Cancer Stem Cell Niche in Brain Tumors

描述（由申请人提供）：已经提出，罕见的，耐治疗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“生态位”的信号来进行自我更新。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自我更新，最近的研究发现，胶质母细胞瘤（GBM）的CSCs中Notch活性升高。我们最近的数据表明，在体外和体内，γ -分泌酶抑制剂抑制Notch通路可降低CD133的表达，并减少胶质母细胞瘤神经球的增殖。在目前的应用中，我们建议使用GBM神经球培养来确定Notch激活在CSCs中的机制和利基依赖性。具体来说，我们将试图确定Notch激活是由复制经典侧抑制过程的肿瘤细胞间的近胞嘧啶信号驱动的，还是由基质生态位信号驱动的，或者两者兼而有之。目的1 -确定Notch在CSCs中的激活是否由通过Notch配体在分化较好的肿瘤细胞中表达的近胞嘧啶信号介导。目的2 -通过向胶质母细胞瘤中的CSC提供Notch配体，确定内皮细胞是否具有CSC生态位的功能。目的3 -确定内皮细胞Notch活性的调节是否有助于GBM的非功能性微血管增殖。回答这些问题将促进新疗法的发展，并增强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.