POPULATION STABILITY IN TUMOR DORMANCY

肿瘤休眠，一种恶性肿瘤静止的状态， 已经被很好地记录了几种人类癌症。一个重要的 休眠的含义是，在某些情况下，恶性的 肿瘤可以受到生长抑制。小鼠BCL1淋巴瘤 系统提供了一种实验模型，其中休眠可以 可重复地建立和研究。先前的工作表明， 休眠是通过信号转导途径在这个系统中诱导的。 来源于膜免疫球蛋白(MIG)。在体外，参与 MIG诱导细胞周期停滞(CCA)，细胞周期进展和 细胞凋亡，以及Lyn和Syk酪氨酸激酶的激活。在……里面 此外，在Long和Long中，淋巴瘤细胞数量保持不变 在长期培养和休眠动物中，表明细胞周期 进展必须通过细胞死亡来平衡。我们的工作假设是 I)LYN的激活对于CCA响应和Syk对于 凋亡反应；ii)细胞周期进程和凋亡 在这些单元中相互连接；iii)这种连接导致 一个子细胞死亡而另一个子细胞死亡的不对称细胞分裂 在细胞周期中继续进行；iv)这种平衡是 对体内肿瘤休眠至关重要。 这个项目的具体目标是：1.确定关系 CCA、细胞周期进程、细胞凋亡和种群稳定性 在抗Ig治疗的淋巴瘤培养中。2.确定余额是否 导致人口长期稳定的增长和死亡之间的关系 在文化上是通过在两个随机的 种群中的过程或涉及不对称的定向过程 细胞分裂。3.改变BCL1.3B3中Syk和Lyn激酶的活性 并确定对CCA、细胞周期进程、细胞凋亡和 体外种群稳定性。4.确定Syk中的更改如何 而Lyn激酶活性影响诱导、维持和逃逸 在活体内休眠。 我们研究的长期目标是-识别信号 转导级联反应控制细胞凋亡和细胞周期进程， 确定这些过程与体内肿瘤的关系 生长(尤其是肿瘤休眠，这是一种相对未经探索的临床 问题)，并利用这些知识进行改进的设计 治疗方法。此外，人口有可能 稳定性由不对称的细胞分裂决定，平衡生长和 死亡是一种新事物，对理解肿瘤具有重要意义 从根本上控制增长和正常的人口动态平衡。

Tumor dormancy, a state in which a malignant tumor becomes quiescent, has been well documented for several human cancers. An important implication of dormancy is that under certain circumstances a malignant tumor can be brought under growth restraint. The mouse BCL1 lymphoma system provides an experimental model in which dormancy can be reproducibly established and investigated. Previous work indicates that dormancy is induced in this system through signal transduction pathways originating from membrane immunoglobulin (mIg). In vitro, engagement of mIg induces cell cycle arrest (CCA), cell cycle progression and apoptosis, and the activation of the Lyn and Syk tyrosine kinases. In addition, the lymphoma cell population remains constant both in long term cultures and in dormant animals, indicating that cell cycle progression must be balanced by cell death. Our working hypotheses are that i) activation of Lyn is important for the CCA response and Syk for the apoptotic response; ii) cell cycle progression and apoptosis are interconnected in these cells; iii) this connection results in an asymmetric cell division in which one daughter cell dies while the other continues to progress through the cell cycle; iv) this balance is essential for tumor dormancy in vivo. The specific aims of this project are: 1. To determine the relationship between CCA, cell cycle progression, apoptosis and population stability in anti-Ig-treated lymphoma cultures. 2. To determine if the balance between growth and death that results in long term population stability in culture is achieved by an overall balance between two stochastic processes in the population or as directed process involving asymmetric cell division. 3. To alter Syk and Lyn kinase activities in BCL1.3B3 and determine effects on CCA, cell cycle progression, apoptosis and population stability in vitro. 4. To determine how alterations in Syk and Lyn kinase activities affect the induction, maintenance and escape of dormancy in vivo. The long term objectives of our studies are - to identify signal transduction cascades controlling apoptosis and cell cycle progression, to determine the relationship between these processes and in vivo tumor growth (especially tumor dormancy, a relatively unexplored clinical problem), and to use this knowledge for the design of improved therapeutic approaches. In addition, the possibility that population stability is dictated by asymmetric cell division balancing growth and death is novel and has important implications for understanding tumor growth control and normal population homeostasis at a fundamental level.