The Roles of Canonical Wnt2 and Wnt10b in Prostate Gland Development and Prostate Cancer Progression

Wnt signaling plays multiple diverse roles during embryonic organ development and in maintenance of adult tissue homeostasis. This study investigates the unique and specific developmental role(s) of Wnt2 and Wnt10b in prostate gland development as well as explores the role(s) for Wnt10b deregulation in PCa progression. Wnt2 studies using rat and murine models demonstrated that Wnt2 is expressed by prostatic mesenchyme and Wnt2 protein is localized to periductal stroma, extracellular matrix and epithelial cells. Wnt2 over-expression demonstrated a growth suppressive effect in newborn rat prostates. Selective overexpression of Wnt2 in embryonic urogenital mesenchymal cells revealed down-regulation of Fgf10. Subsequent culture of newborn rat prostates with overexpression of Wnt2 but addition of exogenous Fgf10 reversed Wnt2 growth suppression suggesting that Wnt2 growth inhibition is mediated, in part, by downregulation of Fgf10. Renal grafts of Wnt2-/- murine prostates indicated a role in maintaining lateral cell to cell connections, luminal cell polarity, and luminal cell differentiation. These findings demonstrated that Wnt2 is essential for normal prostate development where its dysregulation results in aberrant prostate gland development. Wnt10b studies utilizing rat models demonstrated rapid decline in expression during morphogenesis. Wnt10b protein localized to prostate epithelium confirming published reports of prostate epithelial Wnt10b transcripts. Ex vivo analyses of newborn rat prostates cultured in exogenous Wnt10b demonstrated growth suppressive effects. Relevance of this anti-proliferative role to PCa was demonstrated by significant decrease of Wnt10b mRNA and protein in the PB/Tag rat model of localized PCa. Human relevance was demonstrated by WNT10B protein screen showing downregulation of WNT10B in localized PCa specimens compared to benign tissue. Conversely, we demonstrated markedly increased WNT10B levels in advanced PCa cell lines suggesting a different role at this disease stage. Downregulation of WNT10B in PC3 cell lines effectively reversed EMT, reduced expression of MMP9, reduced expression of stemness genes, and significantly attenuated the stem-like side population of PC3 cells. Furthermore, serial tumor transplantation demonstrated that down-regulation of WNT10B blocks PC3 tumor propagation. Taken together, these studies establish a role for WNT10B in prostate gland development and PCa progression with WNT10B presented as a novel therapeutic target for advanced PCa.