Cancer Stem Cell Niche in Brain Tumors

脑肿瘤中的癌症干细胞生态位

• 批准号: 8685180
• 负责人: Xing Fan
• 金额: $ 31.3万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685180
• 关键词: Adult; American; Biology; Blocking Antibodies; Brain Neoplasms; Cancer Patient; Capillary Endothelial Cell; Cell physiology; Cells; Data; Dependence; Development; Diagnosis; Disease; Endothelial Cells; Environment; Glioblastoma; Goals; Growth; In Vitro; Knowledge; Lateral; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Microvascular Proliferation; Molecular; Mus; Neoplasms; Notch Signaling Pathway; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Population; Primary Brain Neoplasms; Process; Radiation therapy; Regulation; Research; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Testing; Tumor Stem Cells; Work; Xenograft procedure; base; cancer stem cell; cancer type; cell behavior; gamma secretase; improved; in vivo; inhibitor/antagonist; innovation; neoplastic cell; nerve stem cell; notch protein; novel; novel therapeutics; outcome forecast; prevent; self-renewal; stem; stem cell biology; stem cell niche; tumor; tumor growth; tumor microenvironment

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.

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。