Extracellular vesicle communication between peri-prostatic adipose tissue and epithelial cells in lean and obese men with prostate cancer undergoing robotic radical prostatectomy
File(s)
Author(s)
Tam, Joseph Owen
Type
Thesis
Abstract
Prostate cancer (PC) and obesity affect 1 in 6 and 1 in 3 men in the UK respectively. High Body Mass Index (BMI) is associated with biochemical recurrence in localized PC and increased aggression in advanced PC. Imaging studies have shown that peri-prostatic adipose tissue (PPAT) volume is associated with aggressive PC. PPAT secrete proinflammatory factors, and metalloproteinases which prime the microenvironment, while lipolysis and fatty acid release drives PC progression. Extracellular vesicles (EV) from PC were found to transport key RNA, DNA and proteins which create a favourable microenvironment for tumour growth and metastasis. However, no studies have investigated the impact of EV mediated RNA transfer from PPAT to PC.
In this study, EVs were isolated from PPAT explants from patients with localised PC undergoing radical prostatectomy. EVs were characterized according to Minimal Information for Studies of Extracellular Vesicles (MISEV) 2018 guidelines, and small RNA sequencing performed. PPAT EVs were used to treat PC cell lines and functional assays performed. The differential gene expression of EV treated PC cells was sequenced. All the results were compared between lean (BMI < 25) and obese (BMI ≥ 30) patients.
Obesity is found to be associated with increased operative time and post-operative complications. Under transmission electron microscopy, two groups of EVs are found to be secreted, roughly 20-50nm and >200nm, although this does not seem to be related to BMI. Functional assays show no significant difference between PC cells treated with obese vs lean EVs. Small RNA sequencing has identified differentially expressed microRNAs between lean vs obese EVs. GO analysis was significant for pathways relating to localisation within membrane, actin binding and cytoskeleton, as well as neurogenesis and axon development, while KEGG pathway analysis showed no significant pathways. Further work is ongoing to validate and investigate the effect of EVs transferred factors.
In this study, EVs were isolated from PPAT explants from patients with localised PC undergoing radical prostatectomy. EVs were characterized according to Minimal Information for Studies of Extracellular Vesicles (MISEV) 2018 guidelines, and small RNA sequencing performed. PPAT EVs were used to treat PC cell lines and functional assays performed. The differential gene expression of EV treated PC cells was sequenced. All the results were compared between lean (BMI < 25) and obese (BMI ≥ 30) patients.
Obesity is found to be associated with increased operative time and post-operative complications. Under transmission electron microscopy, two groups of EVs are found to be secreted, roughly 20-50nm and >200nm, although this does not seem to be related to BMI. Functional assays show no significant difference between PC cells treated with obese vs lean EVs. Small RNA sequencing has identified differentially expressed microRNAs between lean vs obese EVs. GO analysis was significant for pathways relating to localisation within membrane, actin binding and cytoskeleton, as well as neurogenesis and axon development, while KEGG pathway analysis showed no significant pathways. Further work is ongoing to validate and investigate the effect of EVs transferred factors.
Version
Open Access
Date Issued
2023-06-16
Date Awarded
2024-04-01
Copyright Statement
Creative Commons Attribution NonCommercial NoDerivatives Licence
Advisor
Bevan, Charlotte
Fletcher, Claire
Ahmed, Hashim
Sponsor
National Institute for Health Research (Great Britain)
Imperial College London
Prostate Cancer Research
Grant Number
WSCC_P75482
Publisher Department
Department of Surgery & Cancer
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)