteins; Cellular Senescence; Humans; Interleukin-6; Interleukin-8; Mice; Neoplasms; NF-kappa B; Proto-Oncogene Proteins B-raf; Receptors, Interleukin-8B

Vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (basic FGF) are angiogenic growth factors which may be useful as biomarkers in drug development, where they could give early information on the antiangiogenic activity of novel anticancer compounds.. We compared two commercially available assays, enzyme linked immunosorbent assay (ELISA) and a multiplexed bead-based immunoassay (xMAP), for the quantification of these factors in plasma samples from more than 100 cancer patients and healthy individuals.. For VEGF and IL-8, but not for basic FGF, xMAP was more sensitive than the respective ELISA. This was true for healthy subjects as well as for cancer patients. Intraassay precision was comparable between both assay formats. Linear regression analysis of VEGF concentrations demonstrated a good correlation between ELISA and xMAP. Bland-Altman analysis showed a systematic difference between both assays, with ELISA giving higher concentration values. VEGF levels were higher in female volunteers, and both assays were able to detect this difference.. Multiplexed microsphere-based immunoassays have the potential to substitute ELISA for the detection of proangiogenic growth factors in clinical studies. Their shorter assay times and their ability to quantify multiple analytes in a small sample volume are advantageous.

Topics: Adult; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Fibroblast Growth Factor 2; Health; Humans; Immunoassay; Interleukin-8; Linear Models; Male; Microspheres; Middle Aged; Neoplasms; Reference Standards; Sensitivity and Specificity; Sex Characteristics; Vascular Endothelial Growth Factor A

Recent experiments show that vascular endothelial growth factor (VEGF) is the crucial mediator of downstream events that ultimately lead to enhanced endothelial cell survival and increased vascular density within many tumors. The newly discovered pathway involves up-regulation of the anti-apoptotic protein Bcl-2, which in turn leads to increased production of interleukin-8 (CXCL8). The VEGF-Bcl-2-CXCL8 pathway suggests new targets for the development of anti-angiogenic strategies including short interfering RNA (siRNA) that silence the CXCL8 gene and small molecule inhibitors of Bcl-2. In this paper, we present and validate a mathematical model designed to predict the effect of the therapeutic blockage of VEGF, CXCL8, and Bcl-2 at different stages of tumor progression. In agreement with experimental observations, the model predicts that curtailing the production of CXCL8 early in development can result in a delay in tumor growth and vascular development; however, it has little effect when applied at late stages of tumor progression. Numerical simulations also show that blocking Bcl-2 up-regulation, either at early stages or after the tumor has fully developed, ensures that both microvascular and tumor cell density stabilize at low values representing growth control. These results provide insight into those aspects of the VEGF-Bcl-2-CXCL8 pathway, which independently and in combination, are crucial mediators of tumor growth and vascular development. Continued quantitative modeling in this direction may have profound implications for the development of novel therapies directed against specific proteins and chemokines to alter tumor progression.

Topics: Computer Simulation; Interleukin-8; Models, Biological; Neoplasms; Neovascularization, Pathologic; Proto-Oncogene Proteins c-bcl-2; Vascular Endothelial Growth Factor A

Enzastaurin (LY317615) is a novel serine/threonine kinase inhibitor, targeting Protein Kinase C-beta (PKC-beta), and PI3K/AKT pathways to inhibit angiogenesis and tumor cell proliferation. The aims of this study were to determine whether Enzastaurin has direct antitumor activity against freshly explanted tumor cells and to correlate mRNA expression of genes related to the proposed mechanism of action of enzastaurin with in vitro chemosensitivity.. Freshly biopsied tumor cells were studied using soft-agar cell cloning experiments (SACCE) to determine the in vitro chemosensitivity to enzastaurin. An aliquot of the same tumor specimens was shock-frozen and total RNA was isolated for standardized multiplex rt-PCR experiments for gene expression of PKC-beta1, PKC-beta2, IL-8, IL-8RA, IL-8RB, Glycogen Synthase Kinase 3 beta (GSK-3beta) and TGF-beta1. Correlations, threshold optimization, sensitivity, specificity, and efficiency were analyzed using the appropriate statistical methodologies.. Seventy-two tumor samples were collected and 63 were fully evaluable. Low levels of mRNA expression of GSK-3beta and high levels of mRNA expression of IL-8 were highly significantly correlated with chemosensitivity to enzastaurin. Optimization analyses demonstrated threshold values of 4,000 copies for IL-8 and three copies for GSK-3beta relative to 10(4) copies of beta-actin. However, no correlation between mRNA expression of PKC-beta1, PKC-beta2, IL-8RA, IL-8RB and chemosensitivity to enzastaurin was observed. Expression of TGF-beta1 mRNA was not detectable in the specimens investigated.. mRNA expression levels of IL-8 and GSK-3beta correlate with antitumor activity of enzastaurin. These results form a rational basis for clinical trials to evaluate the expression of these genes as potential predictors for treatment outcome after enzastaurin chemotherapy.

Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Gene Expression; Glycogen Synthase Kinase 3; Humans; Indoles; Interleukin-8; Neoplasms; RNA, Messenger; Tumor Cells, Cultured

Patients with chemotherapy-related neutropenia and fever are usually hospitalized and treated on empirical intravenous broad-spectrum antibiotic regimens. Early diagnosis of sepsis in children with febrile neutropenia remains difficult due to non-specific clinical and laboratory signs of infection. We aimed to analyze whether IL-6 and IL-8 could define a group of patients at low risk of septicemia.. A prospective study was performed to assess the potential value of IL-6, IL-8 and C-reactive protein serum levels to predict severe bacterial infection or bacteremia in febrile neutropenic children with cancer during chemotherapy. Statistical test used: Friedman test, Wilcoxon-Test, Kruskal-Wallis H test, Mann-Whitney U-Test and Receiver Operating Characteristics.. The analysis of cytokine levels measured at the onset of fever indicated that IL-6 and IL-8 are useful to define a possible group of patients with low risk of sepsis. In predicting bacteremia or severe bacterial infection, IL-6 was the best predictor with the optimum IL-6 cut-off level of 42 pg/ml showing a high sensitivity (90%) and specificity (85%).. These findings may have clinical implications for risk-based antimicrobial treatment strategies.

Topics: Adolescent; Adult; Anti-Bacterial Agents; C-Reactive Protein; Ceftazidime; Child; Child, Preschool; Female; Fever; Germany; Humans; Infant; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Prospective Studies; Risk Factors; Sepsis

The bone marrow microenvironment is further enriched by growth factors released during osteoclastic bone resorption. It has been reported that the chemokine interleukin (IL)-8 is a potent and direct activator of osteoclastic differentiation and bone resorption. However, the effect of bone-derived growth factors on the IL-8 production in human cancer cells and the promotion of osteoclastogenesis are largely unknown. The aim of this study was to investigate whether osteoblast-derived TGF-beta1 is associated with osteolytic bone diseases.. IL-8 mRNA levels were measured using RT-PCR analysis. MAPK phosphorylation was examined using the Western blot method. siRNA was used to inhibit the expression of TGF-beta1, BMP-2, and IGF-1. DNA affinity protein-binding assay and chromatin immunoprecipitation assays were used to study in vitro and in vivo binding of c-fos, c-jun, p65, and p50 to the IL-8 promoter. A transient transfection protocol was used to examine IL-8, NF-kappaB, and activator protein (AP)-1 activity.. Osteoblast conditioned medium (OBCM) induced activation of IL-8, AP-1, and NF-kappaB promoter in human cancer cells. Osteoblasts were transfected with TGF-beta1, BMP-2, or IGF-1 small interfering RNA, and the medium was collected after 48 h. TGF-beta1 but not BMP-2 or IGF-1 siRNA inhibited OBCM-induced IL-8 release in human cancer cells. In addition, TGF-beta1 also directly induced IL-8 release in human cancer cells. Activation of AP-1 and NF-kappaB DNA-protein binding and MAPKs after TGF-beta1 treatment was shown, and TGF-beta1-induced IL-8 promoter activity was inhibited by the specific inhibitors of MAPK cascades.. In this study, we provide evidence to show that the osteoblasts release growth factors, including TGF-beta1, BMP-2, and IGF-1. TGF-beta1 is the major contributor to the activation of extracellular signal-related kinase (ERK), p38, and c-Jun N-terminal kinase (JNK), leading to the activation of AP-1 and NF-kappaB on the IL-8 promoter and initiation of IL-8 mRNA and protein release, thereby promoting osteoclastogenesis.

