interleukin-8 and Cachexia

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

Cytokines secreted in the tumor microenvironment function in cancer cachexia (CC), a common clinicopathological syndrome associated with adipocyte wasting and skeletal muscle atrophy. Extracellular vesicles (EVs) secreted by cancer cells actively engage in inter-tissue communication; EVs and enclosed cytokines are largely undefined in CC adipocytes wasting.. EVs derived from Lewis lung carcinoma (LLC) and colorectal cancer C26 cells were extracted and characterized. Conditioned medium and EVs from cancer cells were applied to 3 T3-L1 adipocytes. Recombinant IL-8, IL-8 neutralizing antibody, CXCR2 and NF-κB inhibitor were examined in functional assays. Lipolysis of adipocytes was monitored by Western blots, Oil red O staining and glycerol assays. Furthermore, LLC and C26 cell lines were established as cachexia model to explore the relevance of IL-8 and NF-κB signaling in CC adipose wasting. Adipose tissues were collected for histology analyses.. LLC and C26 cell-derived EVs induced lipolysis of 3 T3-L1 adipocytes. Specially, Dil-labeled EVs were effectively taken up by 3 T3-L1 adipocytes, which were motivated by the delivered IL-8 to elicit the NF-κB pathway. In comparison, special IL-8 neutralizing antibody relieved that lipolysis of 3 T3-L1 adipocytes induced by EVs together with conditioned medium of LLC and C26 cells, respectively. Consistently, both CXCR2 and NF-κB inhibitors would lessen the phenotype of lipolysis in 3 T3-L1 adipocytes. In the in vivo settings, both LLC and C26-tumor bearing mice had higher serum IL-8 levels as compared to the control groups. Two typical lipolysis markers, PGC1α and UCP1, were also up-regulated in the adipose tissues of LLC and C26-tumor mice groups, respectively.. EVs secreted by LLC and C26 tumor cells would induce adipocyte wasting via extracellular IL-8-mediated NF-κB signaling. Our study pointed out the physiological and therapeutic values of exosomal IL-8 in CC lipolysis.

Topics: Adipocytes; Animals; Antibodies, Neutralizing; Cachexia; Colonic Neoplasms; Culture Media, Conditioned; Cytokines; Interleukin-8; Lipolysis; Lung Neoplasms; Mice; Muscular Atrophy; NF-kappa B; Signal Transduction; Tumor Microenvironment

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

Interleukin (IL)-8 promotes cellular proliferation and angiogenesis in patients with non-small-cell lung cancer (NSCLC) and may be related to cachexia. Our aim was to investigate the relationship of IL-8 levels with nutritional status, and clinical outcome of patients with NSCLC. Patients with metastatic NSCLC referred for first-line therapy were eligible. Baseline IL-8 levels were measured in plasma. The Mini Nutritional Assessment (MNA) was used for the evaluation of the nutritional status, and patients were classified into 3 groups: A (score 24-30) "well nourished," B (score 17-23.5) "risk of malnutrition," and C (0-16.5) "malnourishment." Response to first-line chemotherapy, time-to-tumor progression (TTP), and overall survival (OS) were also recorded. In total, 114 patients (101 males, 88.5%; mean age = 67.5 yr) were evaluated. Performance status was 0-1 in 62% of the patients. According to the MNA, the majority of patients (71%) was either at nutritional risk or malnourished. IL-8 levels were significantly different between MNA groups (P = 0.023) and correlated with TTP (P = 0.013) and OS (P = 0.001) in univariate analysis. Baseline IL-8 levels correlate with the nutritional status of patients with metastatic NSCLC, suggesting that this cytokine may be related with cachexia.

Topics: Aged; Cachexia; Carcinoma, Non-Small-Cell Lung; Female; Follow-Up Studies; Humans; Interleukin-8; Lung Neoplasms; Male; Malnutrition; Middle Aged; Multivariate Analysis; Nutrition Assessment; Nutritional Status; Predictive Value of Tests; Prognosis

Interleukin (IL)-8 has been implicated in a wide range of diseases. The polymorphism of IL-8 gene, which may affect the production level of the cytokine, may be associated with cancer cachexia. To test this hypothesis, we investigated the potential influence of the polymorphisms of the IL-8 gene, -251 A/T and +781 C/T, on susceptibility to cachexia from patients with gastric cancer in a Chinese population, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A significantly increased frequency of +781 T allele was noted in patients with cachexia (OR = 1.765, 95% CI: 1.192-2.615, P = 0.004). The +781 TT genotypes were observed to be associated with a significantly increased risk of cachexia (OR = 2.156, 95% CI: 1.056-4.400, P = 0.033), and the difference was enhanced beyond the level of statistical significance when logistic regression was applied (OR = 3.500, 95% CI: 1.406-8.710, P = 0.007). Haplotype analysis revealed that A(251)T(781) haplotype (defined by SNPs at positions -251 and +781) was associated with a significantly increased risk of cachexia as compared with the T(251)C(781) haplotype (OR = 1.69; 95% CI: 1.08-2.62; P = 0.022). These results suggest that the genetic polymorphisms of proinflammatory cytokine IL-8 may contribute to the pathogenesis of cachexia in gastric cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Cachexia; China; Female; Gene Frequency; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Humans; Interleukin-8; Male; Middle Aged; Polymorphism, Genetic; Stomach Neoplasms

