Prostate cancer cell extracellular vesicles increase mineralisation of bone osteoblast precursor cells in an in vitro model

Lanning, Ben, Webber, Jason ORCID: https://orcid.org/0000-0003-4772-3014, Uysal-Ongane, Pinar, Jiang, Wen Guo ORCID: https://orcid.org/0000-0002-3283-1111, Clayton, Aled ORCID: https://orcid.org/0000-0002-3087-9226 and Dart, Dafydd Alwyn 2021. Prostate cancer cell extracellular vesicles increase mineralisation of bone osteoblast precursor cells in an in vitro model. Biology 10 (4) , 318. 10.3390/biology10040318

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Abstract

Skeletal metastases are the most common form of secondary tumour associated with prostate cancer (PCa). The aberrant function of bone cells neighbouring these tumours leads to the devel-opment of osteoblastic lesions. Communication between PCa cells and bone cells in bone envi-ronments governs both the formation/development of the associated lesion, and growth of the secondary tumour. Using osteoblasts as a model system, we observed that PCa cells and their conditioned medium could stimulate and increase mineralisation and osteoblasts’ differentiation. Secreted factors within PCa-conditioned medium responsible for osteoblastic changes included small extracellular vesicles (sEVs), which were sufficient to drive osteoblastogenesis. Using MiR-seq, we profiled the miRNA content of PCa sEVs, showing that miR-16-5p was highly ex-pressed. MiR-16 was subsequently 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 of gene downregulation and an increased mineralisation. Ingenuity® Pathway Analysis (IPA®) revealed that 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 sEV miR-16-5p using luciferase UTR (untranslated region) reporters. Conversely, the overexpression of PLSCR4, ADRB2 and DLL1 lead to decreased osteoblastogene-sis. These results indicate that miR-16 is an inducer of osteoblastogenesis and is transmitted through prostate cancer-derived sEVs. The mechanism is a likely contributor towards the for-mation of osteoblastic lesions in metastatic PCa

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Additional Information:	This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).
Publisher:	MDPI
Funders:	The Cardiff University?Peking University Cancer Institute.
Date of First Compliant Deposit:	10 April 2021
Date of Acceptance:	7 April 2021
Last Modified:	16 Aug 2023 06:42
URI:	https://orca.cardiff.ac.uk/id/eprint/140424

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