Asymmetric Cell Division and Notch Signaling in Lung Cancer Stem Cells

肺癌干细胞中的不对称细胞分裂和Notch信号传导

• 批准号: 7892613
• 负责人: Sharon R. Pine
• 金额: $ 17.96万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892613
• 关键词: Cancer Etiology; Cancer cell line; Cell Division Process; Cell Fraction; Cell division; Cell physiology; Cells; Cessation of life; Colony-Forming Units Assay; DNA; Development; Disease; Down-Regulation; Drug Delivery Systems; Early Diagnosis; Equilibrium; Frequencies; Genes; Goals; Homeostasis; Human; Lead; Lung; Lung Neoplasms; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Molecular Profiling; NOD/SCID mouse; Nature; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Pathway interactions; Pharmaceutical Preparations; Phenotype; Population; Primary Neoplasm; Process; Property; Proteins; RNA; Reporting; Research; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Seeds; Series; Side; Signal Transduction; Solid Neoplasm; Specimen; Stem cells; Surface; Survival Rate; Testing; Therapeutic; Tissues; Tumor Biology; Tumor Cell Biology; Tumor Cell Line; United States; Work; cancer cell; cancer stem cell; clinical application; daughter cell; design; in vivo; inhibitor/antagonist; innovation; neoplastic cell; new therapeutic target; notch protein; novel; research study; self-renewal; stem cell niche; stem cell population; therapy resistant; tumor; tumor growth; tumor initiation

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer death and is estimated to claim over 160,000 lives in the United States in 2008; thus, the study of lung tumor cell biology is critical for discovering novel targets to treat the disease. Recent evidence suggests that solid tumors comprise a small fraction of lung cancer stem cells that seed the tumor bulk and may be responsible for metastases and resistance to therapy. The mechanisms regulating how lung cancer stem cells undergo self-renewal and maintain tumor growth are unknown. In recent experiments, it was determined that a small fraction of lung cancer cells asymmetrically divide their template DNA, and that the process is abrogated by Notch pathway inhibitors. This finding has broad implications in normal and tumor cell homeostasis research. The central hypothesis of this proposal is that Notch signaling regulates the lung cancer stem cell pool by maintaining a dynamic balance between asymmetric and symmetric divisions. The objectives are to determine if asymmetrically dividing lung cancer cells are restricted to the cancer stem cell fraction and if Notch signaling regulates asymmetric cell division in lung cancer. The first specific aim to achieve these objectives is to study asymmetric cell division as a fundamental mechanism restricted to the lung CSC pool. The second aim is to investigate canonical Notch signaling as a regulator of asymmetric cell division and CSC self-renewal in lung cancer. This will be achieved by expression analysis of Notch pathway genes in asymmetrically dividing human lung cancer cells, and targeting of identified proteins for disruption of asymmetric cell division and alterations in self-renewal. The rationale of the proposed research is that, once it is known that self-renewal of the CSC pool is regulated by mechanisms that control asymmetric division, those pathways can later be targeted pharmacologically by new and innovative approaches in the treatment of lung cancer. PUBLIC HEALTH RELEVANCE: Cancer of the lung is the leading cause of cancer deaths in the United States. For several decades, there has been limited improvement in lung cancer survival that is attributed to early detection or targeted therapy, and the five-year survival rate hovers at a meager 15-20%. Studies aimed at unraveling the fundamental properties governing how lung tumors are maintained may lead to novel and more efficacious therapies.

描述（由申请人提供）：肺癌是癌症死亡的主要原因，据估计在2008年在美国夺走了160,000多人的生命；因此，对肺部肿瘤细胞生物学的研究对于发现治疗该疾病的新靶标至关重要。最近的证据表明，实体瘤构成了一小部分肺癌干细胞，这些肺癌干细胞将肿瘤大量种植，并可能导致转移和对治疗的耐药性。调节肺癌干细胞如何进行自我更新和维持肿瘤生长的机制尚不清楚。在最近的实验中，确定一小部分的肺癌细胞不对称地划分了模板DNA，并且该过程被Notch途径抑制剂消除了。这一发现对正常和肿瘤细胞稳态研究具有广泛的影响。该提议的中心假设是Notch信号传导通过保持不对称和对称分裂之间的动态平衡来调节肺癌干细胞池。这些目标是确定不对称分裂的肺癌细胞是否仅限于癌症干细胞部分，以及凹口信号是否调节肺癌中的不对称细胞分裂。实现这些目标的第一个特定目的是研究不对称的细胞分裂，作为仅限于肺CSC库的基本机制。第二个目的是研究规范缺口信号传导，作为肺癌中不对称细胞分裂和CSC自我更新的调节剂。这将通过对不对称分裂的人类肺癌细胞中Notch途径基因的表达分析以及靶向鉴定蛋白的靶向破坏不对称细胞分裂和自我更新的改变。拟议的研究的理由是，一旦知道CSC池的自我更新受控制不对称分裂的机制的调节，这些途径后来可以通过治疗肺癌治疗的新的创新方法来针对药理学。 公共卫生相关性：肺癌是美国癌症死亡的主要原因。几十年来，肺癌存活率的改善有限，这归因于早期检测或靶向治疗，而五年生存率则徘徊在15-20％的微薄。旨在阐明管理如何维持肺部肿瘤的基本特性的研究可能会导致新颖，更有效的疗法。