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

调节色素上皮衍生因子的活性作为潜在的治疗方法

基本信息

批准号：
8729648
负责人：
Stephanie Filleur
金额：
$ 5.02万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729648
关键词：
Affect Animals Apoptosis Biological Assay Blood Circulation Cancer Cell Growth Cancer Patient Cell Line Cell Survival Cells Chemotaxis Collaborations Combined Modality Therapy Data Development Disease Disorder by Site Distant Dose DsRed Dunning Prostate Cancer Endothelial Cells Engineering Goals Growth Histopathology Hormones Human Immune In Vitro Inflammation Inflammatory Injection of therapeutic agent Institution Interleukin-8 Investigation Kidney LNCaP Laboratories Lead Liver Lung Malignant Neoplasms Malignant neoplasm of prostate Measures Mediator of activation protein Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Target Monitor Mus Neoplasm Metastasis Normal tissue morphology Organ PC3 cell line Patients Pharmaceutical Preparations Phenotype Placebos Population Pre-Clinical Model Predictive Factor Production Property Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Publishing Rattus Research Resistance Rodent Model Role Site Specimen Spleen System Taxane Compound Testing Therapeutic Travel Treatment Efficacy Tumor Cell Invasion Tumor Immunity Tumor Volume Umbilical vein Up-Regulation Variant Vascularization Western Blotting Work Xenograft procedure androgen independent prostate cancer angiogenesis arginase base bone cancer cell cancer therapy cell growth cell motility cell type chemotherapy cytotoxic density docetaxel fluorescence imaging improved in vivo inhibitor/antagonist lymph nodes macrophage matrigel migration model development monocyte neoplastic cell new therapeutic target novel pigment epithelium-derived factor prostate cancer cell prostate cancer model red fluorescent protein taxane tumor tumor growth tumor initiation tumor microenvironment tumor progression

项目摘要

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.

描述（由申请人提供）：肿瘤微环境中的新血管化（血管生成）和炎症已被描述为对肿瘤细胞生长和存活有利。作为直接结果，肿瘤细胞能够穿过循环，从而定居遥远的器官和位点（转移）。一种称为色素上皮衍生因子（PEDF）的天然蛋白质在正常组织中表达，并在前列腺肿瘤中减少。我们已经证明PEDF是一个有效的血管抑制因子。其他研究表明，PEDF在炎症中的作用。但是，其确切的作用方式仍不清楚，需要进一步研究。在先前的工作中，我们证明了工程前列腺癌细胞增加了PEDF阻断肿瘤的生长并延长体内生存率。我们还表明，PEDF刺激了体外单核细胞和巨噬细胞炎症细胞的募集。因此，PEDF表达，前列腺癌的进展和肿瘤炎症似乎相互关联。但是，它们在前列腺癌增长和转移形成过程中的确切关系尚不清楚。在拟议的研究中，我们将首先评估小鼠前列腺癌模型，PEDF阻止骨转移的形成的能力，骨转移的形成是晚期前列腺癌患者的常见且具有挑战性疾病的疾病部位。我们还将确定PEDF表达影响人前列腺癌的抗肿瘤免疫活性的机制。我们将评估PEDF的体外和体内抗肿瘤活性与低剂量紫杉烷药物的结合。目前，用于转移性前列腺癌患者的紫杉烷药物作为标准化学疗法。这些研究结合了体外，体内和小鼠临床前模型的研究，应使我们能够提供支持PEDF作为前列腺癌治疗的新目标的数据。我们还预计，该项目将导致改善前列腺癌的治疗方法的发展。