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.
Highlights
Epithelial ovarian cancer (EOC) constitutes the sixth most common cancer and the fifth leading cause of cancer-related death among women in developed countries [1]
The cellular expression of CX3CL1 was examined by immunohistochemisty (IHC) in sections isolated from three healthy ovaries, eight serous and mucinous benign tumors, eight serous and mucinous borderline tumors, two ovarian granulosa cell tumors, and from 54 specimens of invasive epithelial ovarian carcinomas (EOC)
CX3CL1 was clearly detected in the ovary surface epithelium (OSE) cells and in the epithelium of the Fallopian tubes (Figure 1A)
Summary
Epithelial ovarian cancer (EOC) constitutes the sixth most common cancer and the fifth leading cause of cancer-related death among women in developed countries [1]. The epithelial tumor microenvironment consists of a complex tissue containing several cell types Most of these cells produce and/or respond to chemokines, which may play key roles in the development and progression of primary epithelial tumors [3,4,5]. Little if anything is known about the role of the chemokine Fractalkine/ CX3CL1 in EOC, it has been evidenced to mediate strong cell adhesion [8] and its presence in epithelial tissues is widely documented [9,10]. We report here the first investigation of the expression and role of CX3CL1 in EOC
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