Regulation of Epithelial Branching Morphogenesis and Cancer Cell Growth of the Prostate by Wnt Signaling

Abstract

Although Wnt signaling has been shown to be important for embryonic morphogenesis and cancer pathogenesis of several tissues, its role in prostatic development and tumorigenesis is not well understood. Here we show that Wnt signaling regulated prostatic epithelial branching morphogenesis and luminal epithelial cell differentiation in developing rat prostate organ cultures. Specifically, Wnt signaling regulated the proliferation of prostate epithelial progenitor cells. Assessment of the expression levels of a Wnt pathway transcriptional target gene, Axin2, showed that the Wnt pathway was activated in the developing prostate, but was down-regulated in the adult. Castration resulted in an upregulation of Axin2 whereas androgen replacement resulted in a down regulation of Axin2. Such dynamic changes of Wnt activity was also confirmed in a BAT-gal transgenic mouse line in which β-galactosidase reporter is expressed under the control of β-catenin/T cell factor responsive elements. Furthermore, we evaluated the role of Wnt signaling in prostate tumorigenesis. Axin2 expression was found upregulated in the majority of human prostate cancer cell lines examined. Moreover, addition of a Wnt pathway inhibitor, Dickkopf 1 (DKK1), into the culture medium significantly inhibited prostate cancer cell growth and migration. These findings suggest that Wnt signaling regulates prostatic epithelial ductal branching morphogenesis by influencing cell proliferation, and highlights a role for Wnt pathway activation in prostatic cancer progression.

Androgen-mediated improvement of body composition and muscle function involves a novel early transcriptional program including IGF1, mechano growth factor, and induction of β-catenin

“…This phenomenon has been reported in the testosterone-treated ORX mouse prostate (Wang et al 2008). Axin mRNA and protein were repressed through 7 days (Fig.…”

Secreted frizzled related proteins: Implications in cancers

“…AXIN, which is transcriptionally activated through Wnt signalling [40], directs β-catenin for degradation through ubiquitin-dependent proteolysis and was previously reported to be upregulated in prostate cancer cell lines [41].…”

Prostate-specific Klf6 Inactivation Impairs Anterior Prostate Branching Morphogenesis through Increased Activation of the Shh Pathway

“…Tissues were then sectioned and stained with H&E. Tissues for immunofluorescent staining were fixed in 4% paraformaldehyde/phosphate-buffered saline prior to Declere antigen retrieval (Cell Marque) using a pressure cooker for 10 min and then blocked in 10% donkey serum/ phosphate-buffered saline. Primary antibodies used include rabbit anti-Klf6 (Santa Cruz Biotechnology, Santa Cruz, CA), rabbit anti-Ki67 (LabVision), rabbit anti-␤-galactosidase (1:10,000, MP Biomedical, without antigen retrieval) (19), rabbit anti-androgen receptor (Upstate), rabbit anti-smooth muscle actin (LabVision), rabbit anti-desmin (EuroDiagnostica), rabbit anti-ck14 (Covance), mouse anti-ck8 (Novus), rabbit anti-phospho-Smad1/5/8 (1:500, Cell Signaling), and mouse anti-E-cadherin (BD Pharmingen). Secondary antibodies used to detect respective primary antibodies were anti-rabbit Alexa 488 (Invitrogen) and anti-mouse Alexa 594 (Invitrogen).…”

“…In addition, the number of main ducts and complexity of ductal branching vary among the three lobes. A number of growth factors/pathways have been implicated in regulating prostatic epithelial proliferation and differentiation, including hedgehog (Hh), 4 bone morphogenic proteins (BMPs), fibroblastic growth factors (FGFs), and Notch and Wnt pathways (12)(13)(14)(15)(16)(17)(18)(19). For example, work done in our laboratory and others showed that sonic hedgehog (Shh) produced in the prostatic epithelium is a negative regulator of prostatic branching morphogenesis, mediated indirectly by periepithelial mesenchymal cells (12)(13)(14)(15).…”