interleukin-8 and angiogenin

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

Left ventricular (LV) systolic function is a significant prognostic factor in patients after myocardial infarction (MI). Multiple angiogenic and inflammatory factors are involved in postinfarction LV remodelling process. In addition, CD34+progenitor cells mobilised from bone marrow and tissue niches participate in regeneration of the infarcted myocardium.. To examine relationships between LV ejection fraction (LVEF) and wall motion score index (WMSI) and the number of CD34+ cells and plasma levels of vascular endothelial growth factor (VEGF), angiogenin and such inflammatory factors as interleukin 6 (IL-6), interleukin 8 (IL-8), and high-sensitivity C-reactive protein (hsCRP) in patients with ST-elevation MI (STEMI).. The study group included 61 patients with STEMI treated with primary percutaneous coronary intervention (PCI)involving bare metal stent implantation. Plasma levels of the evaluated angiogenic and inflammatory factors were measured by flow cytometry at 4 time points (just before PCI, 24 h later, at hospital discharge, and 30 days after STEMI). LVEF and WMSI were measured by echocardiography at hospital discharge, 1 month later, and 6 months later. We compared angiogenic and inflammatory factor levels in patients with no improvement of the LV systolic function during the follow-up (group 1, n = 22)vs. those with improved LV systolic function (group 2, n = 39).. No differences in the levels of VEGF, angiogenin, IL-6, IL-8, and hsCRP, and the number of CD34+ cells were observed between the two groups. Despite this, we found significant negative correlations between hsCRP level and LVEF,and positive correlations between hsCRP level and WMSI in both patient groups, but these correlations were much stronger in group 1. We also found a significant negative correlation between WMSI at 6 months and the number of CD34+ cells measured 24 h after PCI.. 1. Evaluation of plasma VEGF, angiogenin, IL-6, IL-8, and hsCRP levels and the number of CD34+ cells at different time points in patients with STEMI did not allow predicting the direction of changes in LVEF and WMSI. 2. Observed significant correlations between hsCRP level and LVEF and WMSI may suggest a harmful effect of inflammation on postinfarction myocardial remodelling. 3. A significant negative correlation between the number of CD34+ and WMSI suggests that increased mobilisation of these cells might have a beneficial effect on systolic function after MI.

Topics: Antigens, CD34; C-Reactive Protein; Female; Follow-Up Studies; Hematopoietic Stem Cell Mobilization; Humans; Interleukin-6; Interleukin-8; Male; Middle Aged; Myocardial Infarction; Predictive Value of Tests; Ribonuclease, Pancreatic; Stroke Volume; Ultrasonography; Vascular Endothelial Growth Factor A

The use of intra-oral soft-tissue-engineered devices has demonstrated potential for oral mucosa regeneration. The aim of this study was to investigate the temporal expression of angiogenic biomarkers during wound healing of soft tissue reconstructive procedures comparing living cellular constructs (LCC) with autogenous free gingival grafts. Forty-four human participants bilaterally lacking sufficient zones of attached keratinized gingiva were randomly assigned to soft tissue surgery plus either LCC or autograft. Wound fluid samples were collected at baseline and weeks 1, 2, 3, and 4 post-operatively and analyzed for a panel of angiogenic biomarkers: angiogenin (ANG), angiostatin (ANT), PDGF-BB, VEGF, FGF-2, IL-8, TIMP-1, TIMP-2, GM-CSF, and IP-10. Results demonstrated a significant increase in expression of ANT, PDGF-BB, VEGF, FGF-2, and IL-8 for the LCC group over the autograft group at the early stages of wound repair. Although angiogenic biomarkers were modestly elevated for the LCC group, no clinical correlation with wound healing was found. This human investigation demonstrates that, during early wound-healing events, expression of angiogenic-related biomarkers is up-regulated in sites treated with LCC compared with autogenous free gingival grafts, which may provide a safe and effective alternative for regenerating intra-oral soft tissues (ClinicalTrials.gov number, NCT01134081).

