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Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model

Ben Lanning, Jason Webber Orcid Logo, Pinar Uysal-Onganer Orcid Logo, Wen Guo Jiang Orcid Logo, Aled Clayton, Dafydd Alwyn Dart Orcid Logo

Biology, Volume: 10, Issue: 4, Start page: 318

Swansea University Author: Jason Webber Orcid Logo

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DOI (Published version): 10.3390/biology10040318

Abstract

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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Published in: Biology
ISSN: 2079-7737
Published: MDPI AG 2021
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URI: https://cronfa.swan.ac.uk/Record/cronfa61404
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spelling v2 61404 2022-10-03 Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model 25d1a26f9b8bb556bd9412080e40351d 0000-0003-4772-3014 Jason Webber Jason Webber true false 2022-10-03 BMS 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. Journal Article Biology 10 4 318 MDPI AG 2079-7737 10 4 2021 2021-04-10 10.3390/biology10040318 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University Another institution paid the OA fee The Cardiff University–Peking University Cancer Institute. 2023-09-13T16:56:22.4687443 2022-10-03T14:32:26.2173823 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Ben Lanning 1 Jason Webber 0000-0003-4772-3014 2 Pinar Uysal-Onganer 0000-0003-3190-8831 3 Wen Guo Jiang 0000-0002-3283-1111 4 Aled Clayton 5 Dafydd Alwyn Dart 0000-0003-3801-8583 6 61404__25611__1048f75022d44102bb328f819feb8c5b.pdf 61404_VoR.pdf 2022-10-28T17:06:30.7011483 Output 2695069 application/pdf Version of Record true © 2021 by the authors.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license true eng https://creativecommons.org/licenses/by/4.0/
title Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
spellingShingle Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
Jason Webber
title_short Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
title_full Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
title_fullStr Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
title_full_unstemmed Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
title_sort Prostate Cancer Cell Extracellular Vesicles Increase Mineralisation of Bone Osteoblast Precursor Cells in an In Vitro Model
author_id_str_mv 25d1a26f9b8bb556bd9412080e40351d
author_id_fullname_str_mv 25d1a26f9b8bb556bd9412080e40351d_***_Jason Webber
author Jason Webber
author2 Ben Lanning
Jason Webber
Pinar Uysal-Onganer
Wen Guo Jiang
Aled Clayton
Dafydd Alwyn Dart
format Journal article
container_title Biology
container_volume 10
container_issue 4
container_start_page 318
publishDate 2021
institution Swansea University
issn 2079-7737
doi_str_mv 10.3390/biology10040318
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
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description 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.
published_date 2021-04-10T16:56:24Z
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