The Fn14 Receptor and Brain Tumor Invasion

Fn14 受体和脑肿瘤侵袭

• 批准号: 7738478
• 负责人: JEFFREY A WINKLES
• 金额: $ 32.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-19 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7738478
• 关键词: Apoptosis Promoter; Astrocytes; Astrocytoma; Base of the Brain; Brain Neoplasms; Cell Proliferation; Cell Surface Receptors; Cells; Chimeric Proteins; Cytotoxin; Excision; Exotoxins; Fibroblasts; Gene Expression; Genes; Glioblastoma; Glioma; Growth Factor; Human; In Vitro; Incidence; Infiltration; Invaded; Laboratories; Ligands; Malignant - descriptor; Malignant Glioma; Matrix Metalloproteinases; Mediating; Molecular Target; Mus; Names; Neuroglia; Nuclear; Oligodendroglia; Pathway interactions; Patients; Primary Brain Neoplasms; Production; Proteins; Pseudomonas; Public Health; Radiation; Signal Pathway; Specimen; Tumor Cell Invasion; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; brain tissue; cell motility; cytokine; cytotoxic; glioma cell line; in vivo; neoplastic cell; novel; outcome forecast; overexpression; prevent; receptor; tumor

Gliomas, tumors that originate from glial cells (e.g., astrocytes, oligodendrocytes), are the most common group of primary brain tumors with an estimated incidence in the USA of ~18,500 new cases per year. Patients with glioblastoma multiforme (GBM), the most malignant and lethal astrocytic tumor, have a poor prognosis, with a median survival of ~1 year. Malignant glioma cells are highly invasive and their efficient infiltration into adjacent normal brain tissue prevents complete surgical removal or effective destruction by lethal radiation exposure. The Fn14 gene, initially discovered in our laboratory during a screen for growth factor-inducible genes in murine fibroblasts, encodes a cell surface receptor for the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK). We have found that Fn14 gene expression is frequently elevated in glioma cells located in both the tumor core and invasive rim regions of GBM specimens. We have also shown that Fn14 overexpression in transfected cells activates the nuclear factor (NF)-kB signaling pathway. We hypothesize that Fn14 overexpression in glioma cells promotes constitutive, ligand-independent activation of the NF-kB signaling pathway, and that the hyperactivation of this pathway contributes to glioma cell invasiveness in vivo. In addition, we hypothesize that the Fn14 cell surface receptor may be a novel target for ligand:cytotoxin fusion protein-based brain tumor therapy. Accordingly, the Specific Aims of this proposal are:(1) To determine whether Fn14 overexpression in transfected human glioma cell lines stimulates NF-kB activation, cell proliferation, cell migration, matrix metalloproteinase production or cell invasion in vitro, (2) To determine whether Fn14 overexpression in transfected human glioma cell lines stimulates cell invasion ex vivo or in vivo, (3) To determine whether NF-kB activation is critical for Fn14-mediated glioma cell invasion, and (4) To determine whether aTWEAK-Pseudomonas exotoxin fusion protein is cytotoxic to Fn14-positive glioma cells. Relevance to public health: Many brain tumors are highly invasive and consequently very difficult to treat. The proposed studies will examine whether a protein named Fn14 contributes to tumor cell invasiveness and whether it could be a novel molecular target for anti-invasive therapy in humans.

神经胶质瘤，起源于神经胶质细胞（例如星形胶质细胞，少突胶质细胞），是最常见的 一组原发性脑肿瘤每年在美国估计发病率约为18,500例。 胶质母细胞瘤多形（GBM）的患者，最恶性和致命的星形胶质细胞肿瘤患者 预后，中位生存期约1年。恶性神经胶质瘤细胞高度侵入性，其有效 渗透到邻近的正常脑组织中可防止完全手术切除或有效破坏 致命的辐射暴露。 FN14基因，最初在我们的实验室中发现的生长屏幕 鼠成纤维细胞中因子诱导基因，编码多功能细胞因子的细胞表面受体 肿瘤坏死因子样细胞凋亡的弱诱导剂（TWEAK）。我们发现FN14基因表达 在GBM的肿瘤核心和侵入性边缘区域的神经胶质瘤细胞中经常升高 标本。我们还表明，转染细胞中的FN14过表达激活核因子 （NF）-KB信号通路。我们假设神经胶质瘤细胞中的FN14过表达促进了构成型， NF-KB信号通路的非配体非依赖性激活，并且该途径的过度激活 在体内有助于神经胶质瘤细胞的侵袭性。另外，我们假设FN14细胞表面 受体可能是配体的新靶标：基于细胞毒素融合蛋白的脑肿瘤疗法。因此， 该提案的具体目的是：（1）确定转染的人类中的FN14是否过表达 神经胶质瘤细胞系刺激NF-KB激活，细胞增殖，细胞迁移，基质金属蛋白酶 在体外的生产或细胞侵袭，（2）确定FN14转染的FN14是否过表达 神经胶质瘤细胞系刺激细胞侵袭离体或体内，（3），以确定NF-KB激活是否为 FN14介导的神经胶质瘤细胞侵袭至关重要，（4）确定是否atweak-pepeudomonas 外毒素融合蛋白是FN14阳性神经胶质瘤细胞的细胞毒性。 与公共卫生有关：许多脑肿瘤具有高度侵入性，因此很难治疗。 拟议的研究将检查名为FN14的蛋白质是否有助于肿瘤细胞的侵袭性 以及它是否可以成为人类抗侵入性疗法的新分子靶标。