ADAM 17 and glioma-tumor progression and treatment

摘要 目前还没有治疗多形性胶质瘤的方法可以大大延长生命。背后的原因 不能有效治疗神经胶质瘤仍然不清楚。在本提案中，基于可靠的初步数据，我们 提出了一种新的假说，即这种酶，一种去整合素和金属蛋白酶-17，也被称为肿瘤 坏死因子转化酶（ADAM 17，TACE）促进胶质瘤侵袭、增殖和存活。 因此，抑制ADAM 17将有效减少肿瘤生长。我们提出三个具体目标， 相应的假设，旨在充分研究ADAM 17作为促肿瘤剂的潜力 和抑制ADAM 17作为抗肿瘤治疗。目的1：研究ADAM 17在胶质瘤中的作用 体外侵袭、增殖和存活以及体内肿瘤进展。假设1a：增加 体外实验中ADAM 17活性诱导胶质瘤细胞侵袭并促进细胞增殖和存活， 促进体内肿瘤进展。假设1b：ADAM 17激活表皮生长因子（EGF） 信号通路通过刺激PI 3 K/Akt促进胶质瘤侵袭、细胞增殖和存活 通路目的2：探讨ADAM 17在缺氧应激条件下胶质瘤进展中的作用。 假设2：缺氧诱导的细胞应激上调了ADAM 17的转录和蛋白水解活性， 并且这种增加导致神经胶质瘤增殖、侵袭性和存活率增强。目标3：调查 靶向ADAM 17的RNAi基因治疗U87和HF 66人脑胶质瘤的疗效观察 裸鼠模型中的异种移植物。假设3：靶向ADAM 17的RNAi基因治疗降低了ADAM 17 表达和蛋白水解活性，从而减少肿瘤进展和复发。 具有颅内胶质瘤异种移植物的裸鼠的存活率。神经胶质瘤的体外和体内模型都是 在拟议的研究中使用。使用的方法范围从siRNA到激光捕获共聚焦显微镜， 磁共振成像，试图剖析ADAM 17对肿瘤进展的贡献， 阐明肿瘤进展和有效治疗的分子基础。我们的长期目标是发展 一种有效的治疗这种毁灭性的脑瘤的方法，并将我们的发现从实验中转化出来。 系统对人类。

ABSTRACT There are no treatments of glioma multiforme that substantially extend life. The reasons behind the inability to effectively treat glioma remain obscure. In this proposal, based on robust preliminary data, we develop a novel hypothesis, that the enzyme, a disintegrin and metalloproteinase-17, also known as, tumor necrosis factor converting enzyme (ADAM17, TACE) fosters glioma invasion, proliferation and survival. Thereby inhibition of ADAM17 will be effective in reducing tumor growth. We propose three specific aims and corresponding hypotheses, directed at fully investigating the potential of ADAM17 as a pro tumorgenic agent and inhibition of ADAM17 as an anti-tumor treatment. Aim 1: Characterize the function of ADAM17 in glioma invasion, proliferation and survival in vitro, and in tumor progression in vivo. Hypothesis 1a: Increased ADAM17 activity induces invasion and promotes cell proliferation and survival of glioma cells in vitro and promotes tumor progression in vivo. Hypothesis 1b: ADAM17 activation of the epidermal growth factor (EGF) signaling pathway promotes glioma invasion, cell proliferation and survival, by stimulating the PI3K/Akt pathway. Aim 2: Investigate the role of ADAM17 in glioma progression in the context of hypoxic stress. Hypothesis 2: ADAM17 transcription and proteolytic activity are up-regulated by hypoxia-induced cellular stress, and this increase leads to enhanced glioma proliferation, invasiveness and survival. Aim 3: Investigate the therapeutic effectiveness of ADAM17-targeting RNAi gene therapy to treat U87 and HF66 human glioma xenographs in nude mouse models. Hypothesis 3: ADAM17-targeting RNAi gene therapy decreases ADAM17 expression and proteolytic activity within glioma cells, and thus reduces tumor progression and prolongs survival of nude mice bearing intracranial glioma xenographs. Both in vitro and in vivo models of glioma are employed in the proposed studies. Methods used range from siRNA to laser capture confocal microscopy and magnetic resonance imaging in an effort to dissect the contribution of ADAM17 to tumor progression and to elucidate the molecular bases for tumor progression and effective treatment. Our long term goal is to develop an effective treatment for this devastating brain tumor and to translate our findings from the experimental system to the human.