Cellular and molecular basis of malignant astrocytoma

描述（由申请人提供）：星形细胞瘤是最常见的原发性脑肿瘤，占所有原发性中枢神经系统（CMS）肿瘤的60%以上。星形细胞瘤的最恶性形式（IV级星形细胞瘤），也称为多形性胶质母细胞瘤（GBM），是最具侵袭性的人类癌症之一，中位生存期小于1年。不幸的是，尽管神经外科、放疗和化疗取得了进展，但在过去的20年里，这种预后并没有显著改变。恶性星形细胞瘤的2个特征在定义疾病的致命性方面起着主要作用。首先，与大多数人类实体瘤不同，星形细胞瘤细胞即使在低级别阶段也会广泛侵入正常脑组织，这基本上阻止了手术治疗。其次，低级别星形细胞瘤有很高的倾向转化为GBM，这是抵抗所有目前的治疗方式。因此，治疗恶性星形细胞瘤的主要挑战之一是了解星形细胞瘤细胞高度侵袭性的细胞和分子基础。特别是，（1）大脑中何种细胞类型导致恶性星形细胞瘤仍然难以捉摸，（2）尽管最近在鉴定与恶性星形细胞瘤发展相关的遗传病变方面取得了进展，但关于特定遗传缺陷如何导致星形细胞瘤细胞的异常表型性状的见解出现得较慢。因此，在这个建议中描述的具体目标的目标是使用遗传，分子和细胞的方法来确定是否神经干细胞（NSC）在成人脑恶性星形细胞瘤的起源细胞。具体而言，我们将确定（1）肿瘤抑制因子p53和1型神经纤维瘤病（NF 1）是否在调节成人脑中NSC增殖、凋亡和分化中发挥生理作用，以及（2）当p53和NF 1突变特异性靶向成人脑中的NSC时，是否可以诱导恶性星形细胞瘤。

DESCRIPTION (provided by applicant): Astrocytomas are the most common primary brain tumors and account for more than 60% of all primary central nervous system (CMS) neoplasms. The most malignant form of astrocytoma (grade IV astrocytoma), also known as glioblastoma multiforme (GBM), is 1 of the most aggressive human cancers with a median survival of less than 1 year. Unfortunately, this prognosis has not changed significantly over the past 2 decades, despite advances in neurosurgery, radiation and chemotherapy. 2 characteristic features of malignant astrocytomas play a major role in defining the deadly nature of the disease. First, unlike most human solid tumors, astrocytoma cells extensively invade normal brain tissue even at the low-grade stage, which essentially prevents surgical cure. Second, low-grade astrocytomas have a high propensity to transform into GBMs, which are resistant to all of the current therapeutic modalities. Thus, 1 of the major challenges for treating malignant astrocytomas is to understand the cellular and molecular basis that underlies the highly invasive nature of astrocytoma cells. Particularly, (1) it remains elusive what cell type(s) in the brain gives rise to malignant astrocytoma, (2) insights have been slower to emerge regarding how the specific genetic defects contribute to the abnormal phenotypic traits of astrocytoma cells, despite recent advances in the identification of genetic lesions associated with the development of malignant astrocytomas. Thus, the goals of the specific aims described in this proposal is to use genetic, molecular and cellular approaches to determine whether neural stem cells (NSCs) in the adult brain are the cell-of-origin for malignant astrocytoma. Specifically, we will determine (1) whether tumor suppressors p53 and Neurofibromatosis type 1 (NF1) play physiological roles in regulating NSC proliferation, apoptosis and differentiation in the adult brain and (2) whether malignant astrocytoma can be induced when p53 and NF1 mutations are specifically targeted into NSCs in the adult brain.