22 Luminal progenitor cells as a new target in castration-resistant prostate cancer (CRPC)

Abstract

IntroductionCastration-resistant prostate cancer (CRPC) is a lethal disease. Therefore the identification and understanding of castration-tolerant cell(s) is mandatory. While there is strong evidence for the existence of castration-tolerant cells within the basal layer of the prostate epithelium, most of human prostate cancers (hormone-naïve and CRPC) exhibit a luminal phenotype devoid of basal cell features. The nature of the putative castration-resistant luminal cell(s) is unknown.We recently identified in the mouse prostate a population of luminal progenitor cells that we called LSCmed (Lin−/Sca-1+/CD49fmed). This population is rare (5%) in healthy prostates but significantly enriched (30%) in premalignant prostates. The aim of this study was to investigate the relevance of LSCmed in prostate cancer.Material and methodsWe compared 6–8 month-old wild type (WT), probasin-prolactin (Pb-PRL) and Pb-Cre4/PTEN floxed (Pten-KO) mice exhibiting healthy, premalignant or malignant prostates, respectively. We used cell sorting (Lin, CD49f, Sca-1) to quantify or enrich the various prostate cell subpopulations from intact versus castrated mice. Transcriptomic profiling of prostate cell subpopulations was performed using GeneChip Mouse Transcriptome Arrays 1.0 (Affymetrix). Tumor-initiating properties of LSCmed cells was determined using the in vivo regeneration assay.Results and discussionsTranscriptomic profiling showed that LSCmed is a distinct cell entity that exhibits a specific gene expression signature, among which cytokeratin 4 (CK4) was validated as a specific marker to track them on tissue sections. Using CK4 immunohistochemistry and cell sorting we discovered that LSCmed represent the major cell component (80%) of aggressive prostate tumours harboured by Pten-KO mice. LSCmed are castration-tolerant in the three genotypes, which correlates their intrinsically low androgen signalling. According to their progenitor properties, Pten-KO LSCmed exhibit cancer-initiating properties in transplantation assays, and generate more aggressive tumours than basal cells used in control. Finally, in Pten-KO prostate tumours, several clusters of LSCmed continue to proliferate after castration.ConclusionLSCmed represent a newly-identified luminal prostatic cell subpopulation. The combination of progenitor, castration-resistance and tumor-initiating properties makes them strong candidates for mediating prostate cancer recurrence under androgen deprivation therapy (CRPC).