Topics: Cell Line, Tumor; Culture Media; Enzyme Activation; Humans; Interleukin-8; Mitogen-Activated Protein Kinases; Neoplasms; NF-kappa B; Osteoblasts; Promoter Regions, Genetic; Protein Binding; Protein Kinase Inhibitors; Transcription Factor AP-1; Transforming Growth Factor beta1

Semaphorins are a large family of evolutionarily conserved morphogenetic molecules originally identified for their repelling role in axonal guidance. Intriguingly, semaphorins have recently been implicated in cancer progression (Neufeld, G., T. Lange, A. Varshavsky, and O. Kessler. 2007. Adv. Exp. Med. Biol. 600:118-131). In particular, semaphorin 3B (SEMA3B) is considered a putative tumor suppressor, and yet we found that it is expressed at high levels in many invasive and metastatic human cancers. By investigating experimental tumor models, we confirmed that SEMA3B expression inhibited tumor growth, whereas metastatic dissemination was surprisingly increased. We found that SEMA3B induced the production of interleukin (IL) 8 by tumor cells by activating the p38-mitogen-activated protein kinase pathway in a neuropilin 1-dependent manner. Silencing the expression of endogenous SEMA3B in tumor cells impaired IL-8 transcription. The release of IL-8, in turn, induced the recruitment of tumor-associated macrophages and metastatic dissemination to the lung, which could be rescued by blocking IL-8 with neutralizing antibodies. In conclusion, we report that SEMA3B exerts unexpected functions in cancer progression by fostering a prometastatic environment through elevated IL-8 secretion and recruitment of macrophages coupled to the suppression of tumor growth.

Topics: Breast Neoplasms; Cell Line, Tumor; Conserved Sequence; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; Humans; Interleukin-8; Membrane Glycoproteins; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Polymerase Chain Reaction; Semaphorins

Severe sepsis is not clinically apparent during the first 24 hours of hospitalization in most children with cancer and febrile neutropenia (FN), delaying targeted interventions that could impact mortality. The aim of this study was to prospectively evaluate biomarkers obtained within 24 hours of hospitalization as predictors of severe sepsis before it becomes clinically evident.. Children with cancer, admitted with FN at high risk for an invasive bacterial infection in 6 public hospitals in Santiago, Chile, were monitored throughout their clinical course for occurrence of severe sepsis. Clinical, demographic and 6 biomarkers [eg, blood urea nitrogen, serum glucose, lactic dehydrogenase, serum C-reactive protein (CRP), interleukin (IL)-8, and procalcitonin] were obtained at the time of admission and after 24 hours. Biomarkers independently associated with severe sepsis diagnosed after the first 24 hours of hospitalization were identified by logistic regression analysis.. A total of 601 high risk FN episodes were enrolled between June 2004 and October 2006; 151 (25%) developed severe sepsis of which 116 (77%) were not clinically apparent during the first 24 hours of hospitalization. Risk factors for severe sepsis were age > or =12 years [odds ratio (OR): 3.85; 95% confidence interval (CI): 2.41-6.15], admission CRP > or =90 mg/L (OR: 2.03; 95% CI: 1.32-3.14), admission IL-8 > or =200 pg/mL (OR: 2.39; 95% CI: 1.51-3.78), 24-hour CRP > or =100 mg/L (OR: 3.06; 95% CI: 1.94-4.85), and 24-hour IL-8 > or =300 pg/mL (OR: 3.13; 95% CI 1.92-5.08).. Age > or =12 years and admission or 24-hour values of CRP > or =90/100 mg/L and IL-8 > or =200/300 pg/mL are predictors of sepsis not clinically apparent during the first 24 hours of hospitalization.

Topics: Adolescent; Age Factors; Biomarkers; Blood Glucose; Blood Urea Nitrogen; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Chile; Female; Fever of Unknown Origin; Hospitalization; Humans; Interleukin-8; L-Lactate Dehydrogenase; Logistic Models; Male; Neoplasms; Neutropenia; Prospective Studies; Protein Precursors; Sepsis

A surface immobilized optical protein sensor has been utilized to detect Interleukin-8 (IL-8) protein, an oral cancer marker, and can reach limit of detection (LOD) at 1.1 pM in buffer without using enzymatic amplification. Only after applying enzymatic amplification to increase the signal level by a few orders of magnitude, ELISA can reach the LOD of 1 pM level. We then develop the confocal optics based sensor for further reducing the optical noise and can extend the LOD of the surface immobilized optical protein sensor two orders in magnitude. These improvements have allowed us to detect IL-8 protein at 4.0 fM in buffer. In addition, these sensitive LODs were achieved without the use of enzymatic signal amplification, such that the simplified protocol can further facilitate the development of point-of-care devices. The ultra sensitive optical protein sensor presented in this paper has a wide number of applications in disease diagnoses. Measurements for detecting biomarkers in clinical sample are much more challenging than the measurements in buffer, due to high background noise contributed by large collections of non-target molecules. We used clinical saliva samples to validate the functionality of the optical protein sensor. Clinical detection of disease-specific biomarkers in saliva offers a non-invasive, alternative approach to using blood or urine. Currently, the main challenge of using saliva as a diagnostic fluid is its inherently low concentration of biomarkers. We compare the measurements of 40 saliva samples; half from oral cancer patients and half from a control group. The data measured by the optical protein sensor is compared with the traditional Enzyme-Linked Immunosorbant Assay (ELISA) values to validate the accuracy of our system. These positive results enable us to proceed to using confocal optical protein sensor to detect other biomarkers, which have much lower concentrations.

Topics: Biomarkers, Tumor; Biosensing Techniques; Equipment Design; Equipment Failure Analysis; Interleukin-8; Microscopy, Confocal; Neoplasm Proteins; Neoplasms; Optics and Photonics; Reproducibility of Results; Saliva; Sensitivity and Specificity

The primary objective of the study was to compare the predictive potential of procalcitonin (PCT), C-reactive protein (CRP), serum amyloid A (SAA), and interleukin (IL)-1beta, IL-6, IL-8, and IL-10, with that of the Multinational Association of Supportive Care in Cancer (MASCC) risk-index score in cancer patients on presentation with chemotherapy-induced febrile neutropenia (FN). Seventy-eight consecutive FN episodes in 63 patients were included, and MASCC scores, as well as concentrations of CRP, SAA, PCT, and IL-1beta, IL-6, IL-8 and IL-10, and haematological parameters were determined on presentation, 72 h later and at outcome. Multivariate analysis of data revealed the MASCC score, but none of the laboratory parameters, to be an accurate, independent variable (P < 0.0001) for prediction of resolution with or without complications and death. Of the various laboratory parameters, PCT had the strongest association with the MASCC score (r = -0.51; P < 0.0001). In cancer patients who present with FN, the MASCC risk-index score is a useful predictor of outcome, while measurement of PCT, CRP, SAA, or IL-1beta, IL-6, IL-8 and IL-10, is of limited value.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Bacterial Infections; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Case-Control Studies; Female; Fever; Humans; Interleukin-10; Interleukin-1beta; Interleukin-6; Interleukin-8; Interleukins; Logistic Models; Male; Middle Aged; Neoplasms; Neutropenia; Predictive Value of Tests; Prognosis; Protein Precursors; Serum Amyloid A Protein; Treatment Outcome

Polymorphisms of promotor region of IL-8, IL-10, and IL-12 genes were analyzed in cancer patients and subjects without history of cancer. The distribution of alleles of the analyzed polymorphisms in the control group coincided with that in other Caucasian populations. The incidences of three IL-10 gene polymorphisms (G-1082A, C-819T, and C-592A) significantly differed in controls and patients. Of 8 theoretically probable IL-10 gene haplotypes determined by these polymorphisms, 3 variants were revealed. Haplotype ACC was more incident in cancer patients, while ATA haplotype was rarer. The results are in line with the findings of other studies indicating the involvement of the immune system genes in the pathogenesis of cancer.

