Periprostatic adipose tissue-derived extracellular vesicles modulate prostate cancer cell behaviour in vitro according to tumour grade

Periprostatic adipose tissue (PPAT) actively interacts with prostate cancer (PCa) cells, partly through the release of extracellular vesicles (EVs). While the cargo of PPAT-derived EVs has been suggested to influence PCa progression, their direct impact on tumour cell behaviour, and importantly, how these effects differ according to patients’ tumour grade, remains unexplored. This study examined whether EVs derived from PPAT of low-risk (ISUP I-II; Low-PPAT EVs) and high-risk (ISUP III-V; High-PPAT EVs) PCa patients differently modulate tumour cell behaviour, immune modulation, and angiogenesis. EVs were isolated from PPAT from low- and high-risk PCa patients and characterized by nanoparticle tracking analysis, electron microscopy and western blot. EVs (2.5 µg/mL) were tested on androgen-sensitive PCa cell lines (LNCaP, 22Rv1), and their functional effects were assessed on cell proliferation, migration, invasion and apoptosis. Activation of AKT and GSK-3β signalling pathways was also evaluated in PCa cells. Macrophage polarization markers were examined in PMA-differentiated THP-1 cells by measuring the expression of CD80, CD86, CD206, CD163, IL-1β, TNF-α, and MCP-1. Angiogenesis was evaluated through tube formation assays and gene expression analysis in HUVEC cells. These findings reveal, for the first time, that human PPAT-derived EVs exert risk-dependent effects on PCa progression, emphasizing their key role in PCa progression and emerging as new targetable factors.