Role of soluble IL-6 receptor in prostate cancer recurrence

Prostate cancer (PC) is the second cause of tumor-related deaths in the Western world. When the disease recurres, due to the spread of metastases, survival of patients is limited to only 1-2 years. The inflammatory cytokine interleukin-6 (IL-6) has a pathogenic role in the progression of this malignancy, therefore representing an attractive target for new therapies. However, in vitro and clinical data show that targeting IL-6 may result in different and unpredictable responses. In order to clarify the mechanisms underlying the different responses to IL-6, we focused our attention on the involvement of the different IL-6 receptors that represent the first element in the cascade of cytokine-activated signallings. Interleukin-6 signal transduction may indeed occur through the membrane IL-6 receptor (classical signalling) and/or through the less studied soluble IL-6 receptor (interleukin-6 trans-signalling, IL-6TS). It has been recently demonstrated that, in PC patients that undergo radical prostatectomy, higher preoperative soluble IL-6 receptor blood levels correlate with higher chances to develop metastases in the following years. Soluble cytokine receptors are usually thought to be agonists or antagonists of the cytokine they bind to, without having the capacity to direct the activation of specific targets. PRELIMINARY DATA: We recently provided the first evidence that IL-6TS specifically accounts for an antiproliferative effect of the cytokine in PC cell lines that are known to respond differently to IL-6 in terms of proliferation. Additionally, we showed that IL-6, through its soluble receptor, increases motility and migration and decreases adhesion of PC cells facilitating thereby those processes that determine metastasis formation. AIM: With this project we would like to get more insight into the specific roles of the soluble IL-6 receptor in PC progression. We will specially focus on changes in adhesion, epithelial phenotype, invasion, and migration of PC cells into the stroma and to the bone, which represents one of the most frequent sites of metastasis formation in PC patients. Due to the complexity of the mechanism of action and to the unpredictability of IL-6 effects, we consider these in vitro investigations absolutely needful before planning preclinical studies. We intend also to analyze the consequences of increased soluble IL-6 receptor levels on the response of PC cells to the currently available anti- cancer drugs. EXPECTATIONS: We expect to understand whether blocking IL-6 by selectively targeting its soluble IL-6 receptor may be successful in retarding or even blocking some of those mechanisms that promote formation of metastases and therefore the recurrence of the disease. This could be of benefit also for those patients that suffer from different malignancies or inflammatory chronic diseases.