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Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
Biology, Volume: 10, Issue: 4, Start page: 318
Swansea University Author: Jason Webber
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DOI (Published version): 10.3390/biology10040318
Skeletal metastases are the most common form of secondary tumour associated withprostate cancer (PCa). The aberrant function of bone cells neighbouring these tumours leads to thedevel-opment of osteoblastic lesions. Communication between PCa cells and bone cells in boneenvi-ronments governs both the...
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Skeletal metastases are the most common form of secondary tumour associated withprostate cancer (PCa). The aberrant function of bone cells neighbouring these tumours leads to thedevel-opment of osteoblastic lesions. Communication between PCa cells and bone cells in boneenvi-ronments governs both the formation/development of the associated lesion, and growth ofthe secondary tumour. Using osteoblasts as a model system, we observed that PCa cells and theirconditioned medium could stimulate and increase mineralisation and osteoblasts’ differentiation.Secreted factors within PCa-conditioned medium responsible for osteoblastic changes included smallextracellular vesicles (sEVs), which were sufficient to drive osteoblastogenesis. Using MiR-seq, weprofiled the miRNA content of PCa sEVs, showing that miR-16-5p was highly ex-pressed. MiR-16 wassubsequently higher in EV-treated 7F2 cells and a miR-16 mimic could also stimulate mineralisation.Next, using RNA-seq of extracellular vesicle (EV)-treated 7F2 cells, we observed a large degree ofgene downregulation and an increased mineralisation. Ingenuity®Pathway Analysis (IPA®) revealedthat miR-16-5p (and other miRs) was a likely upstream effec-tor. MiR-16-5p targets in 7F2 cells,possibly involved in osteoblastogenesis, were included for val-idation, namely AXIN2, PLSCR4,ADRB2 and DLL1. We then confirmed the targeting and dow-regulation of these genes by sEVmiR-16-5p using luciferase UTR (untranslated region) reporters. Conversely, the overexpression ofPLSCR4, ADRB2 and DLL1 lead to decreased osteoblastogene-sis. These results indicate that miR-16is an inducer of osteoblastogenesis and is transmitted through prostate cancer-derived sEVs. Themechanism is a likely contributor towards the for-mation of osteoblastic lesions in metastatic PCa.
Faculty of Medicine, Health and Life Sciences
The Cardiff University–Peking University Cancer Institute.