Lung cancer is now the leading cause of cancer-related death and even for early stage patients, recurrence occurs in about 20% of them after surgery. Therefore, it is significant to find out the prognostic factors to guide individualized precise treatment to improve the survival outcomes. To our knowledge, this is the first study that analyzes the correlation with CXCR5 and prognosis.
Interactions between chemokines and their receptors have been reported to correlate to tumor dissemination, metastasis, tumor growth and cell survival.[35-37] Previous study showed that CXCR5 correlates with the stage/grade of NSCLC and promotes migration. There were also studies revealed the significance of other chemokine/chemokine receptor expression in NSCLCs, and demonstrated that CXCL12/CXCR4,[38-40] CXCL1/CXCR2, CCL2/CCR2,[42-45] CCL19/21/CCR7, CCL25/CCR9, CCL4/CCR5 and other atypical chemokine receptors[49, 50] were associate with tumor progression and prognosis.
CXCR5 was first isolated for Burkitt Lymphoma and named as Burkitt's lymphoma receptor 1 (BLR1), and it is highly expressed on mature recirculating B-lymphocytes, a subpopulation of follicular helper T cells (TFH) and skin-derived migratory dendritic cells (DCs), and controls their migration into secondary lymphoid organs towards the gradient of its ligand, CXCL13.[52-54] CXCL13/CXCR5 axis was involved in the progression of many hematological and solid malignancies like B-cell chronic lymphocytic leukemia, different types of lymphoma,[56-60] prostate cancer,[29, 33] breast cancer,[61-63] oral squamous cell carcinoma[64, 65] and etc. However, the role of CXCR5 in lung cancer is still unclear.
This study examined the level of CXCR5 expression in tissues using immunohistochemical methods, analyzed the correlation among CXCR5 expression, pathological subtypes, patients’ prognosis and other clinicopathological characteristics and investigated the prognostic factors in NSCLC patients. In this study, we demonstrated that CXCR5 expression is significantly higher in tumor tissues. Patients with positive CXCR5 expression are more likely to have LVIs and recurrences. We also found that patients with ACs had a significantly higher level of CXCR5 expression than those with SCCs (Patients with other types of NSCLC were not included in the calculation because of the small sample size) and the positive rate of CXCR5 expression in patients with moderate or poor differentiation was significantly higher than patients with well differentiation, which indicated that CXCR5 expression is correlated to histological type and differentiation of NSCLC. As for pathological subtypes, we found that CXCR5 expression, N stage, recurrence and survival all differed significantly among pathological subtypes. Further analyses showed that positive CXCR5 expression in LP tumors was significantly lower than the other four groups, which may be part of the reason for the pretty good survival outcomes. In addition, SP and MPP group were found to have a more advanced N stage, higher recurrence and worse survival, and these results are consistent with previous studies.[8, 9, 66]
Survival analyses showed that patients with positive CXCR5 expression had a significantly lower DFS while OS was similar, which supported our results that CXCR5 expression is related to cancer recurrence. These results indicate that CXCR5 may be involved in recurrence and metastasis of NSCLC but it may not impact survival. Survival analyses based on pathological subtypes demonstrated that DFS and OS both differed significantly among the groups and intergroup analyses showed that patients with SP and MPP had a significantly lower DFS and OS than those with LP AP and PP. In other words, LP AP and PP are the “good subtypes” while SP and MPP are the “bad subtypes” regarding survival outcomes.
Multivariate analyses showed that CXCR5 expression as well as N stage, tumor differentiation, and LVI are the independent prognostic factors for DFS. While N stage and LVI are the independent prognostic factors for OS.
Aberrantly activation of CXCL13/CXCR5 signaling has been proved to correlate with the development and progression of several human cancers. Wang et al show that benzo(a)pyrene (BaP), an important carcinogen, induces lung carcinogenesis. BaP interacts with aryl hydrocarbon receptor (AhR) and targets CXCL13, and then CXCL13/CXCR5 binding would induce the production of secreted phosphoprotein 1 (SPP1) by tumor-associated macrophages (TAMs). SPP1 may organize a positive feedback loop network via activation and nuclear localization of β-catenin in epithelial and cancer cells, thus promoting EMT and lung cancer progression. Divergent signaling cascades such as extracellular regulated protein kinases (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt, stress-activated protein kinase (SAPK)/c-jun kinase (JNK), and protein kinase C epsilon (PKCε)/nuclear factor-kappa B (NF-kB) were also proved to be involved in CXCL13/CXCR5 associated tumor progressions. Whether these signaling pathways are involved in the tumorigenesis and progression of lung cancer remains to be validated.
In following researches, we would validate the expression of CXCL13, ligand of CXCR5, in tumor and metastatic tissue and peripheral blood samples, investigate how CXCL13/CXCR5 impact cell function and the exact signaling pathway behind.