The Fn14 Receptor and Brain Tumor Invasion

胶质瘤是最常见的起源于神经胶质细胞(如星形胶质细胞、少突胶质细胞)的肿瘤 一组原发脑肿瘤，估计在美国每年新发病例约18,500例。 多形性胶质母细胞瘤是最恶性和最致命的星形细胞肿瘤，患者的预后很差。 预后，中位生存期~1年。恶性胶质瘤细胞具有高度侵袭性和高效性 渗透到邻近的正常脑组织防止完全手术切除或有效破坏 致命的辐射暴露。Fn14基因，最初是在我们实验室的生长筛查中发现的 小鼠成纤维细胞中的因子诱导基因，编码多功能细胞因子的细胞表面受体 肿瘤坏死因子样弱凋亡诱导剂(TWEEP)。我们发现Fn14基因表达 在位于基底膜肿瘤核心区和侵袭性边缘区域的胶质瘤细胞中经常升高。 标本。我们还表明，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结构性， 非配体依赖的核因子-kB信号通路的激活，以及该通路的过度激活 有助于胶质瘤细胞在体内的侵袭性。此外，我们假设Fn14细胞表面 受体可能是一个新的配体靶点：细胞毒素融合蛋白为基础的脑肿瘤治疗。因此， 该方案的具体目的是：(1)确定Fn14在转染人中是否过表达 胶质瘤细胞株刺激核因子-kB活化、细胞增殖、细胞迁移、基质金属蛋白酶 体外生产或细胞侵袭，(2)确定Fn14在转染人中是否过表达 胶质瘤细胞株体外或体内刺激细胞侵袭，(3)确定核因子-kB活化是否 对Fn14介导的胶质瘤细胞侵袭至关重要，以及(4)确定是否存在TWEAK-假单胞菌 外毒素融合蛋白对Fn14阳性胶质瘤细胞具有细胞毒作用。 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性 以及它是否会成为人类抗侵袭治疗的新分子靶点。

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.