Communication of prostate cancer cells with bone cells via extracellular vesicle RNA; a potential mechanism of metastasis

Abstract

The role of extracellular vesicles (EVs) as vehicles for cell-to-cell communication between a tumour and its environment is a relatively new concept. The hypothesis that EVs may be critical in co-opting tissues by tumours to generate distant metastatic niches is particularly pertinent to prostate cancer (PCa), where metastatic-tropism to bone predominates over other tissue types. The potential role of EVs as a means of communication between PCa cells and cells of the bone stroma such as osteoblasts, is yet to be fully explored. In this study, we demonstrate that PCa cell EVs both enhance osteoblast viability and produce a significantly more supportive growth environment for PCa cells when grown in co-culture with EV-treated osteoblasts ( p < 0.005). Characterisation of the RNA cargo of EVs produced by the bone-metastatic PCa cell line PC3, highlights the EV-RNA cargo is significantly enriched in genes relating to cell surface signalling, cell–cell interaction, and protein translation ( p < 0.01). Using novel techniques to track RNA, we demonstrate the delivery of a set of PCa-RNAs to osteoblast via PCa-EVs and show the effect on osteoblast endogenous transcript abundance. Taken together, by using proof-of-concept studies we demonstrate for the first time the contribution of the RNA element of the PCa EV cargo, providing evidence to support PCa EV communication via RNA molecules as a potential novel route to mediate bone metastasis. We propose targeting PCa EVs could offer a potentially important preventative therapy for men at risk of metastatic PCa.

Bone Metastasis: Find Your Niche and Fit in

“…The increased secretion of growth factors by prostate tumor cells may promote recruitment, proliferation, and differentiation of osteoprogenitor cells, leading to osteoblastic metastasis [67]. Tumor-entrained pre-osteoblasts were shown to promote prostate cancer cells growth in a non-contact co-culture system [104]. For breast cancer, our work demonstrated that osteogenic cells form a growth supportive niche for ERα + breast cancer cells in early stage of bone metastasis [62,66].…”

Extracellular Vesicles in Bone Metastasis: Key Players in the Tumor Microenvironment and Promising Therapeutic Targets

“…By using techniques to track RNA, the authors also identified the delivery of a set of PCa-RNAs to osteoblast via EVs, which affected their endogenous transcript abundance. This group showed the contribution of the RNA component of EV cargo, providing evidence to support EV communication via RNA molecules as a potential strategy for mediating bone metastasis [ 67 ].…”

Exosomes in Prostate Cancer Diagnosis, Prognosis and Therapy

“…This study, as well as other studies, shows the biomarker potential of plasma-derived EV-RNA and the advantages with respect to the cost, ease of workflow and likelihood that all (heterogeneous) tumors are represented by a specific EV population. Communication between a tumor and its environment in PCa via extracellular vesicle (EV) RNAs is a potential mechanism of bone metastasis [63]. It has been shown that exosomal miR-375 significantly promoted osteoblast activity [64].…”