Lymphagiogenesis and Lymphatic Metastasis in Prostate Cancer

转移是前列腺癌死亡的主要原因。前列腺癌的治疗方法 过去两年的发展计划使我们能够调查 淋巴管生成与前列腺癌转移的关系我们发现淋巴管生成因子水平升高 前列腺肿瘤中的VEGF-C诱导淋巴管的生长，这反过来又促进肿瘤细胞的增殖。 扩散至区域淋巴结。此外，淋巴扩散过程也极大地影响了 转移到远端器官，如肺和肝。因此，我们目前的工作假设表明， 淋巴循环是一个优选的传播途径，区域淋巴结提供了一个储存库 随后从其扩散到远端部位。本提案将对这一假设进行调查 进一步.特别是，我们将详细研究淋巴管生成途径与 转移的前列腺癌患者，集中我们的分子和组织学分析的患者， 淋巴结阳性和复发性疾病。使用我们机构开发的许多相关临床前模型， 我们的努力将针对两个迫切需要的领域，即治疗干预和 淋巴结转移的影像诊断。我们将研究阻断血管的治疗效果， 特异性VEGFR 3抗体和索拉非尼，一种多激酶 已知靶向VEGFR 3的抑制剂。分子成像技术将用于监测影响 对转移过程的干预。我们还将评估前列腺特异性 成像腺病毒载体特异性检测临床前模型中的淋巴结转移。此外，我们将 开发和评估淋巴管生成途径的潜在循环替代标志物。缺乏 这些标记物已经阻止了抗转移治疗的进展。前列腺癌孢子计划在 华盛顿大学正在启动一项索拉非尼的II期新辅助临床试验， 局部前列腺癌的风险。在这项研究的合作努力中，我们将获得血液和组织， 分析索拉非尼对VEGFR 3通路的分子活性， 肿瘤淋巴管生成轴本提案中采取的各种办法都是为了 提高前列腺癌转移期的临床处理水平。

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.