THE URINARY MICROBIOME AND PROSTATE INFECTION IN PROSTATE CANCER DEVELOPMENT

Embargo until
2024-05-01
Date
2020-06-01
Journal Title
Journal ISSN
Volume Title
Publisher
Johns Hopkins University
Abstract
Inflammation is proposed as an initiating factor for prostate cancer. Although not extensively studied, bacterial infections likely serve as a common stimulus for prostatic inflammation. In this thesis, we explore the relationship between bacterial infections and associated inflammation in prostate carcinogenesis. Chapter 1 describes the most extensive study, to date, on the urinary microbiome associated with prostate cancer. We demonstrate that urine from men with prostate cancer is enriched with pro-inflammatory bacteria previously associated with urinary tract infections and other forms of cancer. However, the bacterial number or overall community structure were similar between urine samples from men with and without prostate cancer. In chapter 2, we describe the presence of bacteria focally in highly inflamed regions of prostate tissue selected for florid inflammation. We show the expression of the colibactin genotoxin in the infecting bacteria by probe-based qPCR and in situ hybridization. We developed a transient infection model and employed both comet assay and ɣH2AX western blot to show that colibactin induces DNA damage in prostate cells. Thus, genotoxic bacterial infection of the prostate induces DNA damage that may ultimately lead to oncogenic driver mutations. Bacterial infections and associated inflammation have been previously linked with indirect oncogenic DNA damage. Chapter 3 investigates the potential of inflammation to directly induce oncogenic gene fusions between TMPRSS2 and ERG in proliferative inflammatory atrophy (PIA) and low-grade prostatic intraepithelial neoplasia (LGPIN) lending support to their oncogenic precursor nature. Although ERG is expressed in prostate cancer glands that harbor TMPRSS2:ERG gene fusions (ERG+), ERG expression in suspected precursor lesions such as PIA was previously unknown. In our inflammation cohort, we show presence of a higher number of PIA and LGPIN foci with luminal epithelial cells expressing ERG (47%) compared to a general cohort not selected for high inflammation (<5%) (p<0.00001). The ERG+ PIA and LGPIN foci were further shown to have TMPRSS2:ERG gene fusions and/or ERG amplification. Overall, these studies strongly implicate bacterial infections in prostate cancer development. The direct (genotoxins) and indirect (inflammation) effects of bacterial infections can lead to early oncogenic changes in prostate epithelial cells that ultimately lead to carcinogenesis.
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Keywords
Bacterial infections, ERG
Citation