The Chemotactic Cytokine Interleukin-8—A Cyst Fluid Marker for Malignant Epithelial Ovarian Cancer?

Ivarsson, Karin; Runesson, Eva; Sundfeldt, Karin; Haeger, M; Hedin, Lars O.; Janson, Per Olof; Brännström, Mats

doi:10.1006/gyno.1998.5198

Cited by 66 publications

(45 citation statements)

References 16 publications

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“…This is in agreement with the fact that NH 2 -terminally truncated forms of CXCL8/IL-8 are more active than the intact form and with the reported chemotactic potency of a natural mixture of leukocyte-derived CXCL8/IL-8-(6 -77) and CXCL8/IL-8-(8 -77) isoforms (28,29). In addition, we found 3-fold higher CXCL8/IL-8 levels (p ϭ 0.01) in ovarian carcinoma compared with nonovarian carcinoma ascites, in support of existing reports on significant CXCL8/IL-8 increases in the ascitic or cyst fluid of epithelial ovarian cancer patients (17,33). With an average CXCL8/IL-8 concentration of 2.0 ng/ml measured in the crude ascitic fluids, the natural mixture of CXCL8/IL-8 isoforms is in theory able to chemoattract neutrophilic granulocytes to the ovarian carcinoma environment.…”

Section: Discussionsupporting

confidence: 90%

Identification of Biologically Active Chemokine Isoforms from Ascitic Fluid and Elevated Levels of CCL18/Pulmonary and Activation-regulated Chemokine in Ovarian Carcinoma

Schutyser¹,

Struyf²,

Proost³

et al. 2002

Journal of Biological Chemistry

200

149

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Chemokines are important in leukocyte homeostasis, inflammation, angiogenesis, and metastasis. Here, the molecular diversity of chemokines present in ovarian carcinoma was studied by purifying the proteins to homogeneity from ascitic fluid. Biologically active intact CCL2 and processed CXCL8, CCL3, and CCL18 isoforms were recovered. CCL7 and CCL20 were also purified, but their levels were 10-fold lower compared with CXCL8, CCL2, and CCL3 and even 100-fold lower than the amounts of CCL18 isolated. In ascitic fluids from patients with ovarian carcinoma (n ‫؍‬ 12), significantly higher levels of CXCL8 and CCL18 (2.0 versus 0.7 ng/ml (p ‫؍‬ 0.01) and 120 versus 44 ng/ml (p ‫؍‬ 0.0002), respectively) were detected compared with those in nonovarian carcinoma patients (n ‫؍‬ 12). In contrast to CXCL8, CCL18 was not inducible in carcinoma cell lines. Immunostaining showed CCL18 expression in tumor-infiltrating cells with monocyte/macrophage morphology but not in the ovarian carcinoma cells. Our data demonstrate that biochemically heterogenous but biologically active forms of several chemokines are present at different concentrations in ovarian carcinoma ascitic fluid. This points to a delicate balance of chemokines in epithelial ovarian cancer and to a potentially major role for CXCL8 and CCL18 in this tumor.Chemokines are small chemotactic cytokines that are structurally divided into C, CC, CXC, and CX 3 C subgroups according to the positioning of conserved cysteine residues (1). This classification corresponds only in part with a biological division of chemokines in groups that selectively attract specific subtypes of leukocytes. For example, CC chemokines are capable to activate and chemoattract multiple leukocytic cell types. Alternative attempts were made to classify chemokines as inflammatory chemokines (i.e. inducible proteins that attract leukocytes to sites of inflammation) or constitutively released homeostatic chemokines that regulate leukocyte homing in the lymphoid system (2). Besides their function in leukocyte migration, chemokines are involved in other normal or pathological processes, like hematopoiesis, angiogenesis, cancer growth, and metastasis (3, 4). This indicates that our understanding of the exact role of a number of chemokines remains limited. As a consequence, a systematic chemokine and chemokine receptor nomenclature based on protein structure rather than on function has been introduced recently (3), despite the fact that not all chemokines nor all their receptors have been identified. Indeed, for some recently cloned chemokines such as CCL18/ pulmonary and activation-regulated chemokine (PARC) 1 (5), the regulated production and function of the natural protein has not yet been investigated in detail, and its agonistic receptor remains unknown.Chemokines are produced by a variety of cell types including leukocytes and cancer cells (6, 7). Tumor-derived chemokines are important for the characteristic recruitment of leukocytes, such as tumor-associated macrophages (TAM) and lymphocytes, to the ...

