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（由申请人提供）：在神经胶质瘤中，成年人中最常见的原发性脑肿瘤，多形胶质母细胞瘤（GBM）是最恶性的。尽管手术，化学疗法和放射线取得了进步，但GBM仍然是一种毁灭性的疾病。 GBM的标志是TS渗透白质区的能力，但对获得不可识别特征的获取的基础的分子机制知之甚少。 PTEN编码磷酸肌醇-3激酶途径的负调节剂，通常在GBMS中突变，并且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中的异常有助于恶性转化。先前的研究已经确定了激活STAT3（转录因子）在神经干细胞为星形胶质细胞分化中的关键作用。在初步数据中，STAT3损失在体外增加了鼠星胶质细胞的迁移。此外，在人类GBM样品中，低PTEN表达与STAT3活性低相关。共同，这些结果加剧了STAT3抑制PTEN缺陷GBMS的侵入性的有趣可能性。这项研究的具体目的是：1）测试STAT3在GBM侵入性中的作用在脑切片分析和体内的作用，2）牙齿化STAT3响应基因，这些基因可以通过表达阵列分析来控制GBM迁移的GBM迁移，而3）以鉴定通过RNA基于RNA的屏幕来调节GBM侵入性的新型细胞插入机制。这些目标将通过分子生物学，细胞培养，脑切片制剂和体内方法的结合来追求。这些目标的完成将阐明STAT3在GBM侵入性中的作用，并有可能揭示针对GBM的新治疗方法。