High Expression Of CX3CL1/CX3CR1Axis Predicts A Poor Prognosis Of Pancreatic Ductal Adenocarcinoma

BackgroundPancreatic adenocarcinoma is the fourth leading cause of cancer deaths in Western countries[1]. Pancreatic ductal adenocarcinoma(PDAC) is characterized by its late presentation, early and aggressive local and distant metastasis, unresponsiveness to most treatment options and an extremely dismal prognosis [2]. As a result, in multimodal treatment strategies, long-term survival has not improved significantly, with a reported median survival of only14-22months [3]. New strategies and therapies are urgently needed whereas we also need to identify new prognostic and predictive biomarkers. Recently, there has been increasing evidence that chemokines have a role in tumor biology.Chemokines are a family of small molecular weight proteins that promote directional migration of leukocytes, endothelial and epithelial cells, and they are classified into four groups:CXC, CC, C, and CX3C chemokines. CX3CL1is the only member of the CX3C class of chemokines. CX3CL1was cloned from activated endothelial cells and neurons and originally termed Fractalkine or Neurotactin, respectively[4,5]. Unlike other chemokines, CX3CL1exists as both a membrane-bound form promoting firm cell-cell adhesion and a soluble form acting as a chemoattractant for cells expressing its sole receptor CX3CR1[6]. CX3CR1belongs to a family of specific G protein-coupled seven-transmembrane domain receptors [7,8], and is expressed on NK cells, CD8+T cells, monocytes, and dendritic cells. CX3CL1is abundantly expressed by the nervous system. In recent years, the CX3CL1/CX3CR1axis was found to be expressed in differet types of cancer, such as colorectal, prostate, and gastric cancer[9,10,11]. Furthermore, a recent study confirmed that whereas the epithelial cells from exocrine normal pancreas were negative, CX3CR1was highly expressed in ductal cancer cells, especially in tumor cells adjacent to intrapancreatic nerves. When the expression of CX3CL1was detected in intrapancreatic nerves, it was happened to find that tumor cells were also faintly positive[12]. However, the expression of CX3CL1in PDAC is still unknown.Chemokines, in particular inflammatory ones, have long been connected with cancer. CX3CL1expressed on tumor cells can recruit CX3CR1-positive cytotoxic effector lymphocytes to the tumor site. As a result of both the adhesion and chemoattractant activities of the chemokine, the CX3CL1/CX3CR1axis may mediate either pro-or anti-tumor effects [13]. In colorectal cancer patients, CX3CL1expression correlates with the increased density of tumor-infiltrating lymphocytes and better prognosis [9].However, in prostate tumor cells, CX3CR1was involved in metastasis to bone, where endothelial cells produce CX3CL1[10]. Recently, CX3CR1was found to be implicated in perineural invasion and tumor recurrence in patients with PDAC [12]. However, the relevance of the CX3CL1/CX3CR1axis in cancer biology and the clinical results in patients with PDAC remain to be elucidated.ObjectiveExpression of CX3CL1and CX3CR1was detected in specimens from PDAC, and matched with clinicopathological parameters and overall survival(OS).MethodsExpression of CX3CL1and CX3CR1in specimens from105patients with PDAC was evaluated by immunohistochemistry on a tissue microarray and matched with clinicopathological parameters and overall survival(OS).ResultsThe expression of CX3CL1was high in81patients (77.1%) and low in24(22.9%). The expression of CX3CR1was high in70patients (66.7%) and low in35(33.3%). The high expression of both CX3CL1and CX3CR1together was observed in63patients (60.0%). No association was observed between CX3CL1and CX3CR1expression and any of the clinical or pathological data. In survival analysis, patients with a high CX3CL1expression tumour had a significantly shorter OS than patients with a low CX3CL1(P=0.021). The patient prognosis was clearly worse with combined high expression of CX3CL1and CX3CR1than otherwise for OS (P=0.009). In multivariate analysis, high CX3CL1expression was a negative independent prognostic factor for OS (Odd Ratio(OR)=1.775, P=0.030).Conclusion Our results clearly indicated that high expression of CX3CL1/CX3CR1axis in the patients with PDAC might predict a poor prognosis of this disease. Therefore, we proposed that the expression level of CX3CL1/CX3CR1axis could provide a potential to valuable prognostic factor as well as to therapeutic target for PDAC.