TUMOR NECROSIS FACTOR ALPHA GENE EXPRESSION IN MALIGNANT GLIOMA CELLS

恶性神经胶质肿瘤，几乎占所有中枢神经系统肿瘤的一半。 神经系统（CNS）肿瘤迄今为止仍然相对不可治愈。 之一 这些肿瘤对治疗反应差的主要原因是 它们广泛的生物变异性。 多形性胶质母细胞瘤（GBM） 细胞在表型和基因型上都是极其异质的， 并在体外对生物反应调节剂表现出不同的反应。 认识到他们的生物和功能与正常人的差异 神经胶质细胞（星形胶质细胞）及其深刻的异质性，导致了 对理解高度专业化的生物学的兴趣增加， GBM。 具体来说，阐明体液因素将是至关重要的 调节GBM生长，并了解，在细胞和分子 水平，其异常生长模式和基因 表情 最近的研究表明，GBM细胞参与了这两个过程。 CNS内的炎症和免疫反应。 特别是，GBM 细胞可以响应和/或分泌多种细胞因子。 我们已经表明 GBM细胞分泌肿瘤坏死因子-α（TNF-α）作为反应， 细胞因子白细胞介素-1（IL-1）。 这构成了一种新颖而具体的 GBM细胞TNF-α表达刺激途径。 我们建议，IL- 1诱导的GBM TNF-α参与介导一些 恶性胶质瘤的临床/病理表现，如 胶质瘤实质内的炎性浸润，异常生长 模式，基因表达的变化，以及这些细胞的侵袭性。 我们认为这种刺激途径（IL-1）与IL-1具有生物学相关性， 可以由CNS内的细胞以及GBM细胞自身产生， 和IL-1已被证明存在于中枢神经系统在各种 炎症反应。 因此，首先了解基本的生物学机制至关重要。 GBM TNF-α产生的潜在调节。 这样做的目的是 项目是详细研究细胞内和分子机制 参与IL-1 β诱导的GBM TNF-α基因表达。 我们将 检查1）由IL-1 β产生的细胞内信号的性质 参与TNF-α诱导的刺激，如蛋白质 激酶C、二酰基甘油、肌醇三磷酸和Ca++; 2）特异性顺式- 作用TNF-α调节元件和IL-10所利用的核蛋白 1 β刺激的GBM细胞; 3）TNF-α对GBM基因的影响 表达和功能，特别是玻连蛋白受体的调节 整合素和肌球蛋白II。 TNF-α对CNS中各种细胞群的多重作用， 包括胶质母细胞瘤的自分泌刺激，表明TNF-α 在增加炎性细胞浸润到 中枢神经系统，脑内免疫反应，改变生物学和 胶质母细胞瘤的功能。

Malignant glial neoplasms, which account for almost half of all central nervous system (CNS) tumors, remain to date relatively incurable. One of the major contributors in the poor response of these tumors to therapy is their extensive biological variability. Glioblastoma multiforme (GBM) cells are extremely heterogenous, both phenotypically and genotypically, and exhibit diverse responses to biological response modifiers in vitro. The recognition of their biological and functional differences from normal glial cells (the astrocyte), and their profound heterogeneity, has led to an increased interest in understanding the highly specialized biology of GBM. Specifically, it will be critical to elucidate the humoral factors that modulate GBM growth, and to understand, at the cellular and molecular levels, the mechanism(s) underlying their aberrant growth patterns and gene expression. Recent studies have implicated GBM cells as being involved with both inflammatory and immunologic responses within the CNS. In particular, GBM cells can respond to and/or secrete a variety of cytokines. We have shown that GBM cells secrete tumor necrosis factor-alpha (TNF-alpha) in response to cytokine interleukin-1 (IL-1). This constitutes a novel and specific stimulatory pathway for GBM cell TNF-alpha expression. We propose that IL- 1 induced GBM TNF-alpha is involved in mediating some of the clinical/pathological manifestations of malignant gliomas such as inflammatory infiltration within the parenchyma of gliomas, aberrant growth patterns, changes in gene expression, and the invasiveness of these cells. We feel this stimulatory pathway (IL-1) is biologically relevant as IL-1 can be produced by cells within the CNS as well as by GBM cells themselves, and IL-1 has been shown to be present in the CNS during various inflammatory reactions. As such, it is critical to first understand the basic biological mechanisms underlying regulation of GBM TNF-alpha production. The aims of this project are to study in detail the intracellular and molecular mechanisms involved with GBM TNF-alpha gene expression induced by IL-1beta. We will examine 1) the nature of the intracellular signals generated by IL-1beta stimulation that are involved in the induction of TNF-alpha such as protein kinase C, diacylglycerol, inositol triphosphates and Ca++; 2) specific cis- acting TNF-alpha regulatory elements and nuclear proteins utilized by IL- 1beta stimulated GBM cells; and 3) the effects of TNF-alpha on GBM gene expression and function, especially modulation of vitronectin receptor integrins and myosin II. The multiple effects of TNF-alpha on various cell populations in the CNS, including autocrine stimulation for glioblastomas, suggests that TNF-alpha has a central role in augmenting infiltration of inflammatory cells into the CNS, intracerebral immune responses, and altering the biology and function of glioblastomas.