Emphasizing the role of Wnt5a protein expression to predict favorable outcome after radical prostatectomy in patients with low‐grade prostate cancer

Abstract

Wnt5a, a member of non-canonical wingless-related MMTV integration site family is a secreted glycoprotein that plays important roles in development and disease. Recent studies have shown that Wnt5a protein levels are up-regulated in prostate cancer, but contrasting reports exist on the role of Wnt5a to predict outcome after radical prostatectomy in patients with localized prostate cancer. Our group has recently shown that preserved high protein expression of Wnt5a in prostate cancer is associated with longer relapse-free time after radical prostatectomy. The present tissue microarray study emphasizes the role of Wnt5a protein expression in a different, well-defined, and independent cohort consisting of 312 prostate cancer patients. Kaplan–Meier curves plotted between Wnt5a expression and time to biochemical recurrence revealed that in low-grade prostate cancer, patients with preserved high-Wnt5a protein levels in their tumor cells have a lower risk of recurrence after radical prostatectomy compared to patients with low-Wnt5a protein expression. When Wnt5a protein expression was added to a Cox regression multivariate analysis, both Wnt5a protein expression and surgical margin status independently predict biochemical free survival. Herein we confirm Wnt5a positivity as a prognostic factor and show that preserved overexpression of Wnt5a protein is associated with increased time to biochemical recurrence in localized low-grade prostate cancer patients after radical prostatectomy. Our results emphasize that Wnt5a can be used as a predictive biomarker, and favoring the view of Wnt5a as a future therapeutic target in prostate cancer patients with tumor cells displaying low expression of Wnt5a.

WNT5A Has Anti-Prostate Cancer Effects In Vitro and Reduces Tumor Growth in the Skeleton In Vivo

“…Using two well‐defined cohorts of patients with prostate cancer, we showed that the expression of WNT5A is increased in prostate cancer tissue compared with nonmalignant prostate tissue. This finding is in line with several other studies, confirming high levels of WNT5A in prostate cancer tissue . Additionally, WNT5A expression was highly correlated with the expression of its cognate receptor FZD5, suggesting that FZD5 could mediate, or even amplify, WNT5A‐induced effects in prostate cancer.…”

“…Our study further indicates that patients with high tumor expression of WNT5A have a longer overall survival and suggests a tumor‐suppressive function of WNT5A in prostate cancer. This result is supported by the work of a Swedish group performed in two different cohorts ( n = 263 and n = 503), which showed that patients with high WNT5A expression in the tumor have a longer biochemical relapse‐free survival after radical prostatectomy . Even though our TMA has an overrepresentation of high‐grade tumors (>60% with Gleason score >7) compared with the Swedish studies, which have included more patients with low‐grade tumors (>75% with Gleason score 3 + 4 in both studies), our study has reached a similar conclusion.…”

“…In the prostate, WNT5A is essential for normal prostate gland development, and several studies have identified a role for WNT5A in prostate cancer . However, although some studies indicated that WNT5A promotes the aggressiveness of prostate cancer, others have identified patients with higher WNT5A protein expression to show a better outcome after radical prostatectomy . Thus, the discrepancy about its role in prostate cancer biology has not been completely clarified, and direct evidence is lacking to pinpoint the role of WNT5A in prostate cancer formation and the development of subsequent metastases.…”

Treatment with the WNT5A-mimicking peptide Foxy-5 effectively reduces the metastatic spread of WNT5A-low prostate cancer cells in an orthotopic mouse model

“…It has previously been shown that preserved expression of WNT5A in the primary tumor is associated with increased time to biochemical recurrence in patients with low-grade prostate cancer [ 26 ]. Moreover, patients with high endogenous WNT5A levels show a longer survival time and an overall better outcome compared to patients with low WNT5A levels [ 25 ].…”

WNT signalling in prostate cancer

“…However, some reports contradict the protumorigenic effect of WNT-5A, correlating high WNT-5A expression with improved outcomes in localized, lowgrade prostate cancer [94][95][96] . In other cancers such as liver, breast and lung, the WNT-5A-FZD2 complex has been reported to associate with the protein tyrosine kinase FYN and signal transducer and activator of transcription 3 (STAT3) to promote the epithelial-mesenchymal transition (EMT) and cell migration 97 .…”