Delta-like 1 (Dlk-1), a Novel Marker of Prostate Basal and Candidate Epithelial Stem Cells, is Downregulated by Notch Signalling in Intermediate/transit Amplifying Cells of the Human Prostate

Background: There is a lack of understanding of the processes that regulate differentiation in the prostate.

Objective: To determine localisation, activity, and regulation of cytodifferentiation-modulatory proteins in the human adult prostate.

Design, Settings, And Participants: Eighteen volunteering patients with organ-confined prostate cancer were prospectively enrolled at a single university hospital.

Intervention: All patients underwent radical prostatectomy, and normal/benign tissue was excised and obtained from the transition zone.

Measurements: Expression and activity of Notch-protein family members, including the Notch-homologous protein Delta-like 1 (Dlk-1/Pref1), were investigated immunohistochemically in normal/benign tissue and explant cultures. The effect of the Notch inhibitor L-685,458 on Dlk-1 expression and cell number was investigated in primary cell cultures, and data were analysed with Student t test.

Results And Limitations: Mature luminal cells were found to co-express Notch-1 and its ligand Jagged1, but epithelia in normal/benign tissue showed no active Notch signalling. The basal cell layer, rare candidate epithelial stem cells, and a subpopulation of neuroendocrine cells expressed the differentiation protein Dlk-1. In explant cultures, luminal cells and Jagged1 expression were lost, whereas intermediate cells downregulated Dlk-1 concomitant with Notch-1 upregulation and activation. Notch inhibition in primary cell cultures led to lower cell densities (p<0.001) and suppressed downregulation of Dlk-1. This is a small study; current results need to be confirmed in larger investigations.

Conclusions: We demonstrate that Notch-1 is upregulated in differentiation of prostate epithelia, and that the novel prostate progenitor marker Dlk-1 is downregulated by Notch signalling in intermediate cells. The identification of Dlk-1-expressing candidate stem and neuroendocrine cells suggests a hierarchical relationship.