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.


METHODS
Eighteen volunteering patients with organ-confined prostate cancer were prospectively enrolled at a single university hospital.


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


METHODS
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.


CONCLUSIONS
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.
Ceder
Jens A
JA
Lund University, Department of Clinical Sciences, Division of Urological Research, University Hospital MAS, Malmö, Sweden. Jens.Ceder@med.lu.se
Jansson
Linda
L
Helczynski
Leszek
L
Abrahamsson
Per-Anders
PA
D002135:Calcium-Binding Proteins; D015536:Down-Regulation; D004847:Epithelial Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D011446:Prospective Studies; D011467:Prostate / Q000166:cytology*; D015398:Signal Transduction; D013234:Stem Cells
D002135:Calcium-Binding Proteins; C512941:DLK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins