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The role of prostate cancer small extracellular vesicles on the bone environment

Lanning, Ben 2019. The role of prostate cancer small extracellular vesicles on the bone environment. PhD Thesis, Cardiff University.
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Skeletal metastases are the most common form of secondary tumour associated with prostate cancer (PCa). Aberrant function of bone cells neighbouring these tumours leads to the development of osteolytic or osteoblastic lesions, with the latter being most commonly seen with PCa. Communication between PCa cells and bone cells at these secondary sites governs both the formation/development of the associated lesion, as well as growth of the secondary tumour. We isolated small extracellular vesicles (sEVs), known to facilitate intercellular communication, from PC3 cells and examined their effect on cells of the bone microenvironment. Using Next Generation Sequencing (NGS), we profiled the miRNA content of sEVs from PC3 cells, showing that miR-221-3p and miR-16-5p were highly expressed. We then showed these PC3 sEVs are able to stimulate increased differentiation of 7F2 osteoblast cells, with Ingenuity® Pathway Analysis (IPA®) revealing miR-16-5p as likely involved in this signalling. Using the NGS data, miR-16-5p targets in 7F2 cells, possibly facilitating the increased osteoblastogenesis, were selected; AXIN2, PLSCR4, ADRB2 and DLL1. We then confirmed the targeting of these genes by sEV miR-16-5p, and subsequently developed 7F2 cell lines overexpressing them. Overexpression of PLSCR4, ADRB2 and DLL1 lead to decreased osteoblastogenesis, whereas AXIN2 overexpression lead to increased osteoblastogenesis. We then examined the effect of PC3 sEVs on RAW 264.7 cells (osteoclast precursors), showing that the addition of PC3 sEVs decreased the osteoclastogenesis of RANKL treated RAW cells. These results indicate that PC3 sEVs induce osteoblastogenesis and inhibit osteoclastogenesis, mirroring, and potentially partially explaining the tendency of PCa secondary tumours to produce osteoblastic lesions.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 2 April 2019
Last Modified: 04 Aug 2022 01:42

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