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Angiogenic Proteins; Angiostatins; Becaplermin; Biomarkers; Chemokine CXCL10; Cohort Studies; Feasibility Studies; Female; Fibroblast Growth Factor 2; Fibroblasts; Follow-Up Studies; Gingiva; Gingival Crevicular Fluid; Gingival Diseases; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-8; Keratinocytes; Male; Middle Aged; Plastic Surgery Procedures; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Ribonuclease, Pancreatic; Tissue Engineering; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Tissue Scaffolds; Vascular Endothelial Growth Factor A; Wound Healing

Mesenchymal stromal cells (MSCs) have emerged as a more beneficial alternative to conventional therapy and may offer a potential cure for unmet medical needs. MSCs are known to possess strong immunomodulatory and anti-inflammatory properties. Moreover, they promote angiogenesis and tissue regeneration through the secretion of trophic factors. For these reasons, the past decade witnessed a sharp increase in the number of clinical trials conducted with stem cells for various vascular diseases requiring angiogenesis. In this study, we evaluated the in vitro angiogenic potency of Stempeucel®, which is an allogeneic pooled human bone marrow-derived mesenchymal stromal cell (phBMMSC) product. We previously established the safety of Stempeucel® in our pre-clinical studies, and clinical trials conducted for critical limb ischaemia and acute myocardial infarction.. Because the proposed mechanism of action of phBMMSCs is mainly through the secretion of pro-angiogenic cytokines, we developed a surrogate potency assay by screening various batches of large-scale expanded phBMMSCs for the expression of angiogenic factors and cytokines through gene expression and growth factor analyses, followed by in vitro functional assays.. The well characterized angiogenic vascular endothelial growth factor (VEGF) was selected and quantified in twenty six manufactured batches of phBMMSCs to establish consistency following the United States Food and Drug Administration recommendations. According to recommendations 21 CFR 211.165(e) and 211.194(a)(2), we also established and documented the specificity and reproducibility of the test methods employed through validation. Moreover, we also attempted to elucidate the mechanism of action of the cell population to ensure appropriate biological activity. The functional role of VEGF has been established through in vitro angiogenic assays and a dose-dependent correlation was observed with in vitro functional results.. The data generated from this study suggest the selection of VEGF as a single surrogate marker to test the angiogenic potency of phBMMSCs. Our study reports the quantification of VEGF in twenty six batches of large-scale manufactured phBMMSCs, and a concentration-dependent correlation of secreted VEGF to endothelial cell functions of migration, proliferation and tube formation, in the conditioned medium obtained from nine phBMMSC batches. To our cognizance, this is the first study in which a single angiogenic factor (VEGF) has been qualified as a surrogate potency marker through all three in vitro functional assays to determine the angiogenic potency of the phBMMSC population.

Topics: Angiogenesis Inducing Agents; Biological Assay; Bone Marrow Cells; Cell Movement; Cell Proliferation; Chemokine CXCL12; Culture Media, Conditioned; Gene Expression; Hepatocyte Growth Factor; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-6; Interleukin-8; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Primary Cell Culture; Ribonuclease, Pancreatic; Transforming Growth Factor beta1; Transplantation, Homologous; Vascular Endothelial Growth Factor A

Hypertension is the most common cardiovascular disease and the main risk factor for stroke, peripheral arterial disease, arterial aneurysms and kidney disease. It has been reported recently that hypertensive patients and animals are characterized by decreased density of arterioles and capillaries in the tissues, called rarefaction. Rarefaction significantly increases peripheral resistance which results in elevated blood pressure, leads to vessel damage and induction of inflammation. Therefore, we hypothesized that hypertension is associated with decreased serum concentration of physiological pro-angiogenic factors and concomitant increased production of angiogenesis inhibitors.. 82 patients diagnosed with hypertension and 34 healthy volunteers were recruited to the study. Flow cytometry and enzyme-linked immunosorbent assay (ELISA) techniques were used to measure serum levels of the following cytokines: endostatin, vascular endothelial growth factor (VEGF), interleukin 8 (IL-8), angiogenin, and basic fibroblast growth factor (bFGF).. Hypertensive patients were characterized by increased serum concentration of endostatin which is an anti-angiogenic factor. In addition, hypertension was associated with decreased levels of physiological pro-angiogenic mediators such as: angiogenin and bFGF. The hypertensive group was also characterized by elevated levels of CRP, VEGF and IL-8 that are the hallmarks of inflammation.. Presented results show that hypertension is characterized by imbalance of pro-angiogenic and anti-angiogenic factors in the background of inflammation.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Endostatins; Female; Fibroblast Growth Factor 2; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Interleukin-8; Male; Middle Aged; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A; Young Adult

