Extracellular Vesicles and Tunnelling Nanotubes as Mediators of Prostate Cancer Intercellular Communication.

Prostate cancer (PCa) pathogenesis relies on intercellular communication, which can involve tunnelling nanotubes (TNTs) and extracellular vesicles (EVs). TNTs and EVs have been reported to transfer critical cargo involved in cellular functions and signalling, prompting us to investigate the extent of organelle and protein transfer in PCa cells and the potential involvement of the androgen receptor. Using live cell imaging microscopy, we observed extensive formation of TNTs and EVs operating between PCa, non-malignant, and immune cells. PCa cells were capable of transferring lysosomes, mitochondria, lipids, and endoplasmic reticulum, as well as syndecan-1, sortilin, Glut1, and Glut4. In mechanistic studies, androgen-sensitive PCa cells exhibited changes in cell morphology when stimulated by R1881 treatment. Overexpression assays of a newly designed androgen receptor (AR) plasmid revealed its novel localization in PCa cellular vesicles, which were also transferred to neighbouring cells. Selected molecular machinery, thought to be involved in intercellular communication, was investigated by knockdown studies and Western blotting/immunofluorescence/scanning electron microscopy (SEM). PCa TNTs and EVs transported proteins and organelles, which may contain specialist signalling, programming, and energy requirements that support cancer growth and progression. This makes these important intercellular communication systems ideal potential targets for therapeutic intervention.