interleukin-8 and Sarcoma

The systemic side effects of isolated limb perfusion (ILP) with rhTNF alpha and melphalan are characterised by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after TNF-ILP. Serum-PCT was analysed in 24 patients (12 male, 12 female), who treated by ILP for regionally metastasized melanoma (n = 8) or locally advanced soft tissue sarcoma (n = 16). Serum samples were analysed pre- and intraoperatively, and at defined intervals after reperfusion of the limb. In addition to PCT, serum IL-6 and IL-8 were analysed in 11 patients. PCT was significantly elevated over baseline after ILP with a maximum between 8 and 36 hours (p < 0.001). Even 96 hours after reperfusion, PCT was still significantly elevated as compared to baseline levels (p = 0.005). There was no correlation to the systemic leakage rate during the perfusion. IL-6 and IL-8 were also significantly increased after ILP (p = 0.001), but the maximum peaks of both cytokines were reached much earlier than for PCT (IL-8 max. at 1 hour and IL-6 max. at 4 hours after reperfusion). Serum procalcitonin is induced as part of the specific SIRS after ILP with rhTNF alpha and melphalan. It may be induced directly by rhTNF alpha or by different cytokines, as serum peaks of IL-6 and IL-8 are reached well before the peak of PCT. Determination of PCT prior to and after ILP with TNF might be useful to assess patients at risk of developing hyperdynamic shock.

Topics: Antineoplastic Combined Chemotherapy Protocols; Calcitonin; Calcitonin Gene-Related Peptide; Chemotherapy, Cancer, Regional Perfusion; Extremities; Female; Humans; Interleukin-6; Interleukin-8; Male; Melanoma; Melphalan; Predictive Value of Tests; Protein Precursors; Sarcoma; Skin Neoplasms; Soft Tissue Neoplasms; Systemic Inflammatory Response Syndrome; Tumor Necrosis Factor-alpha

Following uncontrolled proliferation, a subset of primary tumour cells acquires additional traits/mutations to trigger phenotypic changes that enhance migration and are hypothesized to be the initiators of metastasis. This study reveals an adaptive mechanism that harnesses synergistic paracrine signalling via IL-6/8, which is amplified by cell proliferation and cell density, to directly promote cell migration. This effect occurs in metastatic human sarcoma and carcinoma cells- but not in normal or non-metastatic cancer cells-, and likely involves the downstream signalling of WASF3 and Arp2/3. The transcriptional phenotype of high-density cells that emerges due to proliferation resembles that of low-density cells treated with a combination of IL-6/8. Simultaneous inhibition of IL-6/8 receptors decreases the expression of WASF3 and Arp2/3 in a mouse xenograft model and reduces metastasis. This study reveals a potential mechanism that promotes tumour cell migration and infers a strategy to decrease metastatic capacity of tumour cells.

Topics: Actin-Related Protein 2-3 Complex; Animals; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Humans; Interleukin-6; Interleukin-8; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplasm Invasiveness; Paracrine Communication; Receptors, Interleukin-6; Receptors, Interleukin-8A; RNA, Small Interfering; Sarcoma; Signal Transduction; Sulfonamides; Wiskott-Aldrich Syndrome Protein Family; Xenograft Model Antitumor Assays

We report the case of a 12-year-old boy with primary undifferentiated sarcoma of the left atrium. He had sustained fever during the clinical course and multiple lung and brain metastases. Chemotherapy and irradiation were ineffective; he died 41 days after hospitalization. On retrospective analysis, interleukin-8 (IL-8) was elevated; this was supported by immunohistochemistry and gene expression analysis of tumor samples. IL-8 continued to increase with tumor progression accompanied by elevated neutrophil count and C-reactive protein. IL-8 is involved in malignant tumor proliferation, migration, and angiogenesis and may have been related to the clinical condition and prognosis in the present case.

Topics: Child; Diagnosis, Differential; Disease Progression; Echoencephalography; Fatal Outcome; Fever; Heart Atria; Heart Neoplasms; Humans; Immunohistochemistry; Interleukin-8; Magnetic Resonance Spectroscopy; Male; Sarcoma; Tomography, X-Ray Computed

