CXCL13-CXCR5 Interaction and Prostate Cancer Cell Firm Adhesion and Bone Metastasis; Annual rept. 10 May 2006-9 May 2007

摘要

Metastasis is responsible for most prostate cancer (PCa) related deaths; therefore, therapies designed to prevent the spread of cancer cells and prognostic tests that better predict the outcome of patients are greatly needed. The reason(s) why prostate carcinomas (in some patients) preferentially metastasize to lymph nodes, bone, and brain is not fully understood. While our laboratory and others have shown a propensity of prostatic cancer cells to express CXCR4 and CCR9, we have recently found that PCa cell lines and prostate tissue differentially express CXCR5. The ligand for this receptor is CXCL13, which is expressed by stromal cells and an important chemokine that B cells use to navigate lymphatic endothelium. Here we show that, CCR9-CCL25 interactions mediate cell-signaling cascades involved in PCa progression. We report that CXCL13 stimulates CXCR5-dependent PI3K, ERK, FAK, Src and modest NF-kB activation for adhesion, invasion and survival. These studies on PCa cell involvement with lymphatic, vascular, and inflammatory host components will provide important and new information regarding the cellular and molecular mechanisms, following CXCL13-CXCR5 interaction, that modulate PCa bone-specific metastasis. Importantly, these studies will lead to new (CXCL13 or CXCR5) directed therapies and diagnostics to inhibit and monitor, respectively, PCa progress.