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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.

Ceder, Jens LU ; Jansson, Linda LU ; Helczynski, Leszek LU and Abrahamsson, Per-Anders LU (2008) In European Urology 54. p.1344-1353
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
European Urology
volume
54
pages
1344 - 1353
publisher
Elsevier
external identifiers
  • wos:000261677600018
  • pmid:18375047
  • scopus:55449114581
ISSN
1873-7560
DOI
10.1016/j.eururo.2008.03.006
language
English
LU publication?
yes
id
386a2f1c-a4ed-4fb6-b812-39b69438d4ca (old id 1147960)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/18375047?dopt=Abstract
date added to LUP
2008-05-08 11:19:59
date last changed
2017-09-03 04:52:42
@article{386a2f1c-a4ed-4fb6-b812-39b69438d4ca,
  abstract     = {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&lt;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.},
  author       = {Ceder, Jens and Jansson, Linda and Helczynski, Leszek and Abrahamsson, Per-Anders},
  issn         = {1873-7560},
  language     = {eng},
  pages        = {1344--1353},
  publisher    = {Elsevier},
  series       = {European Urology},
  title        = {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.},
  url          = {http://dx.doi.org/10.1016/j.eururo.2008.03.006},
  volume       = {54},
  year         = {2008},
}