Topics: Alleles; Genetic Predisposition to Disease; Haplotypes; Humans; Interleukin-10; Interleukin-12; Interleukin-8; Neoplasms; Polymorphism, Genetic; Promoter Regions, Genetic

Topics: Bacterial Infections; Biomarkers; Child; Cytokines; Humans; Interleukin-5; Interleukin-8; Neoplasms; Neutropenia; Opportunistic Infections

Angiogenesis is a common feature observed in advanced atherosclerotic lesions. We hypothesized that oxidized phospholipids (OxPLs), which accumulate in atherosclerotic vessels can stimulate angiogenesis. We found that oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) stimulated the formation of sprouts from endothelial cell spheroids and promoted growth of capillaries into Matrigel plugs in mice. OxPLs stimulated expression of vascular endothelial growth factor (VEGF) in vivo and in several normal and tumor cell types in vitro. In addition, OxPAPC upregulated cyclooxygenase (COX)-2 and interleukin (IL)-8. COX-2 inhibitors, as well as blocking antibodies to IL-8 suppressed activation of sprouting by OxPAPC. We conclude that OxPAPC stimulates angiogenesis via autocrine mechanisms involving VEGF, IL-8, and COX-2-generated prostanoids. Our data suggest that accumulation of OxPLs may contribute to increased growth of blood capillaries in advanced lesions, thus leading to progression and destabilization of atherosclerotic plaques.

Topics: ADAM Proteins; ADAMTS1 Protein; Angiogenesis Inducing Agents; Animals; Atherosclerosis; Autocrine Communication; Cell Movement; Cells, Cultured; Cyclooxygenase 2; Endothelial Cells; Female; Interleukin-8; Lipid Metabolism; Mice; Mice, Inbred C57BL; Monocytes; Neoplasms; Neovascularization, Pathologic; Oxidation-Reduction; Phospholipids; Skin; Vascular Endothelial Growth Factor A

Topics: Animals; Humans; Inflammation; Interleukin-8; Mice; Neoplasms; ras Proteins

Pituitary tumor transforming gene1 (PTTG1) is a novel oncogene that is expressed in most tumors. It encodes a protein that is primarily involved in the regulation of sister chromatid separation during cell division. The oncogenic potential of PTTG1 has been well characterized in the mouse, particularly mouse fibroblast (NIH3T3) cells, in which it induces cell proliferation, promotes tumor formation and angiogenesis. Human tumorigenesis is a complex and a multistep process often requiring concordant expression of a number of genes. Also due to differences between rodent and human cell biology it is difficult to extrapolate results from mouse models to humans. To determine if PTTG1 functions similarly as an oncogene in humans, we have characterized its effects on human embryonic kidney (HEK293) cells.. We report that introduction of human PTTG1 into HEK293 cells through transfection with PTTG1 cDNA resulted in increased cell proliferation, anchorage-independent growth in soft agar, and formation of tumors after subcutaneous injection of nu/nu mice. Pathologic analysis revealed that these tumors were poorly differentiated. Both analysis of HEK293 cells transiently transfected with PTTG1 cDNA and analysis of tumors developed on injection of HEK293 cells that had been stably transfected with PTTG1 cDNA indicated significantly higher levels of secretion and expression of bFGF, VEGF and IL-8 compared to HEK293 cells transfected with pcDNA3.1 vector or uninvolved tissues collected from the mice. Mutation of the proline-rich motifs at the C-terminal of PTTG1 abolished its oncogenic properties. Mice injected with this mutated PTTG1 either did not form tumors or formed very small tumors. Taken together our results suggest that PTTG1 is a human oncogene that possesses the ability to promote tumorigenesis in human cells at least in part through the regulation of expression or secretion of bFGF, VEGF and IL-8.. Our results demonstrate that PTTG1 is a potent human oncogene and has the ability to induce cellular transformation of human cells. Overexpression of PTTG1 in HEK293 cells leads to an increase in the secretion and expression of bFGF, VEGF and IL-8. Mutation of C-terminal proline-rich motifs abrogates the oncogenic function of PTTG1. To our knowledge, this is the first study demonstrating the importance of PTTG1 in human tumorigenesis.

Topics: Animals; Cell Line; Cell Proliferation; Cell Transformation, Neoplastic; Fibroblast Growth Factor 2; Humans; Interleukin-8; Kidney; Mice; Mice, Nude; Neoplasm Proteins; Neoplasms; Securin; Transfection; Vascular Endothelial Growth Factor A

We previously reported that most cancer cell lines constitutively express various cytokines including IL-8. But how IL-8 gene expression is regulated in cancer cells is still unclear. p53 tumor suppressor gene plays an important role in the regulation of transcription and is mutated in cancer cell lines. We investigated whether p53 status affects the constitutive expression of IL-8 in human cancer cells. SUIT-2 and RERF-LCOK cancer cells constitutively produced high levels of IL-8 in culture medium. Both cell lines were shown to carry a p53 mutation, and constitutive NF-kappaB transcriptional activity. To analyze whether p53 status mediates IL-8 expression, the effect of wild-type p53 (wt-p53) gene transfer on activation of NF-kappaB was determined in both cell lines. ELISA showed that the IL-8 concentration in medium decreased dose dependently by transient expression of wt-p53. Western-blot analysis showed no marked change in NF-kappaB protein levels in cell nuclei. EMSA showed no repression of NF-kappaB binding activity after transient expression of wt-p53. In contrast, luciferase reporter studies indicated that transcriptional activity of NF-kappaB is suppressed by transfection of wt-p53. These results show that wt-p53 gene transfer inhibits IL-8 production and NF-kappaB transcription activity in cancer cells and suggest that constitutive IL-8 production in cancer cells is associated with mutation of p53.

Topics: Cell Line, Tumor; Down-Regulation; Gene Expression Regulation, Neoplastic; Humans; I-kappa B Proteins; Interleukin-8; Mutation; Neoplasms; NF-kappa B; NF-KappaB Inhibitor alpha; Tumor Suppressor Protein p53

To investigate the feasibility of withholding antibiotics and early discharge for patients with chemotherapy-induced neutropenia and fever at low risk of bacterial infection by a new risk assessment model.. Outpatients with febrile neutropenia were allocated to one of three groups by a risk assessment model combining objective clinical parameters and plasma interleukin 8 level. Patients with signs of a bacterial infection and/or abnormal vital signs indicating sepsis were considered high risk. Based on their interleukin-8 level, remaining patients were allocated to low or medium risk for bacterial infection. Medium-risk and high-risk patients received standard antibiotic therapy, whereas low-risk patients did not receive antibiotics and were discharged from hospital after 12 hours of a febrile observation. End points were the feasibility of the treatment protocol.. Of 196 assessable episodes, 76 (39%) were classified as high risk, 84 (43%) as medium risk, and 36 (18%) as low risk. There were no treatment failures in the low-risk group (95% CI, 0% to 10%). Therefore, sensitivity of our risk assessment model was 100% (95% CI, 90% to 100%), the specificity, positive, and negative predictive values were 21%, 13%, and 100%, respectively. Median duration of hospitalization was 3 days in the low-risk group versus 7 days in the medium- and high-risk groups (P < .0001). The incremental costs of the experimental treatment protocol amounted to a saving of 471 (US $572) for every potentially low-risk patient.. This risk assessment model appears to identify febrile neutropenic patients at low risk for bacterial infection. Antibiotics can be withheld in well-defined neutropenic patients with fever.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Antineoplastic Agents; Bacterial Infections; Child; Child, Preschool; Feasibility Studies; Female; Fever; Humans; Infant; Infant, Newborn; Interleukin-8; Male; Middle Aged; Neoplasms; Neutropenia; Patient Discharge; Predictive Value of Tests; Prospective Studies; Risk Assessment

c-Src is frequently activated in human malignancies, including colon, breast, and pancreatic carcinomas. Several recent studies have shown that activation of Src family kinases leads to tumor progression and metastasis by increasing cellular migration and invasion, promoting cell growth and survival, and deregulating expression of proangiogenic molecules. Therefore, selective inhibitors of Src are being developed for cancer therapy. In this study, we characterize the biological effects of the novel ATP-based Src family kinase inhibitor, AP23846, in tumor cells with high Src activity. As a lead compound, AP23846 is a potent c-Src kinase inhibitor (IC50 approximately 0.5 nmol/L in vitro, approximately 10-fold more potent than PP2, the most widely used commercially available Src family kinase inhibitor). At concentrations of 1 micromol/L, AP23846 led to complete Src inhibition for 48 hours in cells. No cytotoxicity was observed under these conditions, although proliferation rates were slower. Therefore, this was an excellent inhibitor to examine Src-regulated signaling pathways in tumor cells. AP23846 reduced cellular migration, vascular endothelial growth factor, and interleukin-8 in a dose-dependent fashion in pancreatic adenocarcinoma cells grown in vitro. Correspondingly, cell culture supernatants from L3.6pl pancreatic adenocarcinoma cells pretreated with AP23846 failed to promote migration of hepatic endothelial cells in vitro and failed to support angiogenesis into gel foams implanted s.c. in mice in vivo. These results suggest that Src inhibitors affect biological properties of tumor progression and may be useful as cancer therapeutic agents in more advanced disease.