Imiquimod (IMQ) is a synthetic Toll-like receptor (TLR7/8) ligand that can trigger antiviral and antitumor activities. Despite evidence of potent therapeutic effects, the clinical use of IMQ in melanoma is impeded by incomplete understanding of its mechanisms of action. Mice and humans differ in many aspects of immunity, including TLR7 expression patterns, thus impeding the use of mouse models in translating discoveries into clinical applications. In this article, we investigated the mechanisms behind IMQ effects in vivo in a human context of melanoma and immunity using an innovative melanoma-bearing humanized mouse model. In this model, IMQ strongly inhibited melanoma tumor development through prompt mobilization of plasmacytoid dendritic cells and by triggering their cytotoxic functions, and through upregulation of expression of type 1 IFN response genes. IMQ also drastically impeded tumor vascularization by inducing the downregulation of angiogenic factors vascular endothelial growth factor, angiogenin, IL-8, and fibroblast growth factor. Our results revealed the short- and long-term multifactorial effects of IMQ converging toward inhibition of melanoma development. By providing a better understanding of the mechanisms of action of IMQ in melanoma, our study opens the way for its further clinical use in the treatment of metastatic melanoma.

Topics: Administration, Topical; Aminoquinolines; Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Dendritic Cells; Disease Models, Animal; Down-Regulation; Fibroblast Growth Factors; Humans; Imiquimod; Interleukin-8; Melanoma; Mice; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Middle Aged; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Skin Neoplasms; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Angiogenin (ANG) is reportedly multifunctional, with roles in angiogenesis and autoimmune diseases. This protein is involved in the innate immune system and has been implicated in several inflammatory diseases. Although ANG may be involved in the anti-inflammatory response, there is no evidence that it has direct anti-inflammatory effects. In this study we sought to determine whether ANG has an anti-inflammatory effect in human corneal fibroblasts (HCFs) exposed to media containing tumor necrosis factor-alpha (TNF-α). We found that ANG reduced the mRNA expression of interleukin-1 beta (IL-1β), -6, -8 and TNF-α receptors (TNFR) 1 and 2. In contrast, ANG increased the mRNA expression of IL-4 and -10. Protein levels of TANK-binding kinase 1 (TBK1) were reduced by ANG in HCFs treated with TNF-α. Moreover, ANG diminished the expression of IL-6 and -8 and monocyte chemotactic protein- (MCP-) 1. The protein expression of nuclear factor-κB (NF-κB) was downregulated by ANG treatment. These findings suggest that ANG suppressed the TNF-α-induced inflammatory response in HCFs through inhibition of TBK1-mediated NF-κB nuclear translocation. These novel results are likely to play a significant role in the selection of immune-mediated inflammatory therapeutic targets and may shed light on the pathogenesis of immune-mediated inflammatory diseases.

Topics: Cells, Cultured; Chemokine CCL2; Cornea; Fibroblasts; Humans; Interleukin-6; Interleukin-8; NF-kappa B; Protein Serine-Threonine Kinases; Ribonuclease, Pancreatic; Tumor Necrosis Factor-alpha

Lysophosphatidic acid (LPA) has been found to mediate myeloid differentiation, stimulate osteogenesis, alter cell proliferation and migration, and inhibit apoptosis in chondrocytes. The effect of LPA on the angiogenic capability of chondrocytes is not clear. This study aimed to investigate its effect on the angiogenic capability of human chondrocytes and the underlying mechanism of these effects. Human chondrocyte cell line, CHON-001, commercialized human chondrocytes (HC) derived from normal human articular cartilage, and human vascular endothelial cells (HUVECs) were used as cell models in this study. The angiogenic capability of chondrocytes was determined by capillary tube formation, monolayer permeability, cell migration, and cell proliferation. An angiogenesis protein array kit was used to evaluate the secretion of angiogenic factors in conditioned medium. Angiogenin, insulin-like growth factor-binding protein 1 (IGFBP-1), interleukin (IL)-8, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF) mRNA and protein expressions were evaluated by Q-RT-PCR and EIA, respectively. LPA receptor (LPAR) expression was determined by RT-PCR. Signaling pathways were clarified using inhibitors, Western blot analysis, and reporter assays. The LPA treatment promoted the angiogenic capability of CHON-001 cells and HC, resulting in enhanced HUVEC capillary tube formation, monolayer permeability, migration, and cell growth. Angiogenin, IGFBP-1, IL-8, MCP-1, MMP-9, and VEGF mRNA and protein expressions were significantly enhanced in LPA-treated chondrocytes. LPA2, 3, 4 and 6 were expressed in CHON-001 and HC cells. Pretreatment with the Gi/o type G protein inhibitor, pertussis toxin (PTX), and the NF-kB inhibitor, PDTC, significantly inhibited LPA-induced angiogenin, IGFBP-1, IL-8, MCP-1, MMP-9, and VEGF expressions in chondrocytes. The PTX pretreatment also inhibited LPA-mediated NF-kB activation, suggesting the presence of active Gi/NF-kB signaling in CHON-001 and HC cells. The effect of LPA on the angiogenesis-inducing capacity of chondrocytes may be due to the increased angiogenesis factor expression via the Gi/NF-kB signaling pathway.

