History Features TRAMP and the Neuroendocrine Phenotype Uses TRAMP HistoPathology- self guided slide show Video Instruction Manual and Guide Prevention of Prostate Cancer Prevention can be hard to study, especially in a clinical setting, because of the time required to complete a study (often years). In a more basic research setting, prevention can be hard to study because much of the available research material such as cell lines (LnCaP, PC-3, DU-145) or explants (xenografts like CWR-22) derived from clinical specimens often represent more advanced stage disease, and, a priori, preclude the opportunity to truly study prevention. In contrast, growth and development of the prostate glands in the TRAMP mice occurs normally until rising circulating levels of androgen direct the prostate specific probasin regulated transgene to express the SV40 early genes (T/t antigens) thereby initiating the transformation process. In the TRAMP model the expression of the transgene is detected as early as 4 weeks of age and is maximal by the time the mice are approximately 12 weeks of age. Over a 30 week period, and as a consequence of transgene expression and subsequent stochastic events, 100% of the male TRAMP mice will develop prostate disease. It has been demonstrated that the earliest form of disease is low grade PIN (prostatic intraepithelial hyperplasia), and that older mice will display high grade PIN (8-12 weeks), well differentiated adenocarcinoma (as early as 12 weeks) moderately differentiated carcinoma (usually between 12 - 24 weeks), and ultimately poorly differentiated carcinoma (usually between 24 - 30 weeks). Distant site metastasis (hematogenous and lymphatic) have been detected as early as 12 weeks of age and by the time the mice are 24-30 weeks of age the incidence of metastasis approaches 100%. Hence, the tumors develop only after the normal growth and development of the prostate gland, and at a rate slow enough to facilitate intervention studies and yet fast enough data for collection in a timely manner. Currently, numerous investigators around the world are using the TRAMP model to study various chemoprevention strategies, including dietary and hormonal manipulation, on the timing, incidence and nature of spontaneous prostate cancer. Furthermore, becuase the TRAMP mice were generated in the pure C57BL/6 background, they have an intact immune system and therefby facilitate studies designed to exploit the immune response in vaccine based prevention studies, a clear advantage over other "in vivo" models that require the use of immunodeficient nude mouse hosts. Detection and Diagnosis of Prostate Cancer The detection of prostate cancer has been greatly facilitated through the development of serum tests such as the PSA serum assay, the digital rectal exam (DRE), transrectal ultrasonography (TRUS), and other imaging techniques, and fine needle biopsy. However, because prostate cancer is a heterogenous disease it has been hard to diagnose the exact nature of the disease, tumor volume or response to chemotherapy (such as hormonal manipulation) based on these detection methods alone. To this end, and since cancer is essentially a "gene-disease", many groups are taking a molecular approach to detection and diagnosis by isolating individual genes and sets of genes believed to be causally related to the development, progression, metastasis and hormone refractory nature of prostate cancer. Unfortunately, many clinical samples are derived from advanced disease and therefore it is hard to isolate the "early molecular events" that may indicate how the disease began, or even distinguish them from "late molecular events" that may occur as a consequence of the genomic instability associated with cancer cells. Furthermore, the genetic heterogeneity of the human population further complicated such analysis making it difficult to identify, isolate, and analyze specific genetic "hits" . However, the TRAMP model, developed in the C57BL/6 inbred strain of mice, reproducibly develops spontaneous autochthonous prostate cancer only AFTER normal development and growth of the prostate gland. Hence this model is ideally suited to the identification, isolation and characterization of "early molecular events" in prostate cancer progression. Furthermore, the TRAMP model can be used to identify and isolate genetic markers throughout the natural history of the disease. It is anticipated that these markers will be used to develop new predictive molecular diagnostic assays. Our lab has already isolated a number of such markers and we are in the process of evaluating them in pre-clinical trials to see if we can predict the occurence of hormone refractory or metastatic prostate cancer from a simple biopsy specimen. Therapy for Prostate Cancer (this section is currently being updated....sorry!)