Topics: Adenosine Triphosphate; Animals; Base Sequence; Blotting, Western; Cell Line, Tumor; Cell Movement; DNA Primers; Endothelium, Vascular; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Humans; Immunoprecipitation; Interleukin-8; Mice; Mice, Inbred C3H; Neoplasms; Neovascularization, Pathologic; Phosphorylation; RNA, Small Interfering; src-Family Kinases; Vascular Endothelial Growth Factor A

To compare serum levels of interleukin-6, interleukin-8 and interleukin-10 in bacteremic and non-bacteremic episodes of febrile neutropenia in children with malignant diseases, and determine their changes and correlation with C-reactive protein (CRP).. Between January 2003 and June 2004, we examined 41 episodes of febrile neutropenia in 24 children with malignant diseases who were receiving polychemotherapy. C-reactive protein was measured at the onset of febrile episodes and on days 3 and 5 from beginning of therapy. The soluble interleukins-6, -8, and -10 were determined in the serum using enzyme bound immunosorbent analysis at the onset of fever and at 24 and 72 hours after initiation of an empiric antibiotic therapy.. The CRP baseline levels differentiated the patients with unexplained fever from those with local infection but did not differentiate them from those with bacteremia. Interleukin-8 at 24 hours differentiated bacteremic from non-bacteremic episodes (P < 0.05) and at a cut-off value of 130 pg/ml it had a sensitivity of 72% and a specificity of 84% to differentiate bacteremia. Interleukin-10 at 24 hours yielded higher values in Gram (-) bacteremia in comparison with the non-bacteremic episodes (P < 0.001) and Gram (+) bacteremia (P < 0.05). Interleukin-6 at 24 hours had significantly higher values in febrile episodes of more than 3 days duration (P < 0.05).. Interleukin-8 could differentiate in the first 24 hours bacteremic from non-bacteremic episodes in febrile neutropenia, while interleukin-10 is perhaps a more accurate marker for Gram (-) bacteremia.

Topics: Adolescent; Adult; Analysis of Variance; Bacteremia; Biomarkers; C-Reactive Protein; Child; Child, Preschool; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant; Interleukin-10; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Statistics, Nonparametric

The purpose of this study is to develop a high-throughput approach to detect protein expression from hundreds and thousands of samples and to apply this technology to profile circulating angiogenic factor protein levels in patients with gynecological tumors.. Analytes containing a mixture of protein are immobilized onto antibody-coated surface of support in array format. The presence of protein in analytes is detected with biotin-labeled antibody coupled with an enhanced chemiluminescence or fluorescence detection system. The exact amount of protein can be quantitatively measured. The expression levels of five angiogenic factors (angiogenin, interleukin 8, vascular endothelial growth factor, platelet-derived growth factor, and epidermal growth factor) from 157 samples were quantitatively measured using this novel protein array technology and were statistically analyzed. The expression patterns of angiogenic factors were analyzed using two-way hierarchical cluster analysis approach.. A novel protein array technology, which can simultaneously and quantitatively measure few protein levels from hundreds and thousands of samples was developed. Only minute amounts of sample are required for the assay. This approach also features high sensitivity and specificity. Using this novel protein array approach, we analyzed the plasma expression levels of five angiogenic factors in 137 patients diagnosed with a tumor and 20 controls. Statistical analysis reveals different expression levels of angiogenic factors between patients and controls. Cluster analysis suggests a possible classification of normal subjects from patients.. Enhanced protein profiling arrays provide a high-throughput and sensitive system to detect one or few protein from hundreds and thousands of samples. Such an approach should have broad application in biomedical discovery.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biotin; Cell Line, Tumor; Cluster Analysis; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; Female; Genital Neoplasms, Female; Humans; Immunoglobulin G; Interleukin-8; Luminescent Measurements; Microscopy, Fluorescence; Middle Aged; Multigene Family; Neoplasms; Neovascularization, Pathologic; Oligonucleotide Array Sequence Analysis; Platelet-Derived Growth Factor; Protein Array Analysis; Ribonuclease, Pancreatic; Sensitivity and Specificity; Tissue Distribution; Vascular Endothelial Growth Factor A

Enterocolitis in oncology patients remains an important complication, but there is a lack of insight into its likely severity from microbial, pathological and inflammatory aspects. Paediatric oncology patients admitted with neutropenic fever, who developed abdominal pain and diarrhoea, were monitored by the takers of rectal biopsies, cultures, and inflammatory marker measurements. Twenty-five patients were included (mean age 7.1 years). 8 patients (32%) needed intensive care treatment, 3 (12%) patients died. Gram-positive bacteraemia was diagnosed in 4 patients (16%). Most patients had negative blood and stool cultures. Predictors of a severe clinical course of the enterocolitis were an increased serum interleukin-8 (IL-8) (>1000 pg/ml) level and an increased serum C-reactive protein level (CRP) (>150 mg/l) level, both measured on the first day of clinical illness. Relative risks (RR) for admission to an Intensive Care Unit (ICU) were 11.3 (95% Confidence Interval (CI) 1.6-77.9) for elevated IL-8 levels and 6.4 (95% (CI) 0.92-45.1) for increased CRP levels. Rectal biopsies and pathology could not predict outcome (P=0.22). IL-8 analysis at the onset of enterocolitis symptoms can identify high-risk patients, which might be used clinically to design future intervention trials.

Topics: Abdominal Pain; Biopsy; C-Reactive Protein; Child; Diarrhea; Enterocolitis; Female; Fever; Humans; Interleukin-8; Male; Neoplasms; Neutropenia; Physical Examination; Prognosis; Prospective Studies; Rectum

Topics: Biomarkers; Child; Fever; Genotype; Humans; Infections; Interleukin-6; Interleukin-8; Neoplasms; Neutropenia; Point Mutation; Promoter Regions, Genetic

In the last decade, several groups have shown a direct correlation between the inappropriate or ectopic release of interleukin (IL)-8 by tumor cells in vitro and their growth and metastatic potential using in vivo models of tumor growth. IL-8 is a potent neutrophil chemoattractant. Neutrophils, as "early responders" to wounds and infections, release enzymes to remodel the extracellular matrix of the tissues through which they migrate to reach the site of the wound or infection. It is proposed that the host's cellular response to IL-8 released by tumor cells enhances angiogenesis and contributes to tumor growth and progression. The activities released by the responding neutrophils could serve as enablers of tumor cell migration through the extracellular matrix, helping them enter the vasculature and journey to new, metastatic sites. The reactive oxygen species produced by neutrophilic oxidases to kill invading organisms have the potential to interact with tumor cells to attenuate their apoptotic cascade and increase their mutational rate. It is proposed that the increase in metastatic potential of tumors ectopically releasing IL-8 is, in part, attributable to their ability to attract neutrophils. Discussed here are possible mechanisms by which the neutrophils responding to ectopic IL-8 contribute to the in vivo growth, progression, and metastatic potential of tumor cells. Possible targets are also presented for the development of therapies to attenuate the effects of the ectopic IL-8 release by tumor cells.

Topics: Apoptosis; Cell Movement; Disease Progression; Extracellular Matrix; Humans; Hypochlorous Acid; Interleukin-8; Models, Chemical; Mutagens; Mutation; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Neutrophils; Phenotype; Reactive Oxygen Species

The role of Ras oncogenes in promoting cellular transformation is well established. However, the contribution of Ras signaling to interactions between tumor cells and their host environment remains poorly characterized. Here, we demonstrate that the inflammatory mediator interleukin-8 (CXCL-8/IL-8) is a transcriptional target of Ras signaling. Using a tumor xenograft model, we show that Ras-dependent CXCL-8 secretion is required for the initiation of tumor-associated inflammation and neovascularization. Collectively, our data identify a novel mechanism by which the Ras oncogene can elicit a stromal response that fosters cancer progression.

