WNT5A/ROR1 signaling in stromal–epithelial cell communication enhances prostate cancer growth

Non-canonical WNT signaling pathways regulate prostate cancer progression; however, the precise mechanism remains elusive. We found high WNT5A expression in human prostate stromal cells, and suppression of WNT5A in prostate stroma-derived WPMY1 cells reduced expression of cancer-related genes and growth factors. WNT5A ligands induced proliferation and invasion of PC3 and LNCaP cells. WNT5A expression was directly regulated by the ligand-inducible androgen receptor. These results indicate that WNT5A secreted from stromal cells induced by the androgen receptor modulates the release of cytokines and enhances prostate cancer progression. Receptor tyrosine kinase-like orphan receptor 1 (ROR1), a WNT5A receptor, is strongly expressed in cancer cells in human prostates, and its expression level is significantly correlated to high-grade prostate cancer. We demonstrated that a ROR1 inhibitor dramatically suppressed cancer cell growth. These finding suggest that cell-to-cell communication between stromal cells and prostate cancer cells enhances cancer progression via the WNT5A/ROR1 signaling pathway, and ROR1 may be a novel therapeutic target for prostate cancer.