Role of Wnt5a in Prostate Cancer

Sammanfattning: Wnt5a is a non-canonical secreted glycoprotein of the Wnt family that plays important roles in organ development and tissue orientation. Previous studies have reported that Wnt5a was upregulated at both mRNA and protein levels in prostate cancer, but information regarding its role in predicting clinical outcome in patients after radical prostatectomy is limited. The aim of the present thesis is to define the role of Wnt5a protein expression in prostate cancer. We started by evaluating Wnt5a protein expression by immunohistochemistry in a large, well-defined and population-based cohort and found Wnt5a protein expression to be upregulated in prostate cancer cells compared to benign epithelium. Interestingly, it predicted a favorable outcome for patients after radical prostatectomy as patients with preserved overexpression of Wnt5a protein in tumor cells had longer biochemical recurrence free time compared to patients with low Wnt5a protein expression. We demonstrated that this effect may be explained by the ability of Wnt5a to impair invasion in prostate cancer cells as recombinant Wnt5a treatment decreased invasion in 22Rv1 and DU145 cells while Wnt5a knockdown resulted in increase in invasion in LNCaP and 22Rv1 cells. In the light of conflicting reports on the role of Wnt5a in prostate cancer outcome, we validated our findings in an external population-based cohort. Again, we showed that Wnt5a protein expression was predictive of recurrence after radical prostatectomy in patients with low-grade prostate cancer and this was further enhanced whenWnt5a was combined with prostate cancer tissue biomarkers of known predictive value. We also demonstrated a positive correlation between Wnt5a and ERG protein expressions and that high Wnt5a protein and presence of ERG expression predicted a more favorable outcome. Despite this we observed that rWnt5a treatment of VCaP cells significantly decreased their ERG protein expression. Therefore, the relation between Wnt5a and ERG clearly need further exploration to better understand their functional interplay. In conclusion, our study indicates a tumor suppressor function of Wnt5a protein in localized PCa and that it can be used as a predictive tissue biomarker. Further, we suggest a novel therapeutic approach for patients with localized PCa targeting Wnt5a signaling to impair progression of PCa in these patients by using a Wnt5a mimicking peptide (Foxy5).