We investigated the association between esophageal cancer and cachexia-anorexia syndrome (CAS) of the alimentary tract and leptin, an adipocytokine crucial for body weight regulation, a modulator of inflammatory/immune response, implication of which in cancer and CAS development remains debatable. Circulating leptin was measured in 135 esophageal cancer patients (51 non-cachectic and 84 cachectic) and 83 controls (63 non-cachectic and 20 cachectic) and referred to cancer stage, CAS, and inflammatory and nutritional indices. Leptin was down-regulated in cancer patients and cachectic controls as compared to non-cachectic controls, with more pronounced hypoleptinemia in advanced cancers. Leptin correlated directly with BMI, TNF-alpha, albumin, and hemoglobin and indirectly with IL-6, IL-8, and hsCRP. The correlations, except for hsCRP, were more pronounced in females. BMI alone (females) and BMI and hsCRP (males) were independent predictors of leptin explaining over 60% of its variability. Following adjustment for BMI and gender, cancer-related CAS but not cancer itself negatively affected leptin. Leptin and BMI were independently associated with cancer-related and non-malignant CAS with diagnostic accuracy of 93% in identifying subjects with CAS. Pro-inflammatory, angiogenic and mitogenic properties of leptin do not seem to be important for esophageal cancer development but hypoleptinemia, independently from co-occurring reduction of adiposity, appears to be strongly associated with esophageal cancer-related CAS and non-malignant CAS of the alimentary tract.

Topics: Adenocarcinoma; Anorexia; Body Mass Index; C-Reactive Protein; Cachexia; Carcinoma, Squamous Cell; Down-Regulation; Esophageal Neoplasms; Female; Gastrointestinal Tract; Hemoglobins; Humans; Inflammation; Interleukin-6; Interleukin-8; Leptin; Male; Serum Albumin; Syndrome; Tumor Necrosis Factor-alpha

Proinflammatory cytokines are involved in cancer-related weight loss, but the involvement of VEGF-A, VEGF-C, IL-8 and midkine in gastroesophageal cancer patients remains unknown.. Serum IL-1, IL-6, IL-8, TNF-alpha, VEGF-A, VEGF-C, and midkine were evaluated in 96 cancer patients and 42 controls using ELISAs and were related to the occurrence of weight loss, patient's age, gender and BMI, cancer TNM status and blood cell counts.. All cytokines were elevated in cancer patients with further up-regulation of IL-6, IL-8, midkine and VEGF-A in cachexia. Underweight, midkine and VEGF-A were found independent indicators of weight loss. Primary tumor seems to be a major source of pro-cachectic cytokines, yet neutrophils and platelets also contribute to cytokine elevation.. IL-6 and IL-8, and probably midkine and VEGF-A, appear to participate in the development of cancer-related cachexia in gastroesophageal malignancies, although a detailed mechanism underlying cytokine involvement needs to be elucidated.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Cachexia; Carcinoma, Squamous Cell; Case-Control Studies; Cytokines; Esophagogastric Junction; Female; Gastrointestinal Neoplasms; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Midkine; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Weight Loss

A novel proteoglycan, proteolysis inducing factor (PIF), is capable of inducing muscle proteolysis during the process of cancer cachexia, and of inducing an acute phase response in human hepatocytes. We investigated whether PIF is able to activate pro-inflammatory pathways in human Kupffer cells, the resident macrophages of the liver, and in monocytes, resulting in the production of pro-inflammatory cytokines. Normal liver tissue was obtained from patients undergoing partial hepatectomy and Kupffer cells were isolated. Monocytes were isolated from peripheral blood. Following exposure to native PIF, pro-inflammatory cytokine production from Kupffer cells and monocytes was measured and the NF-kappaB and STAT3 transcriptional pathways were investigated using electrophoretic mobility shift assays. We demonstrate that PIF is able to activate the transcription factor NF-kappaB and NF-kappaB-inducible genes in human Kupffer cells, and in monocytes, resulting in the production of pro-inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. PIF enhances the expression of the cell surface molecules LFA-1 and CD14 on macrophages. PIF also activates the transcription factor STAT3 in Kupffer cells. The pro-inflammatory effects of PIF, mediated via NF-kappaB and STAT3, are important in macrophage behaviour and may contribute to the inflammatory pro-cachectic process in the liver.

