Upregulation of interleukin-8 and polarized epithelial expression of interleukin-8 receptor a in ovarian carcinomas

Ivarsson, Karin; Ekerydh, Anne; Fyhr, Ing‐Marie; Janson, Per Olof; Brännström, Mats

doi:10.1080/00016340009169193

Cited by 5 publications

(7 citation statements)

References 20 publications

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“…Therefore, if CXCL8/IL-8 is implicated in ovarian carcinoma, it is probably not predominant in the chemoattraction of neutrophils. Instead, CXCL8/IL-8 could promote angiogenesis or influence the motility of the ovarian epithelial tumor cells, expressing the CXCL8/IL-8 receptor CXCR1 (34,35). As a contrast, out of 14 investigated chemokine receptors including CXCR1, only CXCR4 was expressed on ovarian cancer cells (19).…”

Section: Discussionmentioning

confidence: 97%

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: Discussionmentioning

confidence: 97%

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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“…This effect of IL-6 may contribute to the poor prognosis in ovarian cancer patients overexpressing IL-6 (13). It is not clear how the cytokines IL-6 and IL-8 may modulate cellular responses to chemotherapeutic agents although ovarian cancer cells are known to express IL-6 and IL-8 receptors (14,60).…”

Section: Discussionmentioning

confidence: 99%

“…As both IL-6 and IL-8 are strongly implicated in ovarian cancer progression and prognosis (13)(14)(15)(17)(18)(19)(20), it is critically important to understand the mechanisms underlying overexpression of these factors in ovarian cancer and to explore strategies to restrain their expression. When ovarian cancer cells are analyzed for transcriptional changes in response to LPA, the IL-8 gene is dramatically induced by LPA (12), suggesting that it represents a target gene of LPA.…”

Section: Discussionmentioning

confidence: 99%

“…These studies suggest that LPA may contribute to cancer progression through regulation of gene expression. As IL-8 and its related pro-inflammatory molecule IL-6 are important mediators of ovarian cancer (13)(14)(15)(17)(18)(19)(20), we focused on the effect of LPA on the expression of these two molecules. In a number of ovarian carcinoma cell lines including OVCAR-3, SKOV-3, and DOV-13, LPA stimulates production of not only IL-8 but also IL-6 in a dose-dependent manner ( Fig.…”

Section: Lpa Induces Production Of Il-6 and Il-8 In Ovarian Cancermentioning

confidence: 99%

“…Interestingly, in ovarian cancer patients, serum levels of IL-8 and interleukin-6 (IL-6) are elevated (13)(14)(15). The concentrations of IL-8 and IL-6 are several magnitudes higher in ascitic fluid than in serum (13), implying that IL-8 and IL-6 are produced in ascites, probably by cancer cells, and migrate from the peritoneal cavity to the circulation similar to other tumor markers such as CA125 (16).…”

mentioning

confidence: 99%

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Mechanisms for Lysophosphatidic Acid-induced Cytokine Production in Ovarian Cancer Cells

Fang

Bast

et al. 2004

Journal of Biological Chemistry

183

207

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A potential role for lysophosphatidic acid (LPA) in human oncogenesis was first suggested by the observation that LPA is present at elevated levels in ascites of ovarian cancer patients. In the current study, we demonstrated that LPA is a potent inducer of interleukin-6 (IL-6) and interleukin-8 ( The LPA 2 receptor was identified to be the most efficient in linking LPA to IL-6 and IL-8 production although LPA 1 and LPA 3 were also capable of increasing the response to a certain degree. These studies elucidate the transcriptional mechanism and the Edg LPA receptors involved in LPA-induced IL-6 and IL-8 production and suggest potential strategies to restrain the expression of these cytokines in ovarian cancer.

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The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment

Rolny

Capparuccia

Casazza

et al. 2008

The Journal of Experimental Medicine

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

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Upregulation of interleukin-8 and polarized epithelial expression of interleukin-8 receptor a in ovarian carcinomas

Cited by 5 publications

References 20 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

Mechanisms for Lysophosphatidic Acid-induced Cytokine Production in Ovarian Cancer Cells

The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment

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