Topics: Animals; Cell Movement; Endothelial Cells; Gene Expression Regulation, Neoplastic; Genes, ras; HeLa Cells; Humans; Inflammation; Interleukin-8; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Neoplasms; Neovascularization, Pathologic; Phosphatidylinositol 3-Kinases; Signal Transduction; Transfection

Cancer patients who are leukopenic due to chemotherapy are susceptible to bacterial infections. Normally, clinical conditions during bacterial infections are caused by pathogen-associated molecular patterns, which are components that bind to Toll-like receptor (TLR) 2 (TLR-2) and TLR-4 on leukocytes, resulting in the production of inflammatory cytokines. The mechanism of this inflammatory response in cancer patients with diminished numbers of leukocytes is not completely clear. The levels of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha measured in the circulation of leukopenic cancer patients are lower than those measured in that of nonleukopenic patients during bacterial infections, whereas plasma interleukin 8 (IL-8) levels show distinct identical increases during bacterial infections in both leukopenic and nonleukopenic patients. Normally, these cytokines are mainly secreted by leukocytes. In cancer patients with bacterial infections and a diminished number of leukocytes, other sources of IL-8 production, such as endothelial cells, might be expected. Endothelial cells instead of leukocytes become the most important producers of IL-8 during bacterial infections in patients with chemotherapy-induced leukopenia through TLR-2 and TLR-4 signaling. Whole blood samples from six cancer patients were stimulated with lipopolysaccharide (LPS), and then IL-8 concentrations in supernatants were measured. Further, human umbilical vein endothelial cells (HUVECs) were incubated with sera from leukopenic cancer patients with or without bacterial infections, and then IL-8 concentrations in supernatants were measured (n = 6). In addition, the same HUVEC experiment was performed with the addition of neutralizing antibodies against TLR-2 and TLR-4. During leukopenia (<10(9) cells/liter), LPS stimulation of whole blood did not result in an increase in IL-8 levels. However, when endothelial cells were incubated with sera from leukopenic cancer patients during bacterial infections, a three- to eightfold increase in IL-8 production was found, compared to the IL-8 production found after incubation with sera from patients without signs of infections. This increase did not reflect a higher level of IL-8 already present in the sera. Further, we demonstrated that IL-8 production induced in endothelial cells by sera from patients with documented gram-negative infections could be reduced significantly by up to 40% when the cells were incubated with neutralizing anti

Topics: Adult; Antineoplastic Agents; Bacterial Infections; Blood Physiological Phenomena; Cells, Cultured; Child; Culture Media; Endothelium, Vascular; Gene Expression Regulation, Neoplastic; Hematologic Neoplasms; Humans; Interleukin-8; Leukopenia; Lipopolysaccharides; Membrane Glycoproteins; Neoplasms; Prospective Studies; Receptors, Cell Surface; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Tumor Necrosis Factor-alpha

Although X chromosome transfer experiments indicated that tumor suppressor genes are present on the X chromosome, they have not been previously identified. In this report, we show that the ETS transcription factor MEF (ELF4), which is located on chromosome Xq26.1, possesses tumor suppressive capability. MEF expression was up-regulated by 5-azacytidine in some cancer cell lines. MEF overexpression induced morphological changes, such as the conversion of normally loose cell-cell contacts to strong interactions similar to those seen in the presence of matrix metalloproteinase (MMP) inhibitor BB94. In the colony formation assay, A549 cells, but not MEF-overexpressing cells, formed colonies in soft agar culture. Furthermore, MEF-overexpressing cells s.c. injected in the nude mice did not grow, whereas the control cells did. The A549 tumors were poorly differentiated, whereas the MEF-overexpressing tumors were well differentiated. By immunostaining with CD31, a marker on vascular endothelial cells, we found that tumor angiogenesis was significantly suppressed in the tumors formed from MEF-overexpressing cells. In addition, the conditioned media from A549 cell cultures stimulated the migration of human umbilical vein endothelial cells, whereas conditioned media from MEF-overexpressing cell cultures had less of an effect. By gelatin zymography, Western blotting analysis, and immunohistochemistry, we found that the expression levels of MMP-9 and MMP-2 were significantly reduced in MEF-overexpressing tumors. Immunohistochemical analyses showed that interleukin (IL)-8 expression was reduced in the MEF-overexpressing tumors in nude mice. Furthermore, IL-8 mRNA expression in vitro was significantly down-regulated in MEF-overexpressing cells, compared with A549 cells. MEF suppressed the transcription and promoter activities of the genes encoding MMP-9 and IL-8, whereas ETS-2 up-regulated these activities. Therefore, we propose that MEF is a candidate tumor suppressor gene on the X chromosome with activities that are opposite to those of ETS-2.

Topics: Animals; Caco-2 Cells; DNA-Binding Proteins; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor; HeLa Cells; Humans; Interleukin-8; Matrix Metalloproteinase 9; Mice; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Promoter Regions, Genetic; RNA, Messenger; Transcription Factors; Transcription, Genetic; Transfection; Up-Regulation; X Chromosome

We investigated inflammatory cytokine response in chronic depressed patients during abdominal surgery. Twenty-five major depressed patients (Group D) and twenty-five patients (Group C) as the control were studied. Plasma interleukin 6 (IL-6), interleukin 8 (IL-8) and tumour necrosis factor-alpha (TNF-alpha) concentrations were measured before and at 15 min after induction of anesthesia, the end of surgery, 24 h and 3 days after the operation. Plasma IL-6 concentrations in Group D at the end of the operation and 24 h after surgery were significantly lower than those of Group C. The plasma IL-6 concentration (87.1+/-55.3 pg/ml) of patients scoring more than 18 points in the Hamilton depression-rating score at the end of the operation was significantly higher than 57.5+/-76.7 pg/ml of patients scoring less than 18 points. Plasma IL-8 concentration (6.1+/-3.2 pg/ml) in Group D at the end of the operation was significantly lower than 8.7+/-4.2 pg/ml of Group C. We conclude that plasma IL-6 and IL-8 response to surgical trauma is inhibited in chronic depressed patients. The IL-6 response to surgical trauma is depending on the clinical state of depression.

Topics: Adult; Anesthesia; Cytokines; Depression; Dose-Response Relationship, Drug; Female; General Surgery; Humans; Interleukin-6; Interleukin-8; Leukocytes; Male; Middle Aged; Neoplasms; Time Factors; Tumor Necrosis Factor-alpha

Vascular endothelial growth factor (VEGF) has been shown to be a potent mediator of angiogenesis that functions as a survival factor for endothelial cells by up-regulating Bcl-2 expression. We have recently reported that human dermal microvascular endothelial cells (HDMECs) seeded in biodegradable sponges and implanted into severe combined immunodeficient (SCID) mice organize into functional human microvessels that transport mouse blood cells. In this study, we implanted sponges seeded with OSCC-3 (oral squamous cell carcinoma) or SLK (Kaposi's sarcoma) together with endothelial cells into SCID mice to generate human tumors vascularized with human microvessels. This model system was used to examine the role of both endothelial cell Bcl-2 and the proangiogenic chemokine interleukin-8 (IL-8) on tumor growth and intratumoral microvascular density. Coimplantation of HDMECs overexpressing Bcl-2 (HDMEC-Bcl-2) and tumor cells resulted in a 3-fold enhancement of tumor growth when compared with the coimplantation of control HDMECs and tumor cells. This was associated with increased intratumoral microvascular density and enhanced endothelial cell survival. To determine whether the enhanced neovascularization mediated by Bcl-2 overexpression in endothelial cells was influenced by the synthesis of endogenous mediators of angiogenesis, we screened these cells for expression of VEGF, basic fibroblast growth factor (bFGF), and IL-8 by ELISA. HDMEC-Bcl-2 cells and VEGF-treated HDMECs exhibited a 15-fold and 4-fold increase, respectively, in the expression of the proangiogenic chemokine IL-8 in vitro, whereas the expression of VEGF and bFGF remained unchanged. Transfection of antisense Bcl-2 into HDMECs blocked VEGF-mediated induction of IL-8. Conditioned media from HDMEC-Bcl-2 induced proliferation and sprouting of endothelial cells in vitro and neovascularization in rat corneas. Anti-IL-8 antibody added to HDMEC-Bcl-2 conditioned media markedly reduced the potency of these responses. SCID mice bearing VEGF-producing tumor implants that were treated with anti-lL-8 antibody exhibited a 43% reduction in microvessel density and a 50% reduction in tumor weight compared with treatment with a nonspecific antibody. These results demonstrate that the up-regulation of Bcl-2 expression in endothelial cells that constitute tumor microvessels enhances intratumoral microvascular survival and density and accelerates tumor growth. Furthermore, endothelial cells that overexpress Bcl-2 h

