Dissecting the relationship between inflammation and the development of preneoplastic lesions in a mouse model of Interleukin-1?-mediated prostatic inflammation

Abstract

Prostate cancer is the second most common cancer in the USA and the fourth most common worldwide. Understanding the molecular mechanisms underlying the onset of this disease could lead to the development of earlier detection methods and effective treatments. Two histologically defined lesions that are precursors to human prostate cancer have been identified. Prostatic Intraepithelial Neoplasia (PIN) manifests as an abnormal accumulation of epithelial cells, often with nuclear atypia and enlarged nucleoli, within preexisting benign prostatic acini or ducts. Proliferative Inflammatory Atrophy (PIA) is described as an inflamed prostate gland with atrophic cells and a high percentage of mitotic epithelial cells. Chronic prostatic inflammation is known to increase prostate cancer risk. To better understand the role of chronic inflammation in the natural history of prostate cancer, with a focus on the emergence of early lesions, I employed a mouse model to undertake detailed molecular and histopathological analyses of the changes that occur in prostate epithelial cells upon prolonged exposure to inflammatory insult. In chapter one I discuss the merits of existing mouse prostatic disease models and highlight the advantages of the Induced Mouse Prostate Inflammation-IL1-driven (IMPI 1) model to study inflammation. In this model, consistent long-term prostatic inflammation occurs upon administration of doxycycline. In chapter two, I report the results of experiments designed to determine the histopathological and transcriptomic consequences of prolonged chronic inflammation in IMPI-1 mice and highlight the discovery of a gene expression signature that mimics key molecular features of human PIA. To gain understanding of the cells involved in the development of PIA and PIN lesions, in Chapter three, I report the results of bioinformatic analyses to compare gene expression profiles from IMPI-1 mice with single-cell RNA sequencing profiles from two genetically engineered mouse prostate cancer models. My results indicate that epithelial cells in IMPI-1 prostates that have been exposed to a prolonged inflammatory environment are enriched for genes that are expressed by Myc-expressing luminal cells and reactive basal and luminal cells in two independent mouse prostate cancer models. Myc-expressing luminal cells and reactive basal and luminal cells have been previously reported to be present in the early stages of prostate cancer development in these models. These data demonstrate that chronic inflammation in the mouse prostate leads to cellular and molecular changes that recapitulate features observed in precursor states of prostate cancer. This data provide strong experimental evidence in support of the longstanding hypothesis that chronic inflammation plays a causal role in the development of human prostate cancer. Future experiments will be required to identify other molecular and cellular alterations that permit precursor lesions to progress to overt adenocarcinoma