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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

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
Antineoplastic Agents, Hormonalpharmacology
Biomarkers, Tumordeficiencygenetics
Cell Lineage
Cell Proliferationdrug effects
Drug Resistance, Neoplasm
Gene Expression Profilingmethods
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Integrin alpha6metabolism
Mice, Inbred C57BL
Mice, Knockout
Neoplasm Recurrence, Local
Neoplastic Stem Cellsdrug effectsenzymologypathologytransplantation
Oligonucleotide Array Sequence Analysis
PTEN Phosphohydrolasedeficiencygenetics
Prostatic Neoplasms, Castration-Resistantdrug therapyenzymologygeneticspathology
Receptors, Androgendrug effectsmetabolism
Signal Transduction

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