Cancer Stem Cell Niche in Brain Tumors

描述（由申请人提供）：已提出罕见的耐药肿瘤干细胞对长期肿瘤生长至关重要。正常的干细胞需要来自基质“小生境”的信号来自我更新。然而，这种小生境信号在调节癌症干细胞（CSC）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（GBM）中的CSC具有升高的Notch活性。我们最近的数据表明，通过γ-分泌酶抑制剂抑制Notch途径降低了CD 133表达，并减少了体外和体内胶质母细胞瘤神经球的增殖。在本申请中，我们提出使用GBM神经球培养物来确定CSC中Notch激活的机制和小生境依赖性。具体而言，我们将试图确定Notch激活是否是由肿瘤细胞之间的阿曲他克林信号传导（复制经典的侧抑制过程）、基质生态位信号或两者驱动的。目的1-确定CSC中Notch的激活是否由阿曲他克林信号转导介导，该信号转导通过在分化较好的肿瘤细胞中表达的Notch配体进行。目的2-定义内皮细胞是否通过向胶质母细胞瘤中的CSC提供Notch配体而作为CSC龛发挥功能。目的3-确定内皮细胞中Notch活性的调节是否有助于GBM中的非功能性微血管增殖。 解决这些问题将有助于开发新的治疗方法，并增强我们对癌症干细胞生物学的理解。 公共卫生相关性：胶质母细胞瘤是成人最恶性的脑肿瘤，在过去的三十年里没有成功的治疗。该提案的目标是了解一个重要的肿瘤微环境（癌症干细胞生态位）如何调节胶质母细胞瘤起始细胞，以便为这种致命疾病开发一种新的治疗策略。

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. PUBLIC HEALTH RELEVANCE: Glioblastoma is the most malignant brain tumor in adult with no successful treatment during the past thirty years. The goal of this proposal is to understand how an important tumor micro-environment (cancer stem cell niche) regulates glioblastoma initiating cells in order to develop a novel therapeutic strategy for this deadly disease.