Mechanisms of glioblastoma multiforme invasion: the role of STAT3

多形性胶质母细胞瘤侵袭机制：STAT3的作用

• 批准号: 7158293
• 负责人: Albert Hong-Jae Kim
• 金额: $ 5.2万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7158293
• 关键词: astrocytes; brain; clinical research; genes; glioblastoma multiforme; glioma; human; neoplasm /cancer; phosphatidylinositols; role; stem cells; transcription factor

DESCRIPTION (provided by applicant): Among gliomas, the most common primary brain tumor in adults, glioblastoma multiforme (GBM) is the most malignant. Despite advances in surgery, chemotherapy, and radiation, GBM remains a devastating disease. A hallmark of GBM is ts ability to infiltrate white matter tracts, but little is known about the molecular mechanisms underlying the acquisition of nvasive characteristics. PTEN, which encodes a negative regulator of the phosphoinositide-3 kinase pathway, is commonly mutated in GBMs and has been implicated in regulation of tumor migration. The underlying hypothesis of this proposal is that abnormalities in processes that determine normal glial development contribute to malignant transformation. Previous studies have identified a critical role for activation of STAT3, a transcription factor, in the differentiation of neural stem cells into astrocytes. In preliminary data, STAT3 loss increased the migration of murine astrocytes in vitro. Moreover, in human GBM samples, low PTEN expression correlated with low STAT3 activity. Together, these results raise the intriguing possibility that STAT3 inhibits invasiveness in PTEN-deficient GBMs. The specific aims of this study are: 1) to test the role of STAT3 in GBM invasiveness in brain slice assay and in vivo, 2) to dentify STAT3-responsive genes that control GBM migration using expression array analysis, and 3) to identify novel cell-intrinsic mechanisms that regulate GBM invasiveness through an RNA interference-based screen. These aims will be pursued using a combination of molecular biology, cell culture, brain slice preparation, and in vivo approaches. Completion of these aims will elucidate the role of STAT3 in GBM invasiveness and potentially reveal new therapeutic argets against GBM.

描述（申请人提供）：在成人最常见的原发性脑肿瘤——胶质瘤中，多形性胶质母细胞瘤（GBM）的恶性程度最高。尽管手术、化疗和放疗取得了进步，GBM 仍然是一种毁灭性的疾病。 GBM 的一个特点是能够浸润白质束，但人们对获得侵袭性特征的分子机制知之甚少。 PTEN 编码磷酸肌醇 3 激酶通路的负调节因子，通常在 GBM 中发生突变，并与肿瘤迁移的调节有关。该提议的基本假设是，决定正常神经胶质发育的过程异常会导致恶性转化。先前的研究已经确定了 STAT3（一种转录因子）的激活在神经干细胞分化为星形胶质细胞中的关键作用。初步数据显示，STAT3 缺失增加了小鼠星形胶质细胞的体外迁移。此外，在人类 GBM 样本中，低 PTEN 表达与低 STAT3 活性相关。总之，这些结果提出了一个有趣的可能性：STAT3 抑制 PTEN 缺陷的 GBM 的侵袭性。本研究的具体目的是：1) 在脑切片测定和体内测试 STAT3 在 GBM 侵袭性中的作用，2) 使用表达阵列分析来鉴定控制 GBM 迁移的 STAT3 响应基因，以及 3) 鉴定新的通过基于 RNA 干扰的筛选来调节 GBM 侵袭性的细胞内在机制。这些目标将通过结合分子生物学、细胞培养、脑切片制备和体内方法来实现。这些目标的完成将阐明 STAT3 在 GBM 侵袭性中的作用，并可能揭示针对 GBM 的新治疗目标。