Identification of the Chemokine CX3CL1 as a New Regulator of Malignant Cell Proliferation in Epithelial Ovarian Cancer

Abstract

BackgroundLittle is known about the molecules that contribute to the growth of epithelial ovarian carcinomas (EOC), which remain the most lethal gynecological cancer in women. The chemokine Fractalkine/CX3CL1 has been widely reported to play a biologically relevant role in tumor growth and spread. We report here the first investigation of the expression and role of CX3CL1 in EOC.ResultsEpithelial cells from the surface of the ovary and the Fallopian tubes and from benign, borderline and malignant tumors all stained positive for CX3CL1. In tumor specimens from 54 women who underwent surgical treatment for EOC diagnosis, CX3CL1 immunoreactivity was unevenly distributed in epithelial tumor cells, and ranged from strong (33%) to absent (17%). This uneven distribution of CX3CL1 did not reflect the morphological heterogeneity of EOC. It was positively correlated with the proliferation index Ki-67 and with GILZ (glucocorticoid-induced leucine zipper), previously identified as an activator of the proliferation of malignant EOC cells. Hierarchical clustering analysis, including age at diagnosis, tumor grade, FIGO stage, Ki-67 index, CX3CL1, SDF-1/CXCL12 and GILZ immunostaining scores, distinguished two major clusters corresponding to low and high levels of proliferation and differing in terms of GILZ and CX3CL1 expression. GILZ overexpression in the carcinoma-derived BG1 cell line resulted in parallel changes in CX3CL1 products. Conversely, CX3CL1 promoted through its binding to CX3CR1 AKT activation and proliferation in BG1 cells. In a mouse subcutaneous xenograft model, the overexpression of GILZ was associated with higher expression of CX3CL1 and faster tumor growth.ConclusionOur findings highlight the previously unappreciated constitutive expression of CX3CL1 preceding tumorigenesis in ovarian epithelial cells. Together with GILZ, this chemokine emerges as a regulator of cell proliferation, which may be of potential clinical relevance for the selection of the most appropriate treatment for EOC patients.

CX3CL1 Promotes Breast Cancer via Transactivation of the EGF Pathway

“…As CX3CL1 can induce metastasis in some models (8, 9), the Ad-CX3CL1-induced increase in tumor multiplicity could be a result of neoplastic cell dissemination due to chemokine overexpression. Analysis of a collection of human breast cancer cell subtypes with distinct metastatic capacity (35) showed no apparent correlation between CX3CL1 or CX3CR1 mRNA (Supplementary Fig.…”

“…CX3CR1 expression is reported in different types of cancer cell lines (8, 9), including those from the breast (10), where it transduces CX3CL1-induced signals involved in phosphoinositide 3-kinase (PI3K)-mediated survival, proliferation and metastases. In apparent contradiction, CX3CL1 is a transcriptional target of TP53 (11), suggesting CX3CL1/CX3CR1 involvement in tumor suppression.…”

Fractalkine Receptor CX3CR1 Is Expressed in Epithelial Ovarian Carcinoma Cells and Required for Motility and Adhesion to Peritoneal Mesothelial Cells

“…CX 3 CL1 is expressed in many cells and tissues, including the small and large intestine, ovary, and kidney (23, 24, 39, 40). CX 3 CL1 exists in either a membrane-inserted form (23, 24) or a soluble form that has been cleaved to facilitate release (41).…”

“…However, some cell lines, including the immortalized cell line IOSE80 and the borderline EOC cell line HuIOSBT-3.3, demonstrated only slight changes in proliferation in response to CX 3 CL1 (Figure 6A). CX 3 CL1 can partner with both EGFR and CX 3 CR1 to induce cell proliferation (25, 40). Therefore, to assess the contribution of EGFR to CX 3 CL1-dependent proliferation, we incubated each of our cell lines with the EGFR inhibitor, AG1478.…”

Pancreatic Stellate Cells and CX3CR1

“…A number of studies demonstrate that CX3CL1 has cell proliferative and anti-apoptotic effects in various cells (microglial cells 89 , neurons 86 , synovicites 90 , vascular smooth muscle cells 83 , mesangial cells 84 and cancer cells 91 ). Our results in PSCs are consistent with these findings in other cells, because we found the CX3CR1 agonist, CX3CL1 stimulated cell proliferation of PSCs.…”