Abstract 5021: Histopathologic and gene expression analysis in mouse models of long-term chronic prostatic inflammation using human prostate cancer-derived bacterial isolates
Authors: Hubbard Gretchen K. , Yu Shu-Han , Shinohara Debika Biswal , Vaghasia Ajay , Nelson William G. , Yegnasubramanian Srinivasan , De Marzo Angelo M. , Sfanos Karen S. 
Published: August 2015

Prostate cancer is the second leading cause of cancer death in the U.S. and afflicts 1 in 6 men in their lifetime. Evidence suggests that inflammation contributes to cancer development by causing cellular and genome damage and contributing to a tumor microenvironment that promotes cellular replication and angiogenesis. In addition, infectious agents are known to be the driving force in many inflammation-associated cancers. For example, in adenocarcinomas of the distal stomach, long-term inflammation caused by Helicobacter pylori infection is frequently observed and implicated as a causative factor. Despite the independent observations of both inflammation and microorganisms in the prostates of cancer patients, to date, virtually no study has definitively demonstrated a causal role for microorganisms in the chronic inflammation observed in prostatectomy specimens. Furthermore, no study has localized these organisms to the inflammation-associated lesions that are the predicted precursor lesions to prostate cancer development. We hypothesize that pathogenic microorganisms play a role in the development of chronic inflammation in the prostate that in turn serves to initiate and/or promote prostate cancer development. In addition, we hypothesize that key molecular changes associated with disease progression are due to the presence of acute and/or chronic inflammation. We aim to study this hypothesis in novel animal models of long-term prostatic infection and inflammation using bacterial isolates from human prostate cancer tissues. To date, we have isolated over 30 strains of bacteria from human radical prostatectomy specimens, and 15 strains were chosen for infection studies in mice. This includes species of bacteria such as Corynebacterium, Neisseria, Propionibacterium, and Staphylococcus. Our results show that the induction of long-term chronic inflammation in the mouse prostate may be bacterial strain dependent. Furthermore, we have noted lesions consistent with prostatic remodeling in animals that have undergone bacteria-induced long-term prostatic inflammation. Finally, Illumina gene expression array analysis of dorsal prostate from mice inoculated with either PBS or P. acnes was used to identify genes differentially expressed in the presence of both acute and chronic inflammation. Early studies identify upregulated genes, including lactoferrin, that are known to be upregulated in both immune cells and in the epithelium in inflamed human prostate. Our ongoing studies evaluate gene expression changes associated with persistent inflammation present up to 6 months post-infection in these mouse models. The goal of these studies is to determine both short- and long-term gene expression profiles associated with bacteria-induced prostatic inflammation and to correlate molecular changes with phenotypic changes in the inflamed mouse prostate.

Citation Format: Gretchen K. Hubbard, Shu-Han Yu, Debika Biswal Shinohara, Ajay Vaghasia, William G. Nelson, Srinivasan Yegnasubramanian, Angelo M. De Marzo, Karen S. Sfanos. Histopathologic and gene expression analysis in mouse models of long-term chronic prostatic inflammation using human prostate cancer-derived bacterial isolates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5021. doi:10.1158/1538-7445.AM2015-5021