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Section: Discussionsupporting

confidence: 90%

Identification of Biologically Active Chemokine Isoforms from Ascitic Fluid and Elevated Levels of CCL18/Pulmonary and Activation-regulated Chemokine in Ovarian Carcinoma

Schutyser¹,

Struyf²,

Proost³

et al. 2002

Journal of Biological Chemistry

200

149

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“…It was shown to increase proliferation of ovarian cancer cells in both cell culture and nude mice and was able to inhibit tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis (24,25). A number of studies reported IL-8 to be elevated in serum and cystic fluid from cancer patients compared with healthy controls and patients with benign cysts (26)(27)(28)(29). Further, increased expression of IL-8 was correlated with higher stages of the disease (30,31).…”

Section: Discussionmentioning

confidence: 99%

Protein Chip Discovery of Secreted Proteins Regulated by the Phosphatidylinositol 3-Kinase Pathway in Ovarian Cancer Cell Lines

2006

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Ovarian cancer has the highest mortality among the gynecologic malignancies. The phosphatidylinositol 3-kinase (PI3K) pathway is frequently activated, leading to increased cell survival. This study aimed to identify secreted proteins regulated by the PI3K pathway in ovarian cancer cell lines. Surface-enhanced laser desorption-ionization time-of-flight mass spectrometry with cation-exchange protein-chips was used to analyze secreted proteins from five ovarian cancer cell lines (SKOV-3, PE01, OVCAR-3, OV167, and OV207). To activate the PI3K pathway, cells were treated with 50 ng/mL epidermal growth factor (EGF) with or without 10 Mmol/L LY294002, a PI3K inhibitor. Proteins induced by EGF and inhibited by LY294002, in the m/z range 7,500 to 9,500, were purified chromatographically, identified by peptide mass fingerprinting and NH 2 -terminal sequencing, and confirmed by immunodepletion. Two immunologically related proteins, m/z f8,385 and 8,922, were identified as truncated and intact forms, respectively, of interleukin 8, a chemokine previously shown to be elevated in serum of ovarian cancer patients. Another protein, m/z 7,866, was identified as CXC chemokine ligand 1 (CXCL1) or GRO-A, a chemokine associated with melanoma formation and some epithelial cancers. EGF-stimulated CXCL1 levels were variably decreased by mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase and p38 MAPK inhibition in the five cell lines, but only LY294002 fully reversed the EGF effect in all cell lines. Immunoreactive CXCL1 levels in 160 conditioned media were highly correlated with corresponding peak intensities at m/z 7,866 by mass spectrometry, indicating the quantitative nature of these analyses. We conclude that proteomic analysis of cell models of human disease may facilitate the discovery of pathway-dependent proteins. (Cancer Res 2006; 66(3): 1376-83)

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“…Lactate dehydrogenase (LDH) was analyzed by a kinetic spectrophotometric method using a kit from Roche on a Modular Analytics P800 analyzer (Roche) with results converted to 30 C. C-reactive protein (CRP) was measured with an immunoturbidimetric assay using reagents from Roche (Roche Diagnostics GmbH) on a Hitachi modular P autoanalyzer (Roche/Hitachi).…”

Section: Sample Collection and Biochemical Assaysmentioning

confidence: 99%

“…22), urothelial tumors (23,24), hepatocellular carcinoma (HCC; refs. 25,26), colorectal cancer (27), gastric cancer (28), pancreatic cancer (29), ovarian cancer (30), breast cancer (31), neurologic tumors (32), lymphoma (33,34), and others (5,35) are available, but its value as a cancer biomarker to predict changes in tumor burden and to monitor response to cancer treatment has been poorly explored.…”

Section: Introductionmentioning

confidence: 99%

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

Sanmamed

Carranza-Rua

Alfaro

et al. 2014

Clinical Cancer Research

210

158

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Purpose: 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.Experimental Design: 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.Results: 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 ¼ 16), renal cell carcinoma (RCC; n ¼ 23), non-small cell lung cancer (NSCLC; n ¼ 21), or hepatocellular carcinoma (HCC; n ¼ 30), serum IL8 concentrations correlated with tumor burden and stage, survival (melanoma, n ¼ 16; RCC, n ¼ 23; HCC, n ¼ 33), and objective responses to therapy, including those to BRAF inhibitors (melanoma, n ¼ 16) and immunomodulatory monoclonal antibodies (melanoma, n ¼ 8). IL8 concentrations in urine (n ¼ 18) were mainly elevated in tumors with direct contact with the urinary tract.Conclusions: IL8 levels correlate with tumor burden in preclinical models and in patients with cancer.

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The Chemotactic Cytokine Interleukin-8—A Cyst Fluid Marker for Malignant Epithelial Ovarian Cancer?

Cited by 66 publications

References 16 publications

Identification of Biologically Active Chemokine Isoforms from Ascitic Fluid and Elevated Levels of CCL18/Pulmonary and Activation-regulated Chemokine in Ovarian Carcinoma

Identification of Biologically Active Chemokine Isoforms from Ascitic Fluid and Elevated Levels of CCL18/Pulmonary and Activation-regulated Chemokine in Ovarian Carcinoma

Protein Chip Discovery of Secreted Proteins Regulated by the Phosphatidylinositol 3-Kinase Pathway in Ovarian Cancer Cell Lines

Serum Interleukin-8 Reflects Tumor Burden and Treatment Response across Malignancies of Multiple Tissue Origins

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