The Fn14 Receptor and Brain Tumor Invasion

神经胶质瘤，起源于神经胶质细胞的肿瘤（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，估计在美国每年约有18，500例新发病例。 多形性胶质母细胞瘤（GBM）是最恶性和最致命的星形细胞肿瘤， 预后，中位生存期约为1年。恶性神经胶质瘤细胞具有高度侵袭性，其有效的 浸润到邻近的正常脑组织中阻止了完全的手术切除或有效的破坏， 致命的辐射Fn 14基因，最初是在我们的实验室中发现的， 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因子（TWEAK）。我们发现Fn 14基因表达 在位于GBM的肿瘤核心和浸润边缘区域的胶质瘤细胞中经常升高 标本我们还表明，转染细胞中Fn 14的过表达激活了核因子 （NF）-kB信号通路。我们假设Fn 14在胶质瘤细胞中的过表达促进了组成性的， NF-kB信号通路的配体非依赖性激活，以及该通路的过度激活 有助于胶质瘤细胞在体内的侵袭力。此外，我们假设Fn 14细胞表面 受体可能是基于配体：细胞毒素融合蛋白的脑肿瘤治疗的新靶点。因此，委员会认为， 本研究具体目的是：（1）确定Fn 14是否在转染的人中过表达 胶质瘤细胞系刺激NF-κ B活化，细胞增殖，细胞迁移，基质金属蛋白酶 （2）检测转染Fn 14基因的细胞是否过表达Fn 14， 神经胶质瘤细胞系刺激细胞侵袭离体或在体内，（3）为了确定是否NF-κ B活化， Fn 14介导的神经胶质瘤细胞侵袭的关键，和（4）为了确定是否aTWEAK-假单胞菌 外毒素融合蛋白对Fn 14阳性胶质瘤细胞具有细胞毒性。 与公共卫生的相关性：许多脑肿瘤具有高度侵袭性，因此很难治疗。 拟议的研究将检查一种名为Fn 14的蛋白质是否有助于肿瘤细胞的侵袭性 以及它是否可能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.