Asymmetric Cell Division and Notch Signaling in Lung Cancer Stem Cells

描述(申请人提供)：肺癌是癌症死亡的主要原因，估计2008年美国有超过16万人死于肺癌；因此，对肺肿瘤细胞生物学的研究对于发现治疗这种疾病的新靶点至关重要。最近的证据表明，实体瘤只占肺癌干细胞的一小部分，这些干细胞是肿瘤的种子，可能是导致肿瘤转移和治疗抵抗的原因。肺癌干细胞如何进行自我更新和维持肿瘤生长的调控机制尚不清楚。在最近的实验中，人们确定了一小部分肺癌细胞不对称地分裂其模板DNA，并且这一过程被Notch途径抑制剂所废除。这一发现在正常和肿瘤细胞动态平衡研究中具有广泛的意义。这一建议的中心假设是，Notch信号通过维持不对称和对称分裂之间的动态平衡来调节肺癌干细胞库。目的是确定肺癌细胞的不对称分裂是否仅限于癌症干细胞部分，以及Notch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具体目标是研究不对称细胞分裂作为限制肺CSC池的基本机制。第二个目的是研究规范的Notch信号在肺癌细胞不对称分裂和CSC自我更新中的调节作用。这将通过分析Notch通路基因在不对称分裂的人类肺癌细胞中的表达，并针对已识别的蛋白质来破坏细胞的不对称分裂和自我更新的变化来实现。这项拟议的研究的基本原理是，一旦知道CSC池的自我更新受到控制不对称分裂的机制的调节，这些途径就可以在以后被治疗肺癌的新的创新方法作为药理学的靶点。 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，由于早期发现或靶向治疗，肺癌存活率的改善有限，五年存活率徘徊在微不足道的15%-20%。旨在揭开肺肿瘤维持方式的基本特性的研究可能会带来新的、更有效的治疗方法。

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.