High coexpression of CCL2 and CX3CL1 is gender‐specifically associated with good prognosis in soft tissue sarcoma patients

Abstract

Chemokines are involved in both the negative and positive regulation of inflammatory processes, angiogenesis and cancer/cancer stem cell proliferation as well as the chemoattraction of tumor cells to metastatic sites. The aim of this study was to measure the mRNA expression levels of three chemokines, CCL2, CCL7 and CX3CL1, in soft tissue sarcomas (STSs) and to assess the correlations between these levels as well as their correlations with clinicopathological data and the disease-specific survival of STS patients. The mRNA levels of CCL2, CCL7 and CX3CL1 were analyzed in tumor tissues from 126 STS patients using qPCR. Low mRNA expression of CCL2 and CX3CL1 was significantly correlated with a worse prognosis (RR 5 1.98; p 5 0.019 and RR 5 2.10; p 5 0.014; multivariate Cox's regression analysis). A combined low expression of CCL2 and CX3CL1 was associated with a significantly increased risk of tumor-related death as compared to patients with high expression levels of both chemokines (RR 5 3.08; p 5 0.003). A gender-specific multivariate analysis revealed that female STS patients with low CX3CL1 mRNA expression had a 3.46-fold increased risk of death (p 5 0.004). Low expression of both CCL2 and CX3CL1 mRNAs resulted in an additive 5.37-fold increased risk of tumor-related death (p 5 0.003) as compared to those with high expression of both parameters in female patients. In conclusion, this is the first study to show a significant correlation between combined low expression of CCL2 and CX3CL1 and a poor prognosis for STS patients, particularly in female patients.Soft tissue sarcomas (STSs) are a heterogeneous group of malignant mesenchymal tumors. 1,2 Clinically relevant prognostic factors include tumor size, tumor grade, the localization of the primary tumor 3 and the type of tumor resection. In addition, several molecular factors with prognostic impact have been identified (reviewed in Refs. 4 and 5). However, there is still an urgent need to characterize further prognosisassociated molecular factors for an improved prognostication and treatment management. In several cancer types, chemokines have been discussed as biomarkers for detecting early metastasis, have been associated with tumor progression, and have been suggested as potential therapeutic targets. Chemokines represent a group of chemotactic cytokines responsible for orchestrating cell recruitment under both homeostatic and inflammatory conditions. The small (8-10 kDa) chemokine proteins are classified into four highly conserved groups-C, CC, CXC and CX3C-based on the position of the first two cysteines that are adjacent to the amino terminus. 6 The binding of the chemokine ligand to its seventransmembrane G-protein-coupled receptor activates downstream signaling that leads to cell movement in development, inflammation, wound healing and cancer. 7 Oncogenic

Differential impact of CX3CL1 on lung cancer prognosis in smokers and non‐smokers

“…Previous studies have shown that H level CX3CL1 in breast cancer, gastric cancer, and soft tissue sarcoma patients correlates with better prognosis . We found that higher levels of CX3CL1 correlate with poor prognosis only in AD/smoker group.…”

“…Previous studies have shown that H level CX3CL1 in breast cancer, gastric cancer, and soft tissue sarcoma patients correlates with better prognosis. 11,12,21 We found that higher levels of CX3CL1 correlate with poor prognosis only in AD/smoker group. Most patients with SQ had smoking history, but patients with AD were either smokers or nonsmokers with a higher percentage of non-smokers.…”

The Fractalkine-Receptor Axis Improves Human Colorectal Cancer Prognosis by Limiting Tumor Metastatic Dissemination

“…In contrast, expression of the ligand has usually been associated with improved patient survival (26,44,53,54). The antitumor effects of CX 3 CL1 are mostly related to attraction of cytotoxic CD8 T lymphocytes and NK cells (40,42,43).…”

CCL2 Expression in Tumor Cells and Tumor-Infiltrating Immune Cells Shows Divergent Prognostic Potential for Bladder Cancer Patients Depending on Lymph Node Stage

“…On the other hand, in resected pancreatic cancer patients, CCL2 is an independent favorable prognostic factor with indirect effects on pancreatic cancer cell growth via cytokines, such as IL1B [35]. Furthermore, in soft tissue sarcoma patients, high CCL2 mRNA expression is associated with a good prognosis [36], and higher CCL2 expression was significantly associated with better OS in non-small-cell lung cancer (NSCLC) patients [37]. In addition, a protective role of the CCR2/CCL2 chemokine pathway has been demonstrated by cytotoxic T lymphocytes' migration toward melanoma cells that secrete CCL2, which results in tumor cell apoptosis [38], and further by the recruitment of subsets of tumor-infiltrating lymphocytes (type 1 cytotoxic gamma-delta T lymphocytes) to tumor beds in a melanoma model [39].…”