Modulation of Pigment Epithelium-Derived Factor's activities as potential therape

描述（由申请人提供）：肿瘤微环境中的新血管形成（血管生成）和炎症被认为有利于肿瘤细胞的生长和存活。直接的结果是，肿瘤细胞能够通过血液循环迁移到远处的器官和部位（转移）。一种被称为色素上皮衍生因子（PEDF）的天然蛋白在正常组织中表达，在前列腺肿瘤中减少。我们已经证明PEDF是一种有效的血管抑制因子。其他研究表明PEDF在炎症中的作用；然而，其确切的作用方式尚不清楚，需要进一步研究。在之前的一项研究中，我们证明了通过基因工程使前列腺癌细胞增加PEDF可阻断肿瘤生长并延长体内生存期。我们也证明了PEDF在体外刺激单核细胞和巨噬细胞的募集。因此，PEDF表达、前列腺癌进展和肿瘤炎症似乎是相互关联的。然而，它们在前列腺癌生长和转移形成过程中的确切关系尚不清楚。在本研究中，我们将首先在小鼠前列腺癌模型中评估PEDF阻断骨转移形成的能力，骨转移是晚期前列腺癌患者常见且具有治疗挑战性的疾病部位。我们还将确定PEDF表达影响人类前列腺癌抗肿瘤免疫活性的机制。我们将评价PEDF与低剂量紫杉烷类药物联合使用的体内外抗肿瘤活性。紫杉烷类药物目前被用作转移性前列腺癌患者的标准化疗药物。这些结合了体外、体内和小鼠临床前模型的研究，应该允许我们提供支持PEDF作为前列腺癌治疗的新靶点的数据。我们也期望这个项目能促进前列腺癌治疗方法的发展。

DESCRIPTION (provided by applicant): Neo-vascularization (angiogenesis) and inflammation in the tumor microenvironment have been described as favorable for tumor cell growth and survival. As a direct result, tumor cells are able to travel through the circulation to colonize distant organs and sites (metastases). A natural protein known as Pigment Epithelium-Derived Factor (PEDF) is expressed in normal tissues and decreased in prostate tumors. We have shown that PEDF is a potent angio- inhibitory factor. Other studies suggest a role for PEDF in inflammation; however its precise mode of action is still unclear and need further investigation. In a previous work, we demonstrated that engineering prostate cancer cells to increase PEDF blocks tumor growth and prolong survival in vivo. We also have shown that PEDF stimulates the recruitment of monocytes and macrophages inflammatory cells in vitro. Thus PEDF expression, prostate cancer progression and tumor inflammation seem interrelated. However, their precise relationship during prostate cancer growth and metastasis formation is still unclear. In the proposed study, we will first evaluate in mouse prostate cancer models, the capacity of PEDF to block the formation of bone metastases, a common and therapeutically challenging site of disease in patients with advanced prostate cancer. We will also identify the mechanisms by which PEDF expression affects the anti-tumor immunity activity in human prostate cancer. We will evaluate the in vitro and in vivo anti-tumor activities of PEDF in combination with low dose taxane drugs. The taxane drugs are currently used as standard chemotherapies for patients with metastatic prostate cancer. These studies which combine both in vitro, in vivo and mouse preclinical models, should allow us to provide data in support of PEDF as novel target for prostate cancer treatment. We also anticipate that this project will lead to the development of improved therapeutic approaches for prostate cancer. PUBLIC HEALTH RELEVANCE: The major goals of this project are to validate PEDF as a novel therapeutic target for prostate cancer and to investigate PEDF anti-cancer efficacy in combination with low dose chemotherapeutic taxane drugs in preclinical models of prostate cancer. We will also identify the mechanisms by which PEDF affects the anti-tumor immunity activity in human prostate cancer.