Topics: Angiogenesis Inducing Agents; Cartilage, Articular; Cell Line; Chemokine CCL2; Chondrocytes; Gene Expression Regulation; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Insulin-Like Growth Factor Binding Protein 1; Interleukin-8; Lysophospholipids; Matrix Metalloproteinase 9; Neovascularization, Physiologic; NF-kappa B; Ribonuclease, Pancreatic; RNA, Messenger; Signal Transduction; Vascular Endothelial Growth Factor A

In multiple myeloma (MM), angiogenesis plays a substantial role in disease progression. Interleukin-8 (IL-8), a pro-inflammatory chemokine with potent pro-angiogenic properties, has been implicated in the pathophysiology of MM. The aim of the study is to measure serum levels of IL-8 in MM patients and to correlate them with markers of angiogenesis, such as circulating levels of platelet derived growth factor-AB (PDGF-AB) and angiogenin (Ang), and bone marrow microvascular density (MVD). Fifty-three newly diagnosed MM patients, 23 of them, who reached plateau phase after effective treatment and 20 healthy controls, were studied. Serum levels of PDGF-AB, Ang and IL-8 were measured by ELISA, whereas bone marrow MVD was estimated by immunohistochemical staining of vessels with anti-CD31. All measured parameters were higher in MM patients compared to controls and in increased disease stages. They all also significantly decreased in plateau phase. IL-8 correlated positively with Ang and PDGF-AB, but not with MVD. The circulating levels of IL-8, PDGF-AB and Ang are elevated in patients with MM. The lack of correlation between IL-8 with MVD suggests that its levels represent the inflammatory element of MM disease and the participation in angiogenesis process is rather complex with multifactorial mechanisms.

Topics: Adult; Aged; Aged, 80 and over; Analysis of Variance; Bone Marrow; Female; Humans; Interleukin-8; Linear Models; Male; Microvessels; Middle Aged; Multiple Myeloma; Neovascularization, Pathologic; Ribonuclease, Pancreatic; Statistics, Nonparametric

We studied the effects of soluble products of the placental tissue from women with normal pregnancy and gestosis on the cytokine secretion by endothelial EA.Hy926 cells. The secretory products of the placental tissue induced the production of angiogenin, bFGF, IL-8, MCP-1, and RANTES by endothelial cells. The secretion of bFGF by EA.Hy926 cells increased, while IL-8 secretion decreased under the effects of factors produced by the placental tissue in gestosis but not in normal pregnancy. This could be aimed at reduction of inflammation intensity in the placental tissue and maintenance of endothelial and trophoblast cells viability.

Topics: Cell Line; Chemokine CCL2; Chemokine CCL5; Cytokines; Endothelial Cells; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Placenta; Pre-Eclampsia; Pregnancy; Ribonuclease, Pancreatic; Trophoblasts

Angiogenesis is a prominent feature of structural tissue remodelling that occurs in chronic airway diseases, including chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the airway levels of VEGF, angiogenin, IL-8 and TNF-α in patients with COPD during the stable phase and during acute exacerbation of the disease. We analysed induced sputum samples from 28 patients with COPD. Thirteen of these patients were followed up and second samples of sputum were obtained during acute exacerbation of the disease. The two control groups consisted of 12 healthy smokers and seven healthy non-smokers, all with normal lung function tests. Concentrations of VEGF, angiogenin, IL-8, TNF-α and bFGF were measured by cytometric bead array. In the induced sputum of patients with stable COPD, concentrations of VEGF (P < 0.001, P = 0.02), angiogenin (P < 0.0001, P < 0.0001), IL-8 (P < 0.0001, P = 0.0021) and TNF-α (P < 0.001, P = 0.03) were significantly elevated in comparison with healthy smokers and non-smokers. No additional elevation of angiogenic factors was demonstrated at the time of exacerbation. There was a significant negative correlation between FEV1 and VEGF (P < 0.05, r = -0.38), angiogenin (P < 0.0001, r = -0.68) and IL-8 (P < 0.001, r = -0.54) among smokers (smoking COPD patients and healthy smokers). No significant differences were observed between groups of healthy smokers and non-smokers. These results showed increased airway angiogenesis in patients with COPD. Moreover, VEGF, IL-8 and angiogenin negatively correlated with pulmonary function, which suggests their important role in COPD airway remodelling. However, no additional angiogenic activation was found during exacerbation of COPD.

