A number of peptide and steroid hormones associated with prostate cancer growth such as basic FGF, insulinlike growth factor I, and androgens have also been shown to regulate expression of VEGF. The mechanism of VEGFR signal transduction is complex.However VEGFR does not appear to signal through the MAPK cascade or induce endothelial cell proliferation, yet it appears to be important in endothelial cell migration. On the other hand, VEGFR is believed to signal through both the MAPK cascade to induce endothelial cell proliferation as well as the PIK to Amifostine activate an antiapoptotic pathway. Equally important to the activators of the angiogenic phenotype are the molecules that inhibit this process.In fact, it has been proposed that a tumor will become vascularized as a consequence of stochastic events that disrupt any balance that exists between the activators and inhibitors. Molecules that posses antiangiogenic properties, such as thrombospondin, IFN ab, tissue inhibitor of metalloproteinase, angiopoietin, endostatin and angiostatin, are currently being isolated, characterized, and exploited as potential therapeutics. It is obvious that a better understanding of the Nintedanib temporal and spatial patterns of expression of molecules that regulate this process will be required to develop more effective diagnostics and therapeutics.The complex nature of the VEGF signaling axis and the inherent interactions between epithelium, stroma, and endothelium have made the angiogenic switch difficult to characterize during the natural history of clinical prostate cancer.Hence, we have chosen to examine the molecular changes in the VEGF signaling axis in the autochthonous spontaneous TRAMP model.Briefly, TRAMP mice express a epithelial neoplasia; PECAM, platelet endothelial cell adhesion molecule; IMVD, intraductal microvessel density; sVEGFR, soluble form of VEGFR.ANGIOGENESIS AND PROSTATE CANCER PBSV early gene construct under prostate specific control of the minimal rat probasin promoter and display mild to severe hyperplasia of the prostate epithelium, resembling PIN by weeks of age. Welldifferentiated neoplasia is generally observed in TRAMP mice between and weeks of age, and between and weeks of age, all of the mice will display primary tumors and metastases to distant sites. The restricted temporal and spatial pattern of prostate cancer progression in TRAMP affords a unique window of opportunity for investigation of the earliest molecular events of the disease.Subsequent analysis of clinical prostate cancer specimens was used to confirm and validate the predictions of the TRAMP model.Slides were hydrated through xylene and graded alcohol and equilibrated in PBS.Antigen retrieval was performed with mgml proteinase K at C for min.Endogenous peroxidases were quenched with HO in methanol.When appropriate, slides were incubated with a rat monoclonal antibody specific for CDPECAM at a: dilution.All of the slides were subsequently washed several times in PBS with. Sections were counterstained with methyl green, dehydrated through graded alcohol into xylene, and mounted under glass coverslips.The number of intraductal vessels was determined by counting three highpower fields of the highest vascular density.Isolation of tail DNA and PCR screening were performed as described previously. TRAMP mice and nontransgenic littermates were randomly assigned into cohorts and sacrificed at, and weeks of age.In addition, a cohort of TRAMP mice were castrated by a scrotal approach at weeks of age and sacrificed at weeks of age.