WNT Signaling in Prostate Development and Carcinogenesis

Abstract

Background. The Wnt signaling pathway is crucial for cell fate decisions, stem cell renewal, regulation of cell proliferation and differentiation. Deregulated Wnt signaling is also implicated in a number of hereditary and degenerative diseases and cancer.Methods and results. This review highlights the role of the Wnt pathway in the regulation of stem/progenitor cell renewal and prostate gland development and how this signaling is altered in prostate cancer. Recent evidence suggests that Wnt signaling regulates androgen activity in prostate cancer cells, enhances androgen receptor expression and promotes the growth of prostate cancer even after androgen ablation therapy. There is also strong evidence that Wnt signaling is enhanced in androgen-ablation resistant tumors and bone metastases.Conclusions. Further study of the modulators of this pathway will be of therapeutic relevance as inhibition of Wnt signaling may have the potential to reduce the self-renewal and aggressive behaviour of prostate cancer while Wnt signaling activation might enhance stem cell activity when tissue regeneration is required.

Why are epididymal tumours so rare?

“…30 Rat epididymal b-catenin released from E-cadherin following castration accumulates in the cytoplasm, not the nucleus, and there is no subsequent hyperplasia. 29 A high expression of the non-canonical pathway Wnt4, which can inhibit the canonical Wnt pathway through competition for common components, 31 has been reported in the epididymis. 32 The regulation and role of Wnt pathways in epididymal tumourigenesis remain unexplored.…”

Regulation of Canonical Wnt Signaling During Development and Diseases

“…The canonical Wnt pathway has been implicated in prostate development (Kharaishvili et al, 2011). Wnt antagonist sFRP2 is highly expressed early in prostate development and downregulated at later time points.…”

“…Canonical Wnt pathway has been widely studied in prostate cancer (Kharaishvili et al, 2011). Wnt ligands are up-regulated in prostate cancer, and their expression often correlates with aggressiveness and metastasis.…”

Prostate Cancer Progression to Androgen Independent Disease: The Role of the Wnt/β-Catenin Pathway

“…Wnt ligands activate the Wnt pathway by binding to a seven-pass transmembrane frizzled (Fzd) receptor in conjunction with its co-receptors, LDL receptor related proteins 5 and 6 (LRP5/6). Other factors such as R-spondin, Norrin and Wise may also facilitate Fzd stimulation (Kharaishvili et al, 2011). Signaling by these powerful morphogens functions to direct cell proliferation, cell adhesion, tissue development, oncogenesis, tumor suppression, and cell-fate determination (MacDonald et al, 2009).…”

“…Certain non-canonical Wnts such as Wnt11 and Wnt5a have been shown to antagonize Wnt/ -catenin signaling, although the mode of action is still unclear (Railo et al, 2008). Proposed mechanisms include competitions for Dvl molecules and alternative degradation pathways involving Siah-APC instead of GSK3 --TrCP (Veeman et al, 2003;Topol et al, 2003;Kharaishvili et al, 2011).…”