Metastasis is the main cause of prostate cancer mortality. The support of prostate cancer SPORE Developmental Program in the past two years has enabled us to investigate the contribution of lymphangiogenesis to prostate cancer metastasis. We discovered that elevated pro-lymphangiogenic factor (VEGF-C) in the prostate tumors induces the growth of lymphatic vessels, which in turn facilitates tumor cell dissemination to regional lymph nodes. Moreover, the lymphatic dissemination process also greatly impacts metastasis to distal organs, such as lung and liver. Hence, our current working hypothesis suggests that lymphatic circulation is a preferred route of dissemination and that regional lymph nodes provide a reservoir from which subsequent dissemination to distal sites occurs. This proposal will investigate this hypothesis further. In particular, we will examine in detail the connection between lymphangiogenic pathways and metastasis in prostate cancer patients, focusing our molecular and histological analyses on the patients with node positive and recurrent disease. Using many relevant preclinical models developed at our institution, our efforts will be directed towards addressing two areas of great need, i.e. therapeutic intervention and diagnostic imaging of nodal metastasis. We will investigate therapeutic effects of blockading the lymphangiogenic tyrosine kinase receptor by specific VEGFR3 antibody, and Sorafenib, a multi-kinase inhibitor known to target both VEGFR3. Molecular imaging technologies will be applied to monitor the impact of these interventions on the metastatic process. We will also evaluate the ability of a prostate-specific imaging adenoviral vector to specifically detect nodal metastases in preclinical models. In addition, we will develop and assess potential circulating surrogate markers for the lymphangiogenic pathways. The lack of such markers has halted progress in anti-metastatic treatment. The prostate cancer SPORE program at University of Washington is initiating a phase II neoadjuvant clinical trial of Sorafenib in patients with high- risk localized prostate cancer. In a collaborative effort with this study, we will obtain blood and tissue samples from the patients to analyze the molecular activity of Sorafenib against the VEGFR3 pathway and tumor lymphangiogenesis axis. The myriad of approaches taken in this proposal is directed towards improving the clinical management of metastasis stage of prostate cancer in the future.