POPULATION STABILITY IN TUMOR DORMANCY

肿瘤休眠中的群体稳定性

• 批准号: 2896642
• 负责人: RICHARD H SCHEUERMANN
• 金额: $ 24.25万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2896642
• 关键词: SCID mouse; apoptosis; biological signal transduction; cell cycle; cell growth regulation; cell population study; cell proliferation; enzyme activity; flow cytometry; immunoprecipitation; laboratory mouse; lymphoma; mathematical model; neoplasm /cancer remission /regression; neoplastic process; polymerase chain reaction; protein tyrosine kinase; protooncogene; single cell analysis; tissue /cell culture; video microscopy; western blottings

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.

肿瘤休眠是指恶性肿瘤处于静止状态，