The role of WNT5A in tumor and tumor surrounding tissue in primary and metastatic prostate cancer

Objectives Prostate cancer (PCa) is the third leading cause of cancer related death in European men. Ninety percent of the patients develop bone metastases. Improved therapies and prolonged life expectancy increase the incidence of skeletal related events (SREs), like instability, fractures and nerval or spinal cord compression. We previously showed that WNT5A plays an important role in primary and metastatic PCa. High WNT5A levels are associated with a better overall survival in patients and less bone metastases in mice. In vitro experiments show increased apoptosis and reduced proliferation of PCa cells highly expressing WNT5A. Tumor surrounding stromal cells also produce WNT5A (stWNT5A). Here, we determine the role of stWNT5A expression in primary PCa. Furthermore, interactions between WNT5A and stWNT5A in bone metastases of PCa patients were analyzed.

Methods A tissue microarray (TMA), consisting of 41 benign prostatic hyperplasia (BPH) controls and 400 PCa patients, who underwent radical prostatectomy between 1996 and 2005, was immunohistochemically analyzed for stWNT5A expression. The cores were scored for staining intensity and quantity of the stromal area.

Human samples of PCa bone metastases, obtained in surgical interventions of SREs and open or CT-guided biopsies were acquired between 2012 and 2019. All 33 samples were stained for tartrate-resistant acid phosphatase (TRAP) and immunohistochemically for WNT5A. Eleven cryopreserved samples were analyzed for WNT5A expression using realtime polymerase chain reaction.

Results and Conclusion Control samples of the TMA revealed a 1.1-1.2 fold higher stWNT5A expression compared to tumor cores (p < 0.001). In accordance to this, Gleason Score showed a negative correlation to stWNT5A (r2 = 0.02387, p < 0.01). However, overall survival was not correlated to stWNT5A. A positive correlation of stWNT5A to tumor WNT5A expression (r2 = 0.01793, p < 0.01) and negative to proliferation (r2 = 0.0382, p < 0.001) and apoptosis (r2 = 0.2771, p < 0.001) was found.

Human SREs intervention group included 25, biopsy group eight patients with bone metastases. Preliminary results indicate more trabecular space (p = 0.04) and a lower bone volume/total volume (p = 0.04) in the biopsies.

Conclusion

These preliminary data suggest that high expression of stroma derived WNT5A is an indicator of benign tissue and low risk primary PCa. Tumor- and stroma-derived Wnt signaling in primary PCa and it’s bone metastases may differently impact on tumor growth, metastatic behavior and SREs. Separate analysis of the WNT5A profile of tumor vs. surrounding tissue is needed.

Stichwörter bone metastases, cancer, WNT5A, Wnt, tumor microenvironment, prostate cancer

Publication History

Article published online:
15 October 2020