Topics: Animals; Antibodies; Carcinoma, Squamous Cell; Cell Division; Cell Transplantation; Disease Models, Animal; Endothelium, Vascular; Gene Expression Regulation; Genes, bcl-2; Humans; Interleukin-8; Mice; Mice, SCID; Mouth Neoplasms; Neoplasm Transplantation; Neoplasms; Neovascularization, Pathologic; Proto-Oncogene Proteins c-bcl-2; Rats; Sarcoma, Kaposi; Transplantation, Heterologous; Up-Regulation

Topics: Biomarkers; C-Reactive Protein; Calcitonin; Fever; Humans; Interleukin-8; Neoplasms; Neutropenia; Protein Precursors

Chemokines effect their proinflammatory and growth regulatory roles through interaction with serpentine receptors. One such receptor, CXCR2, binds multiple CXC chemokines, including interleukin 8, GRO-alpha, GRO-beta, GRO-gamma, and NAP-2. We have previously identified CXCR2 expression on myeloid cells, notably mature granulocytes, and projection neurons.. To determine the expression of CXCR2 by cells of the neuroendocrine system.. Archival specimens from normal neuroendocrine tissues and their malignant counterparts were analyzed by immunohistochemistry with monoclonal antibodies specific for CXCR1 and CXCR2.. Immunohistochemical analysis revealed high-level expression of CXCR2 by cells in the pituitary, adrenal medulla, pancreatic islets, thyroid C cells, scattered Kulchitsky cells in the bronchi, and counterpart neuroendocrine cells in the stomach, small bowel, colon, and appendix. Neuroendocrine neoplasms that demonstrated high-level CXCR2 expression included (1) primary carcinoids localized to the stomach, small bowel, colon, appendix, fallopian tube, ovary, and lung; (2) atypical carcinoids of the lung; (3) metastatic carcinoids; (4) pituitary adenomas; (5) pheochromocytomas; and (6) medullary carcinomas of the thyroid. Small cell lung carcinomas, large cell neuroendocrine carcinomas of the lung, small cell carcinoma of the cervix, Merkel cell carcinomas, neuroblastomas, and malignant melanomas lacked evidence of CXCR2 expression.. The expression of CXCR2 by normal neuroendocrine cells and neoplastic counterparts that have retained phenotypic features of this differentiation program suggests that chemokines may play an important role in functions that are characteristic of this cell type. In addition, this raises the possibility that chemokines may modulate secretion of biologically active products of these cells and their neoplastic counterparts.

Topics: Antibodies, Monoclonal; Antigens, CD; Female; Gastrointestinal Neoplasms; Genital Neoplasms, Female; Humans; Immunohistochemistry; Interleukin-8; Neoplasms; Neuroendocrine Tumors; Neurosecretory Systems; Organ Specificity; Receptors, Chemokine; Receptors, Interleukin; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Reference Values

The diagnostic utility of C-reactive protein (CRP), procalcitonin (PCT) and interleukin-8 (IL-8) were studied in 66 cancer patients with suspected infection (39 with definite foci of infection, 17 with antibiotic responses without foci and 10 with neoplastic fever without infection) and 26 patients scheduled for chemotherapy. The infection group (n=56) had higher median CRP (91 versus 19 mg/l, P<0. 001), PCT (0.28 versus 0.12 ng/ml, P<0.001) and IL-8 values (27.7 versus 16.9 pg/ml, P=0.032) than the non-infection group (n=36). In patients with suspected infection, only PCT was a good marker to discriminate bacteraemia with an area under the receiver operating characteristics curve of 0.92 (95% confidence interval (CI), 0.77-1. 0), but even PCT was less well able to differentiate between non-bacteraemic infections and neoplastic fever (0.56; 95% CI, 0. 35-0.77). In conclusion, PCT was a good indicator for bacteraemia, but none of the three markers were reliable indicators for minor infections in non-neutropenic cancer patients.

Topics: Bacteremia; Bacterial Infections; Biomarkers, Tumor; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Female; Humans; Interleukin-8; Male; Middle Aged; Neoplasm Staging; Neoplasms; Prospective Studies; Protein Precursors

The destruction of newly forming tumor vasculature is a promising approach to inhibit tumor growth. The goal of the present study was to investigate whether human lymphocytes gene modified to express a chimeric receptor specific for the angiogenic endothelial cell receptor, KDR, could react against KDR(+) cells. Gene-modified lymphocytes specifically lysed KDR(+) cells and secreted cytokines in response to KDR(+) target cells including human umbilical vein endothelial cells (HUVECs). Anti-KDR lymphocytes induced HUVECs to secrete the chemokine interleukin 8 and upregulate the adhesion molecules VCAM and E-selectin, which may be important in the recruitment of further immune effector cells to tumor. These KDR-specific lymphocytes may be useful in the adoptive immunotherapy of a broad range of cancers by inducing immune-mediated destruction of tumor neovasculature.

Topics: CD28 Antigens; Cell Adhesion; Cell Line; Cells, Cultured; Cytokines; E-Selectin; Endothelium, Vascular; Flow Cytometry; Gene Transfer Techniques; Humans; Interleukin-8; Neoplasms; Neovascularization, Pathologic; Protein Structure, Tertiary; Receptor Protein-Tyrosine Kinases; Receptors, Fc; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; T-Lymphocytes; Transduction, Genetic; Umbilical Veins; Up-Regulation; Vascular Cell Adhesion Molecule-1

Sensitive parameters of inflammation are rare in neutropenic cancer patients. In this study, procalcitonin (PCT), C-reactive protein (CRP), interleukin 6 (IL-6), IL-8, the soluble IL-2 receptor (sIL-2R) and the soluble tumour necrosis factor receptor II (sTNFRII) were evaluated for their diagnostic relevance in febrile episodes of cancer patients. Plasma or serum levels of these parameters were determined in neutropenic children with febrile episodes (n = 122) classified according to both the kind of infection [60 cases of fever of unknown origin (FUO), 28 cases of localized infection, 13 cases of pneumonia, 20 cases of bacteraemia, one case of fungaemia] and the World Health Organization (WHO) score of chemotherapy-induced mucositis. At baseline and during the febrile episodes, the highest levels of all parameters were observed in cases of gram-negative bacteraemia. However, in FUO and localized infections, low or only slightly elevated median levels of all parameters were documented. The degree of chemotherapy-induced mucositis did not influence the value of any parameter. In comparison with the other inflammatory parameters, PCT (optimum cut-off level 0.5 microg/l) was a more sensitive and more specific parameter in the diagnosis of high-risk (gram-negative bacteraemia) and low-risk (FUO) episodes, as well as in the sequential assessment of all febrile neutropenic episodes.

Topics: Adolescent; Adult; Antigens, CD; Bacterial Infections; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Case-Control Studies; Child; Child, Preschool; Cytokines; Female; Fever; Fever of Unknown Origin; Humans; Infant; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Protein Precursors; Receptors, Interleukin-2; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Retrospective Studies; Sensitivity and Specificity

The pleural space is a potential compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells in a number of respiratory diseases. In an attempt to understand one aspect of the inflammatory process in the pleural space, we compared the responses in three different diseases (congestive heart failure [CHF], tuberculosis [TB], and cancer). Large concentrations of interleukin-8 (IL-8) were detected in cancer and TB effusions, but not in CHF. Surprisingly, the concentration of IL-8 correlated best with lymphocyte recruitment and not with neutrophil recruitment. Pleural fluid from cancer and TB patients was chemotactic for lymphocytes, and this activity was partly blocked by an anti-IL-8 antibody in cancer and completely blocked in TB. To determine whether there was the potential for a chemotactic gradient into the pleural space, pleural effusion cells were analyzed for the expression of IL-8. Cells in the effusions of cancer patients expressed IL-8, whereas IL-8 could not be detected from the cells of TB and CHF effusions. To explore the possible role of pleural macrophages in the regulation of IL-8, pleural effusion cells were treated with culture supernatants from stimulated pleural macrophages. Stimulated pleural macrophages were able to induce expression of messenger RNA (mRNA) for IL-8 and IL-8 protein production, and this activity was abrogated by blocking tumor necrosis factor-alpha. These findings suggest that soluble IL-8 is an important factor for the recruitment of lymphocytes into the pleural space, and that this cytokine is produced by both pleural structural and cancer cells after their activation by macrophage-derived, cytokine-mediated signals.