Topics: Adult; Aged; Female; Fibroblast Growth Factor 2; Flow Cytometry; Humans; Interleukin-8; Lung; Male; Middle Aged; Neovascularization, Pathologic; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Ribonuclease, Pancreatic; Sputum; Statistics, Nonparametric; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A; Young Adult

Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis characterized by inflammation and infiltration of eosinophils at the esophageal mucosa. The underlying etiology of EoE remains elusive. Inflammatory diseases, such as asthma, are associated with structural remodeling of the airways, which includes angiogenesis. The aims of this study were to determine the angiogenic profile of esophageal mucosa in children presenting with EoE and to evaluate the putative mechanism(s) underlying the early inflammatory angiogenic response observed in EoE.. Endoscopically obtained biopsy samples from 18 EoE and 18 control pediatric patients were analyzed for angiogenic markers (CD31, von Willebrand factor, vascular cell adhesion molecule-1) and tissue levels of angiogenic factors (vascular endothelial growth factor [VEGF]-A, VEGF-R2, angiogenin and interleukin [IL]-8). Expression levels of angiogenic factors and markers in EoE and control samples were characterized by immunofluorescence analysis and quantitative reverse transcriptase-polymerase chain reaction. Vascular density of biopsy samples was evaluated by immunofluorescence analysis.. Samples from patients with EoE exhibited higher levels of von Willebrand factor, CD31, and vascular cell adhesion molecule-1, which is suggestive of neovascularization and an activated endothelium. Moreover, EoE biopsies showed greater levels of the angiogenesis promoters VEGFA, angiogenin, and IL-8. Interestingly, there were greater cellular levels of tumor necrosis factor-α in EoE samples compared with controls. Furthermore, there were higher nuclear levels of p50 and p65 subunits of NFκB and lower cellular levels of the inhibitor of NFκB, IκB-α, in EoE samples compared with controls.. We demonstrate increased angiogenesis in the esophageal mucosa of pediatric patients with EoE. The data also provided evidence that the angiogenic factors VEGF-A, angiogenin, and IL-8 were prominently involved in promoting angiogenic remodeling.

Topics: Biomarkers; Biopsy; Child; Eosinophilic Esophagitis; Esophagus; Female; Humans; I-kappa B Proteins; Inflammation; Inflammation Mediators; Interleukin-8; Male; Mucous Membrane; Neovascularization, Pathologic; NF-kappa B; NF-KappaB Inhibitor alpha; Platelet Endothelial Cell Adhesion Molecule-1; Ribonuclease, Pancreatic; Signal Transduction; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Growth Factor A; von Willebrand Factor

Inadequate extracellular conditions can adversely affect the environment of the ER and impinge on the maturation of nascent proteins. The resultant accumulation of unfolded proteins activates a signal transduction pathway, known as the unfolded protein response, which serves primarily to protect the cell during stress and helps restore homeostasis to the ER.. Microarray analysis of the unfolded protein response in a human medulloblastoma cell line treated with thapsigargin revealed that, in addition to known targets, a large number of proangiogenic factors were up-regulated. Real-Time PCR analyses confirmed that four of these factors, VEGFA, FGF2, angiogenin and IL8, were transcriptionally up-regulated in multiple cell lines by various ER stress inducers. Our studies on VEGFA regulation revealed that XBP-1(S), a UPR-inducible transcription factor, bound to two regions on the VEGFA promoter, and analysis of XBP-1 null mouse embryonic fibroblasts revealed that it contributes to VEGFA expression in response to ER stress. ATF4, another UPR-inducible transcription factor, also binds to the VEGFA gene, although its contribution to VEGFA transcription appeared to be fairly modest. We also found that VEGFA mRNA stability is increased in response to UPR activation, via activation of AMP kinase, demonstrating that increased mRNA levels occur at two regulatory points. In keeping with the mRNA levels, we found that VEGFA protein is secreted at levels as high as or higher than that achieved in response to hypoxia.. Our results indicate that the UPR plays a significant role in inducing positive regulators of angiogenesis. It also regulates VEGFA expression at transcriptional, post-transcriptional and post-translational levels and is likely to have widespread implications for promoting angiogenesis in response to normal physiological cues as well as in pathological conditions like cancer.

