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.

Keywords: Androgen receptor; Wnt5a; biochemical recurrence; prostate cancer; tissue microarray.

Figure 1

Wnt5a immunostaining in prostate cancer. (A) and (B) illustrate representative examples of weak Wnt5a protein expression, whereas (C) and (D) show strong Wnt5a protein expression in tissue microarray cores of primary prostate tumors obtained after radical prostatectomy. All inserts in the panels represent higher magnifications of selected areas (arrows) (bars 100 μm). (E) and (F) are histograms showing Wnt5a staining average intensity score (scale 0–3) and fraction of Wnt5a-positive cells (scale 10–100), respectively. In (G), distribution Wnt5a expression is illustrated as low or high multiplication score (average intensity score × fraction of Wnt5a-positive cells) from 0 to 300 with a cut-off at 195 as identified by classification and regression tree analysis.

Figure 2

Associations between Wnt5a protein expression and/or surgical margin status (SMS; positive or negative) and BCR-free time after radical prostatectomy in PCa patients. (A) Kaplan–Meier curves plotted for high (↑) and low (↓) Wnt5a protein expression (for definition, see Results) and BCR-free time in low-grade cancers only (Gleason score ≤3+4). (B) Kaplan–Meier curves plotted between high- or low-Wnt5a protein expression and BCR-free time in the whole patient material (low-grade and high-grade cancers). (C) Kaplan–Meier curves showing the effect of Wnt5a protein expression and SMS on BCR in low-grade cancers. The curves were plotted after combining Wnt5a protein expression and SMS. (D) Kaplan–Meier curves demonstrating the association between SMS and BCR-free survival in all patients. P-values <0.05 indicate statistically significant differences in outcome between the most and least favorable group.