Danny R. Gray, Ph.D.

Dissertation research performed under the direction of Gary J. Smith

ABSTRACT
    This study is predicated on the need for clinicians treating prostate cancer and other prostatic diseases, including benign prostatic hyperplasia, to understand changes in the human prostate microenvironment that are induced by androgen deprivation therapy.  The lack of an experimental prostate model system that faithfully recapitulates human disease with an intact and reactive human microenvironment provided the impetus for the design of this project and defined the questions comprised in each aim.  Expanding on the initial characterization of the Short-Term Human Prostate Primary Xenograft model, published by Presnell, et al., in 2001, this study focused on characterizing the vasculature of the human prostate xenografts and employing the model system to characterize the response of the human prostate microenvironment to androgen deprivation.  The goal of this project was to gain an increased understanding of the prostatic response to androgen ablation therapy, which has been the gold standard treatment for advanced prostate cancer for over 50 years.  To this end, the investigation focused on the following questions: (a) Do the human prostate xenografts contain a human microenvironment, including human blood vessels? (b) What effect does androgen deprivation have on the vasculature and the cellular compartments (epithelium, stroma, and endothelium) of the human prostate microenvironment? (c) Do angiogenesis and androgen deprivation induce a pro-coagulative change in the human prostate microenvironment and are the effects additive?  The results observed after subjecting Short-Term Human Prostate Primary Xenografts to androgen deprivation have established that 1) a majority of the blood vessels in the human xenografts at 30-days following implantation are human and undergo an angiogenic response to engraftment, 2) a short window of opportunity for maximal anti-angiogenesis / anti-vascular therapy exists in the four to seven days immediately following androgen ablation, and 3) the human prostate vasculature becomes increasingly prothrombotic in the two to seven days immediately following androgen ablation.  The results validate the use of Short-Term Human Prostate Primary Xenograft model in the study of prostate cancer and prostatic disease and suggest enhancements to and additional targets for therapeutic intervention.