Topics: Angiogenesis Inducing Agents; Animals; Cell Line; Endoplasmic Reticulum; Fibroblast Growth Factor 2; Humans; Interleukin-8; Mice; Mice, Knockout; Neovascularization, Physiologic; Promoter Regions, Genetic; Protein Processing, Post-Translational; Rats; Ribonuclease, Pancreatic; Transcription, Genetic; Transcriptional Activation; Unfolded Protein Response; Up-Regulation; Vascular Endothelial Growth Factor A

Airway angiogenesis may be an important part of structural remodelling in the pathogenesis of asthma. The development of asthma is frequently preceded by rhinitis.. We sought to determine whether the levels of angiogenesis-related factors are elevated in airways of patients with rhinitis or controlled asthma.. We analysed the induced sputum of 18 rhinitis patients, 16 asthmatic patients, and 15 healthy controls. The concentrations of angiogenin, vascular endothelial growth factor (VEGF), IL-8, fibroblast growth factor (bFGF), and TNF-alpha were measured by cytometric bead arrays.. We found significantly increased angiogenin and VEGF concentrations in the induced sputum supernatant of both rhinitis and asthma patients compared with that of the healthy control group (P< or =0.0005). With the exception of TNF-alpha, there was no difference in the other angiogenic factors; TNF-alpha levels were higher in the rhinitis group than in the control group (P=0.02).. These in vivo results suggest increased airway angiogenesis in patients with rhinitis without asthma as well as in corticosteroid-treated and well-controlled asthma patients.

Topics: Adolescent; Adult; Aged; Angiogenesis Inducing Agents; Asthma; Cell Count; Eosinophils; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Lymphocytes; Macrophages; Male; Middle Aged; Neutrophils; Rhinitis; Ribonuclease, Pancreatic; Sputum; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Sustained angiogenesis, through either local sprouting (angiogenesis) or the recruitment of bone marrow-derived cells (BMDCs) (vasculogenesis), is essential to the development of a tumor. How BMDCs are recruited to the tumor and their contribution to the tumor vasculature is poorly understood. Here, we demonstrate that both IL-8 and angiogenin contribute to the complementary pathways of angiogenesis and BMDC mobilization to increase tumor growth. These two factors are regulated by PHD2 in a HIF-independent but NF-kappaB-dependent manner. PHD2 levels are decreased in human cancers, compared with corresponding normal tissue, and correlate with an increase in mature blood vessels. Thus, PHD2 plays a critical role in regulating tumor angiogenesis.

Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Bone Marrow Cells; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Interleukin-8; Male; Mice; Mice, SCID; Neoplasm Transplantation; Neoplasms, Experimental; Neovascularization, Pathologic; NF-kappa B; Procollagen-Proline Dioxygenase; Ribonuclease, Pancreatic

Temporomandibular joint disorders (TMD) comprise a group of chronic painful conditions of mastication in the temporomandibular joint (TMJ). Although the association between TMD and internal derangement of the TMJ is well documented, the functional relevance is still unclear. Increased concentrations of inflammatory mediators have been identified in the synovial fluid of affected patients with TMD, suggesting an underlying degenerative or inflammatory process. The aim of this study was to generate a comprehensive cytokine expression profile in TMD.. 15 samples from patients with internal derangement of TMJ were analysed using a novel cytokine array that enables the analysis of 79 different cytokines simultaneously.. Cytokine levels were correlated with the presence of joint effusion (JE) determined by MRI. In the majority of synovial fluid samples, angiogenin (Ang), fibroblast growth factor (FGF)-9, insulin-like growth factor-binding protein (IGFBP)-3, interleukin (IL)-1alpha, IL-1beta, IL-8, inducible protein (IP)-10, macrophage inflammatory protein (MIP)-1beta, osteoprotegerin (OPG), transforming growth factor (TGF)-beta2, tissue inhibitor of metalloproteinase (TIMP)-1, TIMP-2, tumour necrosis factor (TNF)-beta and vascular endothelial growth factor (VEGF) were detectable. Furthermore, the expression levels of Ang, brain-derived neurotrophic factor (BDNF), FGF-4, FGF-9, IGFBP-2, IL-8, MIP-1beta, OPG, pulmonary and activation-regulated protein (PARC), TGF-beta2, TIMP-2 and VEGF were significantly associated with the presence of JE; among these, nine cytokines (Ang, BDNF, FGF-4, FGF-9, IGFBP-2, MIP-1beta, PARC, TGF-beta2 and TIMP-2) were hitherto not described in TMD.. This study confirmed previous reports of elevated cytokine levels in TMD. Additionally, we identified previously undescribed cytokines that were upregulated and correlated significantly with the presence of JE. We were able to identify novel cytokines that have hitherto not been described in TMD. Strategies targeting the identified cytokines may represent a novel therapy option in TMD.

