The Role of CXCR3 in Neurological Diseases

Zhou, Ya-Qun; Liu, Dai-Qiang; Chen, Shu-Ping; Sun, Jia; Zhou, Xue-Rong; Xing, Cui; Ye, Da-Wei; Tian, Yu-Ke

Gliomas account for the majority of neoplasms occurring in the CNS, and are one of the most aggressive types of human cancer [55, 56] . It was reported CXCR3 regulates cell invasion, migration and facilitates tumor metastasis to lymph nodes [57, 58] . Furthermore, the expression level of CXCR3 correlates with prognosis of breast cancer [59] , colorectal cancer [60, 61] and renal cell cancer [62] [63] [64] . Maru et al. [65] first reported that CXCR3 and CXCL10 were increased in glioma cells compared with adult human astrocytes. Moreover, they found that the expression level of CXCR3 correlated with malignancy grade of glioma. Glioblastoma multiforme (GBM) is the most aggressive form of human glioma with mean survival approximately 12 months despite intensive and comprehensive treatment [66] . Liu et al. [67] examined the role of CXCR3 in GBM progression using the GL261 murine model of malignant glioma. They found that Murine glioma GL261 cells express CXCL10 in vitro and GL261 tumors express CXCL9 and CXCL10 in vivo. CXCR3 _ / _ mice with glioma had significantly shorter median survival time and reduced numbers of tumor-infiltrated natural killer (NK) and natural killer T (NKT) cells in contrast with WT glioma mice. However, treatment with CXCR3 antagonist NBI-74330 suppressed GL261 tumor growth and increased median survival times of both tumor-bearing WT and CXCR3 _ / _ mice compared with vehicle-treated groups, suggesting that CXCR3 may have an inhibitory effect directly on the tumor cells. Moreover, NBI-74330 had no im-pact on tumor-infiltrated NK and NKT cells, which known to express CXCR3, suggesting that CXCR3 is not the primary means by which NK and NKT cells traffic into glioma. Thus, the absence of tumor-infiltrating NK and NKT cells rather than CXCR3 may account for the shorter survival time of tumor-bearing CXCR3 _ / _ mice. Moreover, both CXCR3 and its ligands are expressed by murine and human glioma cell lines (A172, T98G, U87, U118 and U138). These results suggested that CXCR3 system may be a unique target for human GBM therapy. Recently, Pu et al. [24] investigated the potential prognostic value of CXCR3 in primary GBM and its relationship with the clinicopathological features. Using Kaplan-Meier survival curve analysis with a log-rank comparison of the 65 primary GBM patients, they found that the patients with higher expression levels of CXCR3 had shorter progression free survival and overall survival compared with those with lower expression levels of CXCR3. Using univariate Cox regression analysis, they found that high CXCR3 expression was a risk factor for primary GBM [P < 0.01, hazard ratio (HR) 2.336, 95 % confidence interval (CI) 1.341-4.071]. Furthermore, their multivariate Cox regression analysis showed that CXCR3 expression level was an independent prognostic factor for the overall survival of primary GBM patients. Taken together, these results suggested that CXCR3 might be a useful independent prognostic biomarker for primary GBM patients.