Notch1-expressing Cells Are Indispensable for Prostatic Branching Morphogenesis during Development and Re-growth Following Castration and Androgen Replacement

Abstract

Notch expression is frequently associated with progenitor cells, and its function is crucial for development. Our recent work showing that Notch1 is selectively expressed in basal epithelial cells of the prostate and higher Notch1 expression during development suggests that Notch1-expressing cells may define progenitor cells in the prostate. To test this hypothesis, we have generated a transgenic mouse line in which the Notch1-expressing cells can be ablated in a controlled manner. Specific targeting was achieved by expressing the bacterial nitroreductase, an enzyme that catalyzes its substrate into a cytotoxin capable of inducing apoptosis, under the Notch1 promoter. Cell death in transgenic prostate was confirmed by histological analyses including terminal dUTP nick-end labeling and caspase 3 immunocytochemical staining. We evaluated the consequences of ablation of Notch1-expressing cells in two systems, organ culture of early postnatal prostates and re-growth of prostate in castrated mice triggered by hormone replacement. Our data show that elimination of Notch1-expressing cells inhibited the branching morphogenesis, growth, and differentiation of early postnatal prostate in culture and impaired prostate re-growth triggered by hormone replacement in castrated mice. Furthermore, we found that Notch1 expression following castration and hormone replacement was concomitant with known basal cell markers p63 and cytokeratin 14 and was high in the proliferative human prostate epithelial cells. Taken together, these data suggest that Notch1-expressing cells define the progenitor cells in the prostatic epithelial cell lineage, which are indispensable for prostatic development and re-growth.

Rbp‐j regulates expansion of pancreatic epithelial cells and their differentiation into exocrine cells during mouse development

“…A series of studies revealed that, apart from its well-documented involvement in cell fate decisions, Notch signaling could affect cellular proliferation (Deftos et al, 1998;Shelly et al, 1999;Satoh et al, 2004). During prostate develop- ment, Notch1-expressing cells defined the progenitor cells in the prostatic epithelial cell lineage, and ablation of Notch signaling in those cells inhibits the branching morphogenesis, growth, and differentiation (Wang et al, 2004). In the pancreas, disturbed branching morphogenesis also occurs in mice deficient in Fgf10 or its high-affinity receptor Fgfr2-IIIb (Bhushan et al, 2001;Pulkkinen et al, 2003).…”

Epithelial stem cells in human prostate growth and disease

“…57 Although there is no evidence for an involvement for Notch signalling in human prostate stem-cell regulation, a recent study showed that Notch1 is highly expressed in basal cells during prostate development. 58 Wang and colleagues also showed that Notch1 is downregulated in adult tissue but is upregulated in some cells during tumorigenesis of the TRAMP mouse model. 59 Notch1 was also required for branching morphogenesis during development as well as regeneration following androgen ablation.…”

Androgen Receptor Promotes the Oncogenic Function of Overexpressed Jagged1 in Prostate Cancer by Enhancing Cyclin B1 Expression via Akt Phosphorylation

“…Among these, the Notch signaling pathway, which is present in most multicellular organisms, plays a role in cancer metastasis by governing embryonic development, maintaining tumor stemness, modulating the epithelial-to-mesenchymal transition (EMT), and affecting tumor angiogenesis processes (12)(13)(14). Several studies have demonstrated that the Notch signaling pathway is required for prostatic growth and plays a key role in the progression and metastasis of prostate cancer (15)(16)(17). It had been proved that the expression of both Notch receptors and their ligands would be upregulated in many prostate cancer cells compared with normal prostate cells (18)(19)(20)(21).…”