Topics: Adult; Aged; Chemokine CCL4; Chemokine CXCL10; Chemokines, CXC; Cytokines; Female; Fibroblast Growth Factor 9; Humans; Insulin-Like Growth Factor Binding Protein 3; Interferon-gamma; Interleukin-1alpha; Interleukin-1beta; Interleukin-8; Macrophage Inflammatory Proteins; Male; Middle Aged; Osteoprotegerin; Ribonuclease, Pancreatic; Synovial Fluid; Temporomandibular Joint Disorders; Tissue Inhibitor of Metalloproteinase-1; Tissue Inhibitor of Metalloproteinase-2; Transforming Growth Factor beta2; Vascular Endothelial Growth Factor A

This study was carried out to compare cytometric bead array (CBA) technology with conventional enzyme linked immunosorbent assay (ELISA) for the measurement of both vitreous and serum concentrations of interleukin-8 (IL-8), vascular endothelial growth factor (VEGF), and angiogenin (ANG) in diabetic and non-diabetic patients.. Measurement of vitreous and serum concentrations of IL-8, VEGF, and ANG using both ELISA and CBA was performed in 26 probands (13 diabetics and 13 non-diabetic control subjects).. Vitreous and serum concentrations of IL-8, VEGF, and ANG determined by CBA showed a strong correlation with those measured by ELISA. Vitreous levels of IL-8, VEGF, and ANG were significantly higher in diabetics compared to non-diabetic control subjects. No significant correlation between vitreous and serum levels of any of the investigated parameters were found in either diabetics or control individuals.. The present study is the first to utilize cytometric bead array technology for the measurement of angiogenic factors in the vitreous. Measurements obtained by ELISA and CBA technologies were highly correlated for IL-8, VEGF, and ANG in both vitreous and serum samples. Diabetic individuals showed significant elevation of IL-8, VEGF, and ANG in the vitreous but not in serum samples compared to control subjects. The most striking advantage of the CBA technology is the fact that numerous parameters can be measured in parallel using a comparatively small sample volume. It is therefore more rapid and cost effective than ELISA technology. CBA technology is a new, accurate method to measure IL-8, VEGF, and ANG in the vitreous.

Topics: Aged; Angiogenesis Inducing Agents; Case-Control Studies; Diabetes Mellitus; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Humans; Interleukin-8; Male; Microspheres; Middle Aged; Ribonuclease, Pancreatic; Vascular Endothelial Growth Factor A; Vitreous Body

The growth behaviour of well-differentiated neuroendocrine carcinomas of the gastro-entero-pancreatic system varies greatly and parameters predicting their prognosis are lacking. The aim of our study was to investigate whether tumour growth could be correlated with the release of proangiogenic factors into the circulation.. Circulating vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and angiogenin were measured in 38 patients with advanced neuroendocrine carcinomas and compared to healthy age-matched controls. In 20 patients, angiogenic cytokine levels were measured at consecutive time points and correlated to tumour progression as assessed by abdominal CT scan, MRI and chromogranin A levels.. VEGF levels were elevated in patients compared to controls (P < 0.002) and clearly associated with tumour progression (P < 0.005). Angiogenin levels were significantly higher in patients than in controls (P < 0.003), while high IL-8 levels were predictive of shorter survival. Angiogenin and bFGF levels were correlated neither with tumour growth nor with patient survival.. VEGF and IL-8 are associated with tumour progression and might qualify as markers of prognosis and therapy control in patients with neuroendocrine carcinomas. Our results support the notion that specific anti-angiogenic therapies should be evaluated in neuroendocrine carcinoma patients.

Topics: Adult; Aged; Angiogenic Proteins; Biomarkers, Tumor; Case-Control Studies; Chi-Square Distribution; Female; Fibroblast Growth Factor 2; Humans; Interleukin-8; Intestinal Neoplasms; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Pancreatic Neoplasms; Predictive Value of Tests; Ribonuclease, Pancreatic; Stomach Neoplasms; Survival Rate; Vascular Endothelial Growth Factor A