Topics: Adult; Aged; Body Fluids; Chemotaxis, Leukocyte; Heart Failure; Humans; Interleukin-8; Lymphocytes; Macrophages; Middle Aged; Neoplasms; Osmolar Concentration; Pleura; Pleural Effusion; Tuberculosis

Circulating levels of interleukin (IL)-6, IL-8, soluble Fc gamma receptor type III (sFc gammaRIII), mannose-binding protein (MBP), and C-reactive protein (CrP) were assessed among febrile children with cancer and neutropenia. Levels of IL-6, IL-8, sFc gammaRIII, MBP, and CrP were measured in serum from 56 pediatric cancer patients at the time of admission for 121 episodes of febrile neutropenia (88 febrile episodes without identifiable source, 5 clinically documented infections, 20 episodes of bacteremia due to gram-positive and 5 due to gram-negative organisms, and 3 fungal infections). IL-6 and IL-8 levels were higher in patients with either bacteremia due to gram-negative organisms or fungal infections than in patients with febrile episodes without an identifiable source (P < .00001 for each). IL-6 and IL-8 levels were higher in children with bacteremia due to gram-negative organisms than in those with bacteremia due to gram-positive organisms (P = .0011 and P = .0003, respectively). The measured levels of CrP, MBP, and sFc gammaRIII were not useful for identifying the type of infection. These preliminary results show the potential usefulness of IL-6 and IL-8 as early indicators for life-threatening infections in febrile cancer patients with neutropenia.

Topics: Adolescent; Adult; Bacteremia; C-Reactive Protein; Carrier Proteins; Child; Collectins; Female; Fever; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Humans; Infant; Interleukin-6; Interleukin-8; Male; Neoplasms; Neutropenia; Receptors, IgG; Retrospective Studies; Solubility

The standard therapy for patients with fever and chemotherapy-related neutropenia is hospitalization and infusion of broad-spectrum antibiotics. Early discharge of a defined group of patients at low risk for septicaemia would be of great advantage for these patients. In this study plasma interleukin-8 (IL-8) and interleukin-6 (IL-6) levels measured at start of fever (n = 72) could define a low-risk group of febrile patients with neutropenia due to chemotherapy. For this purpose we collected and analysed data on 72 fever episodes from 53 patients with chemotherapy-related neutropenia, aged between 1 and 66 years. Of the 72 episodes, 18 were classified as bacteraemia and/or clinical sepsis (sepsis group). The IL-6 and IL-8 plasma concentration were significantly increased in patients with chemotherapy-related neutropenia and fever due to bacteraemia versus fever of non-bacterial origin (P = 0.043 and P = 0.022 respectively). Logistic regression analysis, with sepsis as the outcome variable, revealed significant effects of age combined with either IL-6 or IL-8. Sepsis occurrence was lowest for patients <16 years and highest in patients between 16 and 50 years, and was higher in patients with increased IL-6 (P = 0.032) or IL-8 (P = 0.049). No significant effect of leucocyte count, C-reactive protein, sex or underlying malignancy at presentation was detected. The plasma IL-6 and IL-8 levels were fairly strongly correlated (Pearson r = 0.62). Using a cut-off value with 100% sensitivity, both IL-8 and IL-6 could define a low-risk group of neutropenic patients of 28% (CI 15-40%) at the start of the febrile period. Intervention studies are warranted to confirm this result and to investigate whether an early discharge based on IL-8 or IL-6 measurement is safe, increases the quality of life, and results in cost savings.

Topics: Adolescent; Adult; Aged; Antineoplastic Agents; C-Reactive Protein; Child; Child, Preschool; Fever; Humans; Infant; Interleukin-6; Interleukin-8; Leukocyte Count; Middle Aged; Neoplasms; Neutropenia; Risk Factors; Sensitivity and Specificity; Sepsis

We recently developed a method for the isolation and purification of tumour-derived endothelium. In this study the phenotypic and functional properties of human tumour-derived microvascular endothelial cells (TdMEC) were examined. Endothelium obtained from human adrenal gland specimens (HAMEC) was used as a reference microvascular endothelial cell population. TdMEC formed a confluent monolayer with the typical morphological appearance of endothelium and were positive for endothelial markers such as Ulex-1 lectin, CD31 antigen, von Willebrand Factor and VE-cadherin. The addition of acidic Fibroblast Growth Factor (aFGF), basic FGF (bFGF) or Vascular Endothelial Growth Factor (VEGF) substantially improved proliferation of TdMEC; and kidney carcinoma derived endothelial cells were more responsive to FGFs, whereas glioblastoma derived endothelial cells greatly responded to VEGF TdMEC expressed high levels of the VEGF receptors, KDR/flk-1 and Flt-1, as shown by northern blot analysis. TdMEC expressed the adhesion molecules ICAM-1, VCAM-1 and E-selectin that could be further increased by exposing TdMEC culture to interleukin-1. All the TdMEC expressed interleukin-8 mRNA. These findings show that TdMEC in vitro maintain several of the features described for microvasculature. Thus, TdMEC represent a useful tool to study markers for tumor vasculature.

Topics: Antigens, CD; Cadherins; Cell Adhesion Molecules; Cell Division; Endothelial Growth Factors; Endothelium, Vascular; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Humans; Interleukin-8; Lectins; Lymphokines; Microcirculation; Mitogens; Neoplasms; Phenotype; Plant Lectins; Platelet Endothelial Cell Adhesion Molecule-1; Platelet-Derived Growth Factor; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; von Willebrand Factor

Neutrophils from 13 children who received G-CSF for the collection of peripheral blood progenitors while they were in haematological steady state were studied at various times after G-CSF injection for Fc gammaR expression (Fc gammaRI or CD64, Fc gammaRII or CD32, and Fc gammaRIII or CD16) and for their ability to exert antibody-dependent cell cytotoxicity (ADCC) through Fc gammaRI. Changes in IFNgamma, IL8, IL10, MCP1 and TNF alpha mRNA levels in peripheral blood cells were also studied 4 h and 24 h after the first G-CSF injection. Fc gammaRI expression increased strongly after 24 h and then remained at the same level throughout treatment. In contrast, Fc gammaRIII expression sharply decreased at day 1 and diminished even further thereafter. No change in Fc gammaRII was observed. ADCC exerted by neutrophils through Fc gammaRI started to increase after 24 h with the peak level at day 5. Cytokine mRNA analyses indicated a reproducible and strong increase of IL8 mRNA (11/13 children) after 24 h, whereas the changes in the mRNA levels of the other cytokines tested were more heterogenous (TFNgamma: three; IL10: six; MCP1: five: TNF alpha: four, of the 13 children). Therefore this study opens the way to an optimized therapeutic schedule for the combined use of G-CSF and monoclonal antibodies in adjuvant immuno-intervention.

Topics: Adolescent; Antibody-Dependent Cell Cytotoxicity; Child; Child, Preschool; Cytokines; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Infant; Interleukin-8; Leukocyte Count; Male; Neoplasms; Neutrophils; Receptors, IgG; Recombinant Proteins; RNA, Messenger; Up-Regulation

The growth and metastasis of cancer directly correlates with tumor angiogenesis. A better understanding of the expression of regulatory factors controlling angiogenesis is important in exploiting this process therapeutically. Our present study demonstrates that small tumors (3-4 mm in diameter) express more basic fibroblast growth factor (bFGF) and interleukin 8 (IL-8) than large tumors (> 10 mm in diameter), whereas more vascular endothelial growth factor (VEGF) is expressed in large tumors. Immunostaining showed a heterogeneous distribution of angiogenic factors within the tumor; expression of bFGF and IL-8 was highest on the periphery of a large tumor, where cell division is maximum. VEGF expression was higher in the center of the tumor. In vitro studies demonstrated that sparse cultures of tumor cells expressed higher levels of bFGF and IL-8 than confluent cultures. In contrast, the expression of bFGF and IL-8 was not diminished in tumor cells growing on confluent monolayers of normal cells. VEGF expression was upregulated by cell density irrespective of contact with tumor cells or normal cells. These results demonstrate that the expression of different angiogenic factors in tumor cells can be regulated by their proximity to other tumor cells or host cells.