The nematode Spirocerca lupi (S. lupi) induces sarcoma in the dog oesophagus in about 25% of cases. The aim of this study was to compare the differences in the cytokine milieu between dogs with neoplastic (n=29) and non-neoplastic disease (n=49) and age- and gender-matched healthy controls (n=25). We measured IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, GM-CSF and MCP-1 in a specific canine multiplex immunoassay kit. Cytokine concentrations were compared between the different groups using the Kruskal-Wallis test followed by Dunn's test. Only IL-8 and IL-18 showed significant differences in their plasma concentration among the three groups. Kruskal-Wallis test revealed a significant (p=0.001) difference in IL-8 concentration between the neoplastic group (634pg/ml), the non-neoplastic (429 pg/ml) and the control groups (150 pg/ml). Post-test analysis revealed a significance difference between the two S. lupi groups and the control group (p<0.01). The highest IL-18 concentration was found in the non-neoplastic group (53 pg/ml), followed by the control group (46 pg/ml) and finally the neoplastic group (33 pg/ml). IL-18 concentrations were significantly higher in the non-neoplastic group than in the neoplastic group (p=0.05). The increased IL-8 in the spirocercosis groups is consistent with the neutrophilic infiltrate in spirocercosis lesions and in those of other inflammatory-induced neoplasias such as Barret's oesophagus and Helicobacter gastritis. IL-18 showed negative regulatory effect in several worm infections and it is possible that it plays the same role in spirocercosis, allowing the worm to evade the host response and to induce neoplastic transformation.

Topics: Animals; Biomarkers; Cytokines; Dog Diseases; Dogs; Esophageal Neoplasms; Female; Interleukin-18; Interleukin-8; Male; Sarcoma; Spirurida Infections; Thelazioidea

Isolated, hyperthermic limb perfusion (ILP) with recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and melphalan is a highly effective treatment for locoregional metastases of malignant melanoma and for advanced soft tissue sarcoma of the limb. The major systemic side effects are characterized by the induction of a systemic inflammatory response syndrome (SIRS). Procalcitonin (PCT), a serum marker of bacterial sepsis, was investigated with respect to its role in SIRS after ILP.. University surgical oncology division with an integrated eight-bed intensive care unit.. Thirty-seven patients were treated by ILP with rhTNF-alpha and melphalan (n = 26) or with cytostatics alone (n = 11) for soft tissue sarcoma or malignant melanoma.. The course of serum PCT, interleukin (IL)-6, and IL-8 was analyzed intra- and postoperatively. Hemodynamic variables including heart rate, mean arterial pressure, cardiac index, pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary and systemic vascular resistance were recorded in parallel.. PCT was significantly elevated over baseline after ILP with a maximum between 8 hrs (peak level 16.0+/-18.8 (SD) ng/mL) and 36 hrs (13.8+/-15.7 ng/mL) (p < .001). The increase in serum PCT was significantly more pronounced after ILP with rhTNF-alpha/melphalan than after ILP with cytostatics alone (p < .001). IL-6 and IL-8 were also significantly increased after ILP (p = .001), reaching peak concentrations at 1 hr and 4 hrs postoperatively. Significant changes in heart rate, mean arterial pressure, cardiac index, and systemic vascular resistance were observed during and after ILP; however, PCT levels could not be correlated to these variables. Pulmonary arterial pressure, pulmonary capillary occlusion pressure, and pulmonary vascular resistance showed no significant changes.. Serum procalcitonin is induced as part of the SIRS after ILP with rhTNF-alpha/melphalan. It may be induced directly by rhTNF-alpha or other cytokines, because serum peaks of IL-6 and IL-8 precede the peak of PCT. Because there is no correlation between serum levels of PCT and hemodynamic variables, this marker cannot be applied to assess the severity of SIRS reaction after ILP.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Physiological Phenomena; Chemotherapy, Cancer, Regional Perfusion; Cisplatin; Extremities; Female; Glycoproteins; Humans; Interleukin-6; Interleukin-8; Male; Melanoma; Melphalan; Middle Aged; Protein Precursors; Recombinant Proteins; Sarcoma; Time Factors; Tumor Necrosis Factor-alpha

Although preimplantation embryo and decidual cells secrete significant amounts of platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF); its precise function in early pregnancy has yet to be established. To investigate the effect of PAF on cytokine synthesis, we measured the cytokine concentration in the culture media of two human cell lines: normal endometrial stromal cells (ESC) and endometrial stromal sarcoma cells (MaMi), following stimulation with a non-metabolized PAF analogue, carbamyl-PAF (C-PAF). Enzyme-linked immunosorbent assays were used to measure five cytokines: interleukin (IL)-6, IL-8, macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein-1alpha (MIP-1alpha) and tumour necrosis factor-alpha (TNF-alpha). We also evaluated the mRNA expression for IL-6 and IL-8 in ESC after C-PAF stimulation using Northern blot analysis. Non-stimulated ESC and MaMi cells both secreted IL-6, IL-8, and M-CSF, but not MIP-1alpha or TNF-alpha. The concentrations of IL-6, IL-8, M-CSF, MIP-1alpha, and TNF-alpha in the culture media of both cell lines increased in parallel with increasing amounts of C-PAF. C-PAF stimulated IL-6 and IL-8 transcription in ESC. These results suggest that PAF secretion by decidual tissues and developing embryos may induce cytokine synthesis by the ESC, as part of the cytokine network in the feto-maternal unit. An increase in the local cytokine concentration may be an important factor in the maintenance of early stages of gestation.

