The Fn14 Receptor and Brain Tumor Invasion

描述(申请人提供)：胶质瘤是起源于胶质细胞(如星形胶质细胞、少突胶质细胞)的肿瘤，是最常见的原发脑肿瘤，据估计，美国每年约有18,500例新病例。多形性胶质母细胞瘤(GBM)是恶性程度最高、致死率最高的星形细胞肿瘤，预后较差，中位生存期约1年。恶性胶质瘤细胞是高度侵袭性的，它们有效地渗透到邻近的正常脑组织中，防止了完全手术切除或致命辐射暴露的有效破坏。Fn14基因最初是在我们的实验室筛选小鼠成纤维细胞中的生长因子诱导基因时发现的，它编码多功能细胞因子肿瘤坏死因子样弱凋亡诱导因子(TWINE)的细胞表面受体。我们发现Fn14基因在GBM标本的肿瘤核心区和侵袭性边缘区域的胶质瘤细胞中的表达经常升高。我们还发现，在转基因细胞中过表达Fn14可以激活核因子(NF)-kB信号通路。我们假设，Fn14在胶质瘤细胞中的过表达促进了NF-kB信号通路的结构性、非配体依赖性的激活，并且该通路的过度激活有助于胶质瘤细胞在体内的侵袭性。此外，我们推测Fn14细胞表面受体可能是一个新的配体靶点：基于细胞毒素融合蛋白的脑肿瘤治疗。因此，这项建议的具体目的是：(1)确定Fn14在转染人胶质瘤细胞系中过表达是否刺激NF-kB激活、细胞增殖、细胞迁移、基质金属蛋白酶的产生或细胞体外侵袭，(2)确定Fn14过表达是否促进细胞体外或体内侵袭，(3)确定NF-kB激活是否在Fn14介导的胶质瘤细胞侵袭中起关键作用，以及(4)确定TWew-假单胞菌外毒素融合蛋白是否对Fn14阳性胶质瘤细胞具有细胞毒性。与公众健康相关：许多脑瘤具有高度侵袭性，因此很难治疗。这项拟议的研究将检验一种名为Fn14的蛋白质是否有助于肿瘤细胞的侵袭，以及它是否可能成为人类抗侵袭治疗的新分子靶点。

DESCRIPTION (provided by applicant): 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 a TWEAK-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.