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

Abstract

CX3CL1 is a unique chemokine, expressed in both soluble and membrane bound forms, which mediates different biological activities. Recent studies have revealed the potential of CX3CL1 signaling pathway as a target for the treatment of inflammation and cancer. The correlation between expression of CX3CL1 and prognosis of patients varies among cancers. In this study, based on CX3CL1 immunohistochemistry in non-small cell lung cancer, CX3CL1 levels were positively associated with cancer stage (Pearson chi-square, P = 0.048) and lymph node status (P = 0.033). Interestingly, survival effects of CX3CL1 were only observed in patients with smoking history and adenocarcinoma (AD, log rank, P = 0.027), but not in patients with squamous cell carcinoma (SQ). The median survival time of patients with smoking history and low level CX3CL1 expressing AD was 1538 days, while that of patients with smoking history and high level CX3CL1 expressing AD was 396 days. Cox regression models showed adverse effects of high CX3CL1 levels only in AD patients with smoking history (hazard ratio = 3.01, p = 0.034), but not in AD patients without smoking history or in SQ patients with smoking history. The results of this study suggest that CX3CL1 plays different roles in lung tumorigenesis in smokers and non-smokers, and different CX3CL1-based therapeutic strategies are needed depending on patient smoking status and tumor type. Furthermore, high level of CX3CL1 expression enhances nodal metastasis by activating JNK & MMP2/MMP9 activity in lung cancer cells.

Clinical significance of expression level of CX3CL1–CX3CR1 axis in bone metastasis of lung cancer

“…Studies have shown that the CX3CL1-CX3CR1 axis is up-regulated in breast cancer, colon cancer, gastric cancer, prostate cancer and other malignancies. Tumor cells expressing CX3CL1 can promote the invasion and metastasis of CX3CR1-positive tumor cells [17][18][19][20].…”

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

“…Another study by Su et al demonstrated that the CXC3CL1 level showed survival effects in lung adenocarcinoma but not in squamous cell carcinoma (81). The expression of CX3CL1 was found to be increased in lung cancer with higher pathological grades and metastatic lymph nodes (142).…”

Novel prognostic molecular markers in lung cancer (Review)

“…In the entire NSCLC cohort, no correlation between the expression of the protein and clinical course of the disease was observed. Such an unexpected result may be explained by different pathways of carcinogenesis in the smoking and non-smoking patients as well as in SCC and ADC patients (23). High mitotic activity is a known histopathological feature of malignant neoplasms.…”

“…A high level of expression of this protein causes activation of T CD8 + lymphocytes and NK cells within the tumor, which leads to a more effective elimination of the transformed cells (21). A more detailed study into the role of CX3CL1 in the lung tumors revealed that ADC patients with a smoking history and high expression of CX3CL1 had a shorter OS (HR=3.01) (23). Moreover, in the same study, a high CX3CL1 expression in the smoking AD patients happened half as often as in the SCC and ADC non-smoking patients.…”