Abstract
BackgroundCarcinoma cells must circumvent the normally suppressive signals to disseminate. While often considered 'stop' signals for adherent cells, CXCR3-binding chemokines have recently been correlated positively with cancer progression though the molecular basis remains unclear.ResultsHere, we examined the expression and function of two CXCR3 variants in human prostate cancer biopsies and cell lines. Globally, both CXCR3 mRNA and protein were elevated in localized and metastatic human cancer biopsies compared to normal. Additionally, CXCR3A mRNA level was upregulated while CXCR3B mRNA was downregulated in these prostate cancer specimens. In contrast to normal prostate epithelial cells (RWPE-1), CXCR3A was up to half the receptor in the invasive and metastatic DU-145 and PC-3 prostate cancer cells, but not in the localized LNCaP cells. Instead of inhibiting cell migration as in RWPE-1 cells, the CXCR3 ligands CXCL4/PF4 and CXCL10/IP10 promoted cell motility and invasiveness in both DU-145 and PC-3 cells via PLCβ3 and μ-calpain activation. CXCR3-mediated diminution of cell motility in RWPE-1 cells is likely a result of cAMP upregulation and m-calpain inhibition via CXCR3B signal transduction. Interestingly, overexpression of CXCR3B in DU-145 cells decreased cell movement and invasion.ConclusionThese data suggest that the aberrant expression of CXCR3A and down-regulation of CXCR3B may switch a progression "stop" to a "go" signal to promote prostate tumor metastasis via stimulating cell migration and invasion.
Highlights
Prostate cancer is the most frequently diagnosed cancer and a leading cause of cancer death in men, with the mortality and morbidity being mainly due to tumor invasion and metastasis [1]
CXCR3 and its splice variant expression in human prostate carcinoma tissues To study CXCR3 expression in human prostate carcinomas, a human tissue microarray was generated with samples from the University of Pittsburgh Tumor Tissue Bank
CXCR3 was predominantly on the cell membrane in normal prostate tissue and primary carcinomas but this localization was replaced with a whole cell stain in metastatic prostate cancer tissue (Figure 1A, enlarged boxes)
Summary
Prostate cancer is the most frequently diagnosed cancer and a leading cause of cancer death in men, with the mortality and morbidity being mainly due to tumor invasion and metastasis [1]. Many studies have found that invasive prostate cancer cells have enhanced motility in response to paracrine,. A novel potential approach to limit tumor dissemination would be to re-instate the physiological ‘stop’ signals that keep normal and dysplastic epithelial cells localized. Work in this area has mainly focused on downregulation of cell-cell adhesion molecules such as E-cadherin during the acquisition of EMT or upregulation of matrix metalloproteinases [10,12,15,16]. While often considered ‘stop’ signals for adherent cells, CXCR3-binding chemokines have recently been correlated positively with cancer progression though the molecular basis remains unclear
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