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

To determine the predictive value of the angiogenic serum factors angiogenin, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and interleukin-8 (IL-8) for the prognosis of patients with malignant melanoma.. Angiogenin, VEGF, bFGF, and IL-8 were measured in sera of 125 melanoma patients with different stages of disease and with or without current therapy including interferon alfa and different cytostatics in comparison with 30 healthy controls using enzyme-linked immunosorbent assay.. Serum levels of angiogenin, VEGF, bFGF, and IL-8 were significantly increased in melanoma patients compared with healthy controls. Elevated serum concentrations of VEGF, bFGF, and IL-8 were associated with advanced disease stages and tumor burden. Cytostatic therapy of patients was accompanied by increased serum levels of angiogenin, bFGF, and IL-8. As shown by univariate analysis, elevated serum levels of VEGF (P = .0001 and .0036), bFGF (P < .00005 and < .00005), and IL-8 (P < .00005 and < .00005) were strongly correlated with a poor overall and progression-free survival, respectively. Multivariate analysis revealed stage of disease (P = .0238), tumor burden (P = .0347), VEGF (P = .0036), bFGF (P = .0252), and IL-8 (P = .0447) as independent predictive factors of overall survival. Tumor burden (P = .0081), VEGF (P = .0245), and IL-8 (P = .0089) were found as independent predictive factors of progression-free survival.. Our data suggest that the angiogenic serum factors VEGF, bFGF, and IL-8 are useful predictive markers for overall and progression-free survival in melanoma patients.

Topics: Analysis of Variance; Angiogenesis Inducing Agents; Biomarkers; Endothelial Growth Factors; Female; Fibroblast Growth Factor 2; Growth Substances; Humans; Interleukin-8; Lymphokines; Male; Melanoma; Middle Aged; Neoplasm Proteins; Neoplasm Staging; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Ribonuclease, Pancreatic; Survival Analysis; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Alpha-hydroxy acids (AHAs) are widely used for the treatment of hyperkeratotic skin disorders and photodamaged skin.. To investigate the effect of lactic acid (LA) on the secretion of cytokines by keratinocytes (KCs) of human reconstructed epidermis.. Creams containing 1.5%, 3% or 5% LA or vehicle controls were topically applied on to human epidermal equivalents (EEs). After 24 h, EEs were analysed for morphology and for the presence of apoptotic cells. Secretion of vascular endothelial growth factor (VEGF), angiogenin (ANG) and interleukin (IL)-8 was measured in the supernatants by enzyme-linked immunosorbent assay.. LA led to a concentration-dependent increase in apoptotic cells as determined by cell morphology and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labelling. VEGF secretion was increased 2.5- and 2.8-fold (P < 0.05) over vehicle control after treatment with 1.5% and 3% LA, respectively. No significant increase in VEGF secretion was detected with 5% LA. In contrast to VEGF, secretion of ANG was decreased by LA in a concentration-dependent manner (0.5-fold for 5% LA; P < 0.01). No significant changes in IL-8 secretion were found with any of the concentrations tested.. Our data demonstrate that the topical application of AHAs modulates the secretion of cytokines by KCs. Regulation of KC-derived growth factors and cytokines by AHAs might represent a mechanism contributing to their therapeutic effects in disorders such as photoageing.

Topics: Administration, Topical; Apoptosis; Cell Culture Techniques; Dose-Response Relationship, Drug; Endothelial Growth Factors; Epidermis; Humans; Interleukin-8; Keratinocytes; Lactic Acid; Lymphokines; Ointments; Ribonuclease, Pancreatic; Skin, Artificial; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and vascular permeability. We hypothesized that malignant pleural effusions may contain high levels of VEGF protein as well as other cytokines implicated in these processes. Pleural effusions cytologically proven to be malignant were collected from 39 patients with various types of cancer, and VEGF, interleukin-8, and angiogenin levels in the effusions were determined by immunoassay. Negative controls were nonmalignant ascites and serum samples from healthy individuals. VEGF levels were significantly higher than those of control samples in pleural effusions secondary to breast, mesothelioma, and non-small cell lung cancer and when all malignant pleural effusion samples were pooled. Neither interleukin-8 nor angiogenin levels were elevated in malignant pleural effusions relative to the control samples. Vascular permeability, which was measured by using the Miles assay in nude mice, was increased proportionately with VEGF levels in the malignant pleural effusions; this increase in permeability induced by injection of recombinant VEGF or the malignant effusions was reduced by pretreating the mice with a VEGF receptor antibody.

Topics: Angiogenesis Inducing Agents; Animals; Breast Neoplasms; Capillary Permeability; Carcinoma, Non-Small-Cell Lung; Endothelial Growth Factors; Female; Humans; Interleukin-8; Lung Neoplasms; Lymphokines; Lymphoma; Male; Mesothelioma; Mice; Mice, Nude; Pleural Effusion, Malignant; Proteins; Receptor Protein-Tyrosine Kinases; Receptors, Growth Factor; Receptors, Vascular Endothelial Growth Factor; Recombinant Proteins; Ribonuclease, Pancreatic; Sarcoma; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors