CXCL13 blockade abrogates bone metastasis by impairing beta-3 integrin activation and matrix metalloproteinase expression by prostate cancer cells

Prostate cancer (PCa) is the second leading cause of cancer morbidity and mortality among men in the United States. Mortality is not due to primary tumor growth but rather from complications caused by metastasis to vital organs. It is well known that PCa cells preferentially metastasize to bone; however, the molecular, cellular, and anatomic bases of this spread remain obscure. Chemokines and their receptors are thought to play key roles in this multifactorial process. We have recently shown that CXCR5 expression positively correlates with prostate tumor staging, and that PCa cell lines (LNCaP, C4-2B, and PC3) differentially express CXCR5 unlike their normal counterparts (PrEC and RWPE-1). By virtue of its presence in the bone microenvironment during disease and/or tumor burden, we hypothesized that CXCL13 (the ligand for CXCR5) is critical for bone metastasis and prostate tumor progression. We demonstrate CXCL13 is present in bone marrow of xenograft tumor-bearing mice following intracardiac injection of PC3 cells. Luciferase-expressing PC3 cells established skeletal metastases, but CXCL13 blockade significantly delayed prostate tumor formation and spread to bones, than compared to mice treated with control antibody. Immunohistochemical staining of tumors and viscera excised from experimental versus control groups revealed differential matrix metalloproteinase and integrin expression as well as tumor cell phenotype, which were presumably modulated by CXCL13-CXCR5 interactions. In conclusion, the CXCL13-CXCR5 axis partially supports PCa bone metastasis.