Analysis of CC chemokine and chemokine receptor expression in solid ovarian tumours

Abstract

SummaryTo understand the chemokine network in a tissue, both chemokine and chemokine receptor expression should be studied. Human epithelial ovarian tumours express a range of chemokines but little is known about the expression and localisation of chemokine receptors. With the aim of understanding chemokine action in this cancer, we investigated receptors for CC-chemokines and their ligands in 25 biopsies of human ovarian cancer. CC-chemokine receptor mRNA was generally absent from solid tumours, the exception being CCR1 which was detected in samples from 75% of patients. CCR1 mRNA localised to macrophages and lymphocytes and there was a correlation between numbers of CD8 + and CCR1 expressing cells (P = 0.031). mRNA for 6 CC-chemokines was expressed in a majority of tumour samples. In a monocytic cell line in vitro, we found that CCR1 mRNA expression was increased 5-fold by hypoxia. We suggest that the CC-chemokine network in ovarian cancer is controlled at the level of CC-chemokine receptors and this may account for the phenotypes of infiltrating cells found in these tumours. The leukocyte infiltrate may contribute to tumour growth and spread by providing growth survival factors and matrix metalloproteases. Thus, CCR1 may be a novel therapeutic target in ovarian cancer.

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

“…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). Until the present, it has remained unclear whether the expression of CXCL8/IL-8 by ovarian cancer cells is beneficial or detrimental for the tumor progression.…”

“…As a consequence, TAM did not migrate anymore in response to CCL2/MCP-1. Very recently, CC chemokine receptor-1 was found to be the only CC chemokine receptor consistently expressed in the solid ovarian tumor by the infiltrating CD68 ϩ macrophages and CD8 ϩ lymphocytes (32). Further purification and NH 2 -terminal sequence analysis demonstrated the presence of two CXCL8/IL-8 isoforms in the purified ascitic fluid (i.e.…”

“…as growth factor for the tumor cells or as a factor directly or indirectly influencing angiogenesis or metastasis). Indeed, the recent reports on the specific chemokine receptor expression in the ovarian carcinoma environment (19,32) could not take into account the yet unknown PARC receptor. The identification of a functional CCL18/ PARC receptor and of a CCL18/PARC homologue in a laboratory animal would facilitate the search for other possible target cells and relevant functions of CCL18/PARC in ovarian carcinoma.…”

“…Ovarian carcinoma is often accompanied by extensive ascites accumulation, and a number of cytokines have been detected in this peritoneal fluid (16 -18). As far as chemokines are concerned, until the present only CCL2/MCP-1, CXCL8/IL-8, and CXCL12/stromal cell-derived factor-1␣ (15,17,19) could be demonstrated by ELISA, and the CCL2/MCP-1 and CXCL8/ IL-8 levels were reported to be significantly enhanced in ascites from patients with ovarian cancer compared with nonovarian carcinoma patients (15,17). Human ascitic fluid is a rich natural source allowing us to identify molecules that may have important functions in the tumor environment and to study their molecular diversity and biological activity at the protein level.…”

Regulation of CXCR4-mediated chemotaxis and chemoinvasion of breast cancer cells

“…Chemokines and their respective receptors that regulate chemotaxis and the transendothelial migration of leukocytes during immune and inflammatory reactions (Premack and Schall, 1996;Rollins, 1997;Gonzalo et al, 2000;Yoshie, 2000;Camacho et al, 2001) were recently observed to play an important role in the metastasis of various cancers (Luca et al, 1997;Inoue et al, 2000a, b;Mohle et al, 2000;Cass et al, 2001;Geminder et al, 2001;Robledo et al, 2001;Scotton et al, 2001;Libura et al, 2002;Mashino et al, 2002;Murakami et al, 2002;Payne and Cornelius, 2002;Taichman et al, 2002). Chemokine receptors have been found to be expressed in these invasive cells in a distinct and nonrandom pattern.…”