Topics: Acute-Phase Reaction; Blood Proteins; Cachexia; Cell Membrane; Cell Nucleus; Cytokines; Cytoplasm; Flow Cytometry; Humans; Inflammation; Interleukin-6; Interleukin-8; Kupffer Cells; Lipopolysaccharide Receptors; Lipopolysaccharides; Liver; Macrophages; Monocytes; NF-kappa B; Proteoglycans; STAT3 Transcription Factor; Time Factors; Transcription, Genetic; Tumor Necrosis Factor-alpha

Approximately 60-70% of patients with advanced prostate carcinoma (CaP) suffer from cachexia, one of the most devastating conditions associated with advanced malignant disease. The pathophysiology of cachexia is multifactorial, and several cytokines, such as tumor necrosis factor alpha (TNFalpha) and interleukin 1 (IL-1), IL-6, and IL-8, may be involved. The objective of the current study was to determine whether cachexia associated with advanced CaP is accompanied by increased serum levels of TNFalpha, IL-1beta, IL-6, and IL-8.. The levels of TNFalpha, IL-1beta, IL-6, IL-8, and prostate specific antigen (PSA) were examined in serum samples from normal donors (n = 10 donors), from patients with organ-confined CaP (n = 19 patients), from patients with advanced CaP without cachexia (n = 17 patients), and from patients with cachectic CaP (n = 26 patients). DPC Immulite and Abbott IMx Total-PSA assays were used to determine cytokine and PSA levels, respectively.. Levels of TNFalpha, IL-6, and IL-8 were elevated significantly in the group of patients with advanced, cachectic CaP compared with patients who were without cachexia. In the cachectic patients, levels of TNFalpha were correlated positively with IL-8, and there was no correlation between PSA levels and any of the cytokine levels. IL-1beta levels were below the limit of detection in all samples.. The current results show that levels of TNFalpha, IL-6, and IL-8 were increased in CaP patients with cachexia. Increased levels of these cytokines were not correlated with PSA levels, suggesting that they are regulated by a mechanism that is independent of PSA synthesis. Additional fundamental research is needed to determine the mechanisms involved and to identify potential therapeutic targets in patients with cachexia.

Topics: Aged; Cachexia; Cytokines; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Prostate-Specific Antigen; Prostatic Neoplasms; Tumor Necrosis Factor-alpha

A novel protein, proteolysis-inducing factor (PIF), has been isolated from the urine of patients with pancreatic cancer and is capable of inducing muscle proteolysis in vitro. Only adult skeletal muscle and liver exhibit substantial binding of PIF. We have investigated the effect of PIF on hepatic gene expression. Primary cultures of human hepatocytes and the human cell line HepG2 were incubated in the presence of PIF to assess its effects on hepatic transcription factors, proinflammatory cytokine production, and acute phase proteins. PIF activates both the transcription factors NF-kB and STAT3, which result in the increased production of IL-8, IL-6, and C-reactive protein and the decreased production of transferrin. The function of PIF, beyond muscle degradation, is unknown but here we show that it is involved in hepatic gene expression, and is thus likely to be involved in the proinflammatory response observed in cachexia. These results may also suggest a potential role for PIF during embryonic development. The expression of PIF peaks during the embryonic period E8 to E9, a stage that is crucial in the development of skeletal muscle and liver and during which both NF-kB and STAT3 activation can also be observed.

Topics: Blood Proteins; Cachexia; Cells, Cultured; DNA-Binding Proteins; Gene Expression Regulation; Hepatocytes; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Lipopolysaccharides; Models, Biological; NF-kappa B; Proteoglycans; STAT3 Transcription Factor; Trans-Activators; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

To evaluate the possibility of cancer gene therapy by the gene delivery of chemokine, the effects of human macrophage inflammatory protein 1 alpha (hu-MIP-1 alpha), murine-macrophage inflammatory protein 1 alpha (mu-MIP-1 alpha), and human-interleukin 8 (hu-IL-8) on tumor progression and immunization were studied.. Cachexia-inducing and highly tumorigenic adenocarcinoma cells (cell line colon 26, clone 20) were transfected with either a control plasmid, hu-MIP-1 alpha, mu-MIP-1 alpha, or hu-IL-8 expression vector. The production of hu-MIP-1 alpha reached > 1.5 ng/ml in vitro when transfectant cells were cultured at a cell density of 2 x 10(5) cells in 7 ml for 3 days. Immunocompetent BALB/c mice were inoculated into the footpad with the tumor cells, and then primary tumor growth, morphological analyses, and tumor immunogenicity were studied.. The secretion of hu-MIP-1 alpha, mu-MIP-1 alpha, and hu-IL-8 did not affect the growth rate in vitro. Reduced tumorigenicities in vivo were observed in transfected cells with hu-MIP-1 alpha and mu-MIP-1 alpha. Morphologic observation of the site of inoculation of cells transfected with hu-MIP-1 alpha showed infiltration of macrophages and neutrophils on the 5th day after the inoculation. Mice that had rejected cells transfected with hu-MIP-1 alpha gene were immune to a subsequent challenge with the parental cells.. The rejection of the cells depends on cytolysis and generates potent and long lasting antitumor immunity. These data suggest that tumor cells transfected with the MIP-1 alpha gene might be useful as an effective therapy for the treatment of certain tumors.

Topics: Adenocarcinoma; Animals; Cachexia; Chemokine CCL3; Chemokine CCL4; Colonic Neoplasms; Female; Gene Transfer Techniques; Genetic Therapy; Humans; Immunocompetence; Interleukin-8; Lung Neoplasms; Macrophage Inflammatory Proteins; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Recombinant Proteins; RNA, Messenger; RNA, Neoplasm; Tumor Cells, Cultured