Topics: Animals; Blotting, Northern; Disease Progression; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; Gene Expression; Humans; Interleukin-8; Lymphokines; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Rats; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Monocyte chemotactic protein 1 (MCP-1) and interleukin 8 (IL-8) are small, inducible proteins with chemotactic activity for specific subsets of leucocytes. The possibility that MCP-1 and IL-8 are produced in tissues involved by Hodgkin's disease, thus contributing to the inflammatory-type background of the lesion, was investigated.. The presence of RNA transcripts for MCP-1 and IL-8 was investigated in biopsy samples of 24 cases of Hodgkin's disease, 17 non-Hodgkin's malignant lymphomas, 30 solid tumours, and 30 histologically normal tissues by means of reverse transcription-polymerase chain reaction (RT-PCR)/Southern blot analysis.. MCP-1 expression was detected in 23 of 24 cases of Hodgkin's disease, in seven of 17 cases of B cell non-Hodgkin's lymphoma, and in seven of 14 cases of reactive lymphoid hyperplasia. IL-8 was present in six of 14 cases of Hodgkin's disease, and was seen only rarely in B cell non-Hodgkin's lymphoma and in reactive lymphoid tissues. MCP-1 and IL-8 RNA transcripts were detected in 13 of 25 carcinomas originating from the lung, breast, thyroid, and ovary.. These findings are consistent with the possibility that MCP-1 and IL-8 are two additional cytokines involved in the pathogenesis of Hodgkin's disease.

Topics: Blotting, Southern; Chemokine CCL2; Female; Hodgkin Disease; Humans; Interleukin-8; Lymphoma, B-Cell; Neoplasm Proteins; Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Cell Division; Chemokines, CXC; Chemotaxis; Corneal Neovascularization; Endothelium, Vascular; Humans; Interferon-gamma; Interleukin-8; Lung Neoplasms; Microcirculation; Mutagenesis, Site-Directed; Neoplasms; Neovascularization, Pathologic; Rats; Recombinant Proteins

Topics: Alzheimer Disease; Animals; Asthma; Chemokine CCL11; Chemokine CCL2; Chemokines; Chemokines, CC; Chemotactic Factors, Eosinophil; Chemotaxis, Leukocyte; Cytokines; Humans; Inflammation; Interleukin-8; Monocytes; Neoplasms; Neutrophils; Respiratory Distress Syndrome

The role of cytokines was intensively discussed over the course of a two and a half day meeting sponsored by the US-JAPAN Cancer Cooperative Research Program of the Office of International Affairs, National Cancer Institute and held at The National Institutes of Health, Bethesda, Maryland on 15-17 January 1996. Most of the first day was devoted to a discussion of the role of cytokines in modulating angiogenesis and the consequent effect of this on tumor growth and metastases. This was followed by sessions on the effect of various cytokines in enhancing or suppressing immunological responses to tumors. Several presentations focused on the direct inhibitory or growth promoting effects of cytokines on tumor growth. The final session consisted of a comparison of the efficacy of different approaches to tumor vaccination including gene therapy, enhanced antigen presentation, use of polymeric carriers or of DNA vectors. For background information the reader is referred to appropriate chapters on the role of cytokines in neoplastic diseases (Oppenheim JJ, Rossio JL, Gearing AJH, eds. In Clinical Application of Cytokines: Role of Pathogenesis, Diagnosis and Therapy. Oxford University Press, New York, 1993 [1]).

Topics: Acquired Immunodeficiency Syndrome; Angiostatins; Animals; Chemokine CCL2; Colonic Neoplasms; Cytokines; Endothelial Growth Factors; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Genetic Therapy; Glycoproteins; Humans; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-8; Keratinocytes; Lymphokines; Neoplasms; Neovascularization, Pathologic; Peptide Fragments; Plasminogen; Recombinant Proteins; Sarcoma, Kaposi; Th1 Cells; Th2 Cells; Tissue Inhibitor of Metalloproteinases; Tumor Necrosis Factor-alpha; Ultraviolet Rays; Vaccines; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Intravenous (IV) administration of purified lipopolysaccharide (LPS) from Salmonella abortus equi to cancer patients induces the formation of high amounts of endogenous cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). On repeated administration of LPS at 2-week intervals, a marked downregulation of the cytokine response was observed, especially between the first and the second challenge. This study sought to determine whether it would be possible to prevent this downregulation by pretreating patients with interferon-gamma (IFN-gamma), which is known to enhance cytokine production by monocytes and macrophages in vitro. Ten patients with disseminated cancer received a first injection of 4.0 ng LPS/kg. Thereafter, patients were divided into two groups. One group received two further LPS injections (4.0 ng/kg) at 2-week intervals. The second group was pretreated (-12 hours) with 50 micrograms IFN-gamma subcutaneously (SC) before the second and third LPS challenge. To prevent constitutional side effects such as fever and chills, patients received 1,600 mg ibuprofen orally before LPS injection. The results of the current study demonstrate that apart from TNF-alpha and IL-6, two other cytokines, interleukin-8 (IL-8) and granulocyte colony-stimulating factor (G-CSF) are produced in cancer patients in response to LPS. LPS application at 2-week intervals resulted in a transient attenuation of all cytokines (TNF-alpha, IL-6, IL-8, G-CSF) on the second challenge. In the case of TNF-alpha, IL-6, and G-CSF, pretreatment with IFN-gamma not only prevented the downregulation, but enhanced the production of these cytokines to levels higher than those obtained after the first LPS challenge. In contrast, the downregulation of IL-8 remained unaffected by IFN-gamma pretreatment. Further studies are warranted to determine whether the prevention of cytokine downregulation by IFN-gamma following repeated LPS injections is of clinical relevance in respect to the antitumor activity of LPS.

Topics: Adult; Aged; Female; Granulocyte Colony-Stimulating Factor; Humans; Interferon-gamma; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Middle Aged; Neoplasms; Recombinant Proteins; Salmonella; Tumor Necrosis Factor-alpha

Endothelial leukocyte adhesion molecule-1 (ELAM-1) is an endothelial cell adhesion molecule that allows myeloid cells to attach to the walls of blood vessels adjacent to sites of inflammation. ELAM-1 recognizes the sialyl-Lewis X (sialyl-Lex) determinant, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc-, a granulocyte carbohydrate also found on the surface of some tumor cell lines. Binding of myeloid cells to soluble ELAM-1 is inhibited by a monoclonal antibody recognizing sialyl-Lex or by proteins bearing sialyl-Lex, some of which may participate in humoral regulation of myeloid cell adhesion. Stimulated granulocytes also release an inhibitor of ELAM-1 binding that can be selectively adsorbed by monoclonal antibody to sialyl-Lex.

Topics: Amniotic Fluid; Antibodies, Monoclonal; Carbohydrate Sequence; Cell Adhesion; Cell Adhesion Molecules; Cell Membrane; E-Selectin; Endothelium, Vascular; Fucose; Fucosyltransferases; Granulocytes; Immunosorbent Techniques; Interleukin-1; Interleukin-8; Lewis X Antigen; Molecular Sequence Data; Neoplasms; Neuraminidase; Oligosaccharides; Orosomucoid; Sialyl Lewis X Antigen; Tumor Cells, Cultured

The role of complement in the polymorphonuclear leukocyte (PMN)-mediated tumor cell destruction in cancer ascites was investigated in relation to a streptococcal preparation OK-432, a so-called biological response modifier. Incubation of OK-432 with fresh human serum at 37 degrees C for 60 min resulted in the generation of C3a and C5a chemotactic factors. Intraperitoneal (i.p.) injection of the mixture to a patient with cancer ascites revealed an accumulation of PMNs in the ascitic fluid for a longer period with a rapid reduction of the ascitic fluid, than an intraperitoneal injection of OK-432 alone examined in the same patient. PMNs were found to invade clusters of the tumor cells and then form rosettes followed by the destruction of tumor cells. These findings induced by OK-432 continued over 10 days in the presence of fresh serum, while diminished within 3-4 days when OK-432 alone was injected. When fresh human plasma or fresh frozen plasma was used instead of serum and i.p. injected with OK-432 avoiding preincubation, the same cytological and clinical changes were observed in other patients. These data strongly indicate that OK-432 activates human complement either in vitro or in the peritoneal cavity, and induces PMNs to accumulate in the ascitic fluid. Although the mechanism of killing of tumor cells by PMNs is obscure, addition of human serum or plasma to i.p. use of OK-432 seems to be valuable for the management of patients with malignant ascites.

Topics: Ascites; Biological Products; Chemotactic Factors; Complement System Proteins; Humans; Interleukin-8; Neoplasms; Neutrophils; Picibanil