The role of the CXCL12 – CXCR4 chemokine ligand – receptor
interaction in the metastasis of prostate cancer.
Doctoral thesis, UCL (University College London).
The aim was to investigate whether chemokine ligand – receptor interactions are involved in the chemotaxis of prostate cancer to favoured metastatic sites. Initially, chemokine receptor mRNA expression, CXCR and CCR groups, was determined using conventional RT-PCR in cell lines derived from prostate cancer metastases, DU145, LNCaP and PC3, the primary prostate cancer cell line 1542 CPT3X and the normal prostate epithelial/ stromal cell lines 1542 NPTX, Pre 2.8 and S2.13. It was observed that in the cell lines derived from prostate cancer metastases, CXCR4 mRNA expression was relatively high. Using real-time quantitative PCR it was subsequently established that in DU145, LNCaP and PC3 cells, CXCR4 mRNA expression was 1287, 407 and 21 times respectively that of 1542 CPT3X. 1542 NPTX and 1542 CPT3X had similar levels of CXCR4 mRNA (the former had only twice that of the latter) and Pre 2.8 had no detectable CXCR4 mRNA expression. In laser microdissected patient primary tumour samples and patient benign tissue specimens CXCR4 mRNA expression was higher than that of the metastatic cell lines. Flow cytometry analysis showed that significantly higher levels of the CXCR4 protein were present on the cell membrane of the three metastatic cell lines. Cell migration assays revealed that chemotaxis of the metastatic cell lines PC3 and DU145 was enhanced by CXCL12 ligand and inhibited anti-CXCR4 antibody. We have demonstrated that human prostate cell lines derived from metastases express functional CXCR4 receptor and that CXCL12 ligand enhances their migratory capabilities. Also, primary patient tumours and patient benign tissue specimens express CXCR4 mRNA at high levels (it is suggested that in vivo post-transcriptional modification and/ or regulation of CXCR4 receptor at the protein stage may significantly affect cellular protein levels). These results suggest that the CXCL12-CXCR4 axis may be involved in the metastasis of prostate cancer to preferred organs.
|Title:||The role of the CXCL12 – CXCR4 chemokine ligand – receptor interaction in the metastasis of prostate cancer|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Surgery and Interventional Science (Division of) > Research Department of Urology|
Archive Staff Only