Cancer Stem Cell Niche in Brain Tumors

描述(由申请人提供)：有人提出，罕见的、耐药的肿瘤干细胞对肿瘤的长期生长至关重要。正常的干细胞需要来自基质“壁龛”的信号才能自我更新。然而，这种小生境信号在调节癌症干细胞(CSCs)中的作用在很大程度上是未知的。Notch信号通路调节神经干细胞的自我更新，最近的研究发现胶质母细胞瘤中的CSCs具有较高的Notch活性。我们最近的数据显示，伽马分泌酶抑制剂抑制Notch通路减少了CD133的表达，并减少了胶质母细胞瘤神经球在体外和体内的生长。在目前的应用中，我们建议使用GBM神经球培养来确定CSCs中Notch激活的机制和生态位依赖性。具体地说，我们将试图确定Notch激活是由复制经典的侧向抑制过程的肿瘤细胞之间的旁分泌信号驱动的，还是由间质生态位信号驱动的，还是两者兼而有之。目的1-确定CSCs中Notch的激活是否通过Notch配体在分化较好的肿瘤细胞中表达而由旁分泌信号所介导。AIM2-通过为胶质母细胞瘤中的CSC提供Notch配体，确定内皮细胞是否发挥CSC的功能。目的：确定内皮细胞中Notch活性的调节是否与GBM中无功能的微血管增殖有关。回答这些问题将有助于开发新的治疗方法，并增进我们对癌症干细胞生物学的理解。

DESCRIPTION (provided by applicant): It has been proposed that rare, treatment-resistant neoplastic stem cells are critical for long-term tumor growth. Normal stem cells require signals from a stromal "niche" to self-renew. However, the role of such niche-signals in regulating cancer stem cells (CSCs) is largely unknown. The Notch signaling pathway regulates neural stem cell self-renewal, and recent studies found that CSCs in glioblastoma (GBM) have elevated Notch activity. Our recent data shows that Notch pathway inhibition by gamma-secretase inhibitors reduced CD133 expression and reduces glioblastoma neurosphere propagation both in vitro and in vivo. In the current application, we propose using GBM neurosphere cultures to determine the mechanism and niche-dependence of Notch activation in CSCs. Specifically, we will seek to determine if Notch activation is driven by juxtacrine signaling between tumor cells replicating the classical process of lateral inhibition, by stromal niche signals, or both. Aim1 - Determine if activation of Notch in CSCs is mediated by juxtacrine signaling via Notch ligands expressed in better-differentiated tumor cells. Aim2 - Define if the endothelial cells function as CSC niche by providing Notch ligands to CSCs in glioblastoma. Aim3 - Determine if regulation of Notch activity in endothelial cells contributes to the non-functional microvascular proliferation in GBM. Answering these questions will facilitate the development of novel therapies and enhance our understanding of cancer stem cell biology.