Abstract
Proliferation and survival of prostate cancer cells are driven by the androgen receptor (AR) upon binding to androgen steroid hormones. Manipulating the AR signalling axis is the focus for prostate cancer therapy; thus, it is crucial to understand the role of androgens and AR on extracellular vesicle (EV) secretion and cargo. In this study, we report that plasma‐derived circulating vesicles consisting of CD9 and double‐positive for CD9 and Prostate Specific Membrane Antigen (PSMA) are increased in patients with advanced metastatic prostate cancer, whereas double positives for CD9 and CD63 small extracellular vesicles (S‐EVs) are significantly higher in patients with localised prostate cancer. Androgen manipulation by dihydrotestosterone (DHT) and the clinical antagonist enzalutamide (ENZ) altered the heterogeneity and size of CD9 positive S‐EVs in AR expressing prostate cancer cells, while assessment of the total number and protein cargo of total S‐EVs was unaltered across different treatment groups. Furthermore, hormone stimulation caused strong and specific effects on the small RNA cargo of S‐EVs. A total of 543 small RNAs were found to be regulated by androgens including miR‐19‐3p and miR‐361‐5p. Analysis of S‐EVs heterogeneity and small RNA cargo may provide clinical utility for prostate cancer and be informative to understand further the mechanism of resistance to androgen targeted therapy in castration‐resistant prostate cancer.
Highlights
Prostate cancer is the fourth most common cancer worldwide, with 1.3 million men diagnosed and 3600 deaths recorded in 2018 (Bray et al, 2018)
This study reports the heterogeneity of circulating S-extracellular vesicle (EV) in plasma from patients with benign prostate hyperplasia, localised prostate cancer and advanced metastatic prostate cancer, and those secreted by well-described prostate cancer cell lines under androgen manipulation
We found that treatment with DHT or ENZ did not significantly alter the amount and comprehensive profile of small RNAs and micro RNAs (miRNAs) isolated from parental cells or in small extracellular vesicles (S-EVs) (Figure 5c–e)
Summary
Prostate cancer is the fourth most common cancer worldwide, with 1.3 million men diagnosed and 3600 deaths recorded in 2018 (Bray et al, 2018). Most prostate cancers exhibit androgen-dependent growth, and as a result, androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer. ADT aims to inhibit tumour growth by preventing the activation of a nuclear transcription factor, the androgen receptor (AR). The vast majority of men respond initially to ADT, but tumour progression is inevitable and indicated by a rising prostate-specific antigen (PSA) level, new lesions, or progressive symptoms. This lethal phenotype is referred to as castration-resistant prostate cancer (CRPC) but remains driven by persistent AR signalling (Watson et al, 2010). Some factors have been reported to contribute towards the development of CRPC such as those mediated by AR amplification, expression of AR splice variants, AR mutations, extra-gonadal androgen synthesis, enhanced activity of AR co-regulators and upregulation of signalling cascades that further activate the AR pathway (Wyatt & Gleave, 2015)
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