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显著延长生命。其背后的原因是 无法有效地治疗胶质瘤仍然是个未知数。在这项建议中，基于稳健的初步数据，我们 提出了一种新的假设，即这种酶，一种去整合素和金属蛋白酶-17，也被称为肿瘤 肿瘤坏死因子转换酶(ADAM17，TACE)促进胶质瘤的侵袭、增殖和生存。 因此，抑制ADAM17将有效地抑制肿瘤的生长。我们提出了三个具体目标和 相应的假设，旨在充分研究ADAM17作为促肿瘤药物的潜力 抑制ADAM17作为一种抗肿瘤治疗。目的1：研究ADAM17在脑胶质瘤中的功能 体外侵袭、增殖和存活，体内肿瘤进展。假设1a：增加 ADAM17活性诱导胶质瘤细胞体外侵袭并促进细胞增殖和存活 促进体内肿瘤的发展。假设1b：ADAM17激活表皮生长因子(EGF) 信号通路通过刺激PI3K/Akt促进胶质瘤侵袭、细胞增殖和存活 路径。目的：探讨ADAM17在低氧应激条件下脑胶质瘤发生发展中的作用。 假设2：ADAM17转录和蛋白分解活性受低氧诱导的细胞应激上调， 这种增加导致了胶质瘤的增殖、侵袭性和存活率的提高。目标3：调查 ADAM17靶向RNAi基因治疗U87和HF66人脑胶质瘤的疗效观察 裸鼠模型的异种照片。假设3：靶向ADAM17的RNAi基因治疗降低ADAM17 在胶质瘤细胞内的表达和蛋白分解活性，从而减少肿瘤的进展和延长 荷脑胶质瘤裸鼠移植瘤的存活。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和 磁共振成像，以努力剖析ADAM17在肿瘤进展中的贡献和 阐明肿瘤进展和有效治疗的分子基础。我们的长远目标是发展 一种有效的治疗这种毁灭性脑瘤的方法，并将我们的实验结果转化为 系统传给人类。

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.