Topics: Adult; Cell Line; Chemokine CCL3; Chemokine CCL4; Cytokines; Endometrial Neoplasms; Endometrium; Female; Humans; Interleukin-6; Interleukin-8; Macrophage Colony-Stimulating Factor; Macrophage Inflammatory Proteins; Phospholipid Ethers; Platelet Activating Factor; Sarcoma; Stromal Cells; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

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

Uterine endometrial stromal sarcoma is a rare neoplasm with a morphology that closely resembles that of the proliferative endometrial stroma. To understand its pathologic characteristics, we established a novel cell line, MaMi, from a primary culture of an endometrial stromal sarcoma obtained from a 65-year-old Japanese woman.. We observed the morphology of MaMi cells and performed immunohistochemical analysis on the primary tumor and transplants in nude mice. Prolactin, insulin-like growth factor-binding protein-1, interleukin (IL)-6, IL-8, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, E-selectin, vascular cell adhesion molecule-1, and fibronectin production in the culture medium of MaMi cells were also examined.. MaMi cells were shown to exhibit a fibroblast-like morphology in vitro, and they adopted a more elongated appearance in response to 12-O-tetradecanoyl phorbol-13-acetate (TPA). On injection into nude mice, the cells gave rise to subcutaneous tumors. Immunohistologically, both the primary tumor and MaMi cell-induced tumors stained positively with antibodies to neuron-specific enolase or vimentin. MaMi cells constitutively produced IL-6, IL-8, and monocyte chemoattractant protein-1 in vitro. Interleukin-1beta, (100 pmol/L), tumor necrosis factor-alpha (1 nmol/L), and lipopolysaccharide (1 microg/mL) each increased the release of IL-6, IL-8, and monocyte chemoattractant protein-1 by MaMi cells. TPA (10 nmol/L) also stimulated the production of IL-6 and IL-8 by these cells, but inhibited that of monocyte chemoattractant protein-1.. We demonstrated that MaMi cells closely resemble proliferative endometrial stromal cells not only morphologically, but also functionally. This cell line may prove valuable in understanding the role of cytokines produced by tumor cells in the pathogenesis of endometrial stromal sarcoma and may also be useful as an in vitro model of functioning endometrial stromal cells.

Topics: Aged; Animals; Cell Division; Chemokine CCL2; E-Selectin; Endometrial Neoplasms; Female; Fibronectins; Humans; Immunohistochemistry; Insulin-Like Growth Factor Binding Protein 1; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Karyotyping; Mice; Mice, Nude; Neoplasm Transplantation; Prolactin; Sarcoma; Sarcoma, Experimental; Stromal Cells; Tumor Cells, Cultured; Vascular Cell Adhesion Molecule-1

The objective of the present study was to investigate the effects of isolated limb perfusion (ILP) with tumour necrosis factor alpha (TNF-alpha) and melphalan in patients with cancer on, first, plasma levels of cytokines, second, systemic monocyte and T-lymphocyte distribution and, third, the ability of mononuclear cells to produce cytokines upon stimulation in vitro. Six patients undergoing an ILP were entered into the study (group 1). In addition, patients undergoing a major surgical operation (group 2) minor operation (group 3) as well as healthy volunteers (group 4) were included as control groups. Sensitive enzyme-linked immunosorbent assays (ELISAs) were used to measure TNF-alpha and interleukin-6 (IL-6) plasma levels at various time points during and after operation. Furthermore, the percentage of monocytes and T lymphocytes was determined in all studied groups using a FACScan. In addition, cytokine production upon stimulation with lipopolysaccharide (LPS) and a combination of anti-CD3/anti-CD28 monoclonal antibodies in whole-blood cultures was investigated. Increased plasma levels of TNF-alpha and IL-6 in patients undergoing ILP was observed, but only IL-6 appeared to be increased in patients treated with a major operation. No significant fluctuations were found in the other groups studied. Concerning the number of monocytes, a significant decrease was observed only in patients treated with ILP. Furthermore, a decreased production of TNF-alpha, IL-6 and IL-8 upon various types of stimulation in vitro was found in those patients, but also after a major operation. In conclusion, the results of the present study show increased plasma levels of cytokines in patients treated with ILP and major operation. Furthermore, a decrease in numbers of monocytes in the circulation and the ability of mononuclear cells to produce cytokines in vitro may be induced by administration of TNF-alpha in ILP. Although similar results were found in patients treated with major operation, the underlying mechanisms of this phenomenon remain to be elucidated.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; CD28 Antigens; CD3 Complex; Chemotherapy, Cancer, Regional Perfusion; Female; Humans; Interleukin-6; Interleukin-8; Lipopolysaccharides; Male; Melanoma; Middle Aged; Monocytes; Sarcoma; T-Lymphocytes; Time Factors; Tumor Necrosis Factor-alpha

Topics: Base Sequence; Chemokine CCL2; Chemotactic Factors; Humans; Interleukin-8; Interleukins; Molecular Sequence Data; Sarcoma