Longitudinally Monitoring Prostate Cancer Bone Metastasis and Treatment Response via Circulating Extracellular Vesicles.

Lethal prostate cancer (PCa) is dominated by treatment-refractory progression in bone. In this study, we used plasma-derived extracellular vesicles (EVs) for monitoring the tumour and therapy-induced changes in the bone tumour microenvironment (bone-TME) in men with bone metastatic PCa (M1b PCa). Transcriptome analysis of differentially expressed genes in plasma EVs from patients with M1b and localized (M0) PCa, identified a 'bone metastasis signature' (BMS) that reflects tumour-induced bone formation. In preclinical studies, the BMS was enriched in plasma EVs from mice inoculated with bone-metastatic MDA PCa-118b but not with adrenal-metastatic MDA PCa-250 tumours. Longitudinal monitoring of the BMS for up to 50 days showed that the levels of several genes increased prior to detectable growth of bone-forming tumours. Real-time monitoring of the BMS from tumour-bearing mice treated with the bone-targeting agent Ra-223 showed reduction of their expression that correlated with reduction in bone formation and tumour growth. Development of resistance to Ra-223 correlated with the induction of the BMS genes. In a cohort of PCa patients with clinically localized PCa with pathologic lymph node involvement, increases in BMS genes following hormonal therapy correlated with the subsequent development of metastasis during long term follow up. The BMS may enable longitudinal monitoring of the initiation, progression and treatment response of M1b PCa.