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Type of publication: Journal Article
Type of document: Full Paper

Year: 2017

Authors: Sackmann Sala, L; Boutillon, F; Menara, G; De Goyon-Pélard, A; Leprévost, M; Codzamanian, J; Lister, N; Pencik, J; Clark, A; Cagnard, N; Bole-Feysot, C; Moriggl, R; Risbridger, GP; Taylor, RA; Kenner, L; Guidotti, JE; Goffin, V

Title: A rare castration-resistant progenitor cell population is highly enriched in Pten-null prostate tumours.

Source: J Pathol. 2017; 243(1):51-64



Authors Vetmeduni Vienna:

Kenner Lukas
Moriggl Richard

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals
Institute of Animal Breeding and Genetics, Unit for Functional Cancer Genomics


Abstract:
Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen deprivation remain poorly described, despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild-type (WT) mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin- /Sca-1+ /CD49fmed ). Here, we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumourigenesis (Pb-PRL, Ptenpc-/- , and Hi-Myc mice). LSCmed prevalence is low (∼8%, similar to WT) in Hi-Myc mice, where prostatic androgen receptor signalling is unaltered, but is significantly higher in the two other models, where androgen receptor signalling is decreased, rising up to more than 80% in Ptenpc-/- prostates. LSCmed tolerate androgen deprivation and persist or are enriched 2-3 weeks after castration. The tumour-initiating properties of LSCmed from Ptenpc-/- mice were demonstrated by regeneration of tumours in vivo. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signalling is markedly decreased, explaining why LSCmed tolerate androgen deprivation. This also illuminates why Ptenpc-/- tumours are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, there was significant proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. Taken together, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Keywords Pubmed: Androgen Antagonistspharmacology
Animals
Antineoplastic Agents, Hormonalpharmacology
Ataxin-1metabolism
Biomarkers, Tumordeficiencygenetics
Cell Lineage
Cell Proliferationdrug effects
Drug Resistance, Neoplasm
Gene Expression Profilingmethods
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Integrin alpha6metabolism
Keratin-4metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Recurrence, Local
Neoplastic Stem Cellsdrug effectsenzymologypathologytransplantation
Oligonucleotide Array Sequence Analysis
PTEN Phosphohydrolasedeficiencygenetics
Phenotype
Prostatic Neoplasms, Castration-Resistantdrug therapyenzymologygeneticspathology
Receptors, Androgendrug effectsmetabolism
Signal Transduction

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