Towards a personalised medicine strategy to reduce prostate cancer risk in men

Abstract

Prostate cancer is the second most common cancer in men. Studies now indicate a strong association of the disease with chronic bacterial infection, which may ultimately induce oncogenesis. It has been shown that P. acnes is the predominant organism isolated from prostatectomy samples and is significantly associated with organ inflammation. Further evidence suggests that P. acnes is able to chronically infect the prostate gland and in vitro experiments clearly indicate its potential to drive oncogenic changes. This thesis investigates the oncogenic potential of specific prostate-derived P. acnes phylogenetic types, with the ultimate aim of developing risk stratification approaches for the development of the disease. In vitro infection models were used to compare the effects of different phylogenetic types of P. acnes on prostate epithelial cells. Soft agar assays and quantitative PCR (qPCR) were used to investigate the molecular expression profiles associated with endothelial-mesenchymal transition (EMT) and inflammation during bacterial infection. Cells infected with phylotype IA1 were able to form colonies in soft agar assays, indicating cellular transformation. Additionally, qPCR results showed a decrease in the expression of the EMT marker E-cadherin. These findings were supported by immunostaining experiments. Furthermore, qPCR expression analysis revealed that phylotype IA1 infection induces changes suggestive of apoptosis resistance, increased proliferation and androgen-independent growth, all characteristics of advanced treatment-resistant cancer. In contrast, cells infected with type III strain exhibited expression changes consistent with anti-cancer behaviour, including increased apoptosis and androgen-dependent signalling. These findings highlight the strain-specific response to infection and suggest the attractive possibility that infection with P. acnes may be a modifiable risk factor for prostate cancer. Since some phylotypes of P. acnes may be oncogenic, while others are cancer-protective, the development of a screening test to identify the presence of infection may therefore prove valuable to stratify patients at risk of oncogenesis.

Date of Award	May 2018
Original language	English
Sponsors	DEL & Invest NI
Supervisor	Andrew McDowell (Supervisor) & David Gibson (Supervisor)