IN VITRO STUDIES OF HUMAN MESOTHELIAL CELLS

人间皮细胞的体外研究

• 批准号: 6160931
• 负责人: B I GERWIN
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6160931
• 关键词: DNA damage; asbestos; cell cell interaction; clone cells; environment related neoplasm /cancer; gene expression; gene induction /repression; genetic promoter element; growth factor receptors; human genetic material tag; human tissue; mesothelioma; neoplasm /cancer genetics; neoplastic process; platelet derived growth factor; receptor expression; tumor suppressor genes

It is the goal of this project to determine how the interaction of mesothelial cells with the fiber carcinogen, asbestos, leads to the development of mesothelioma. We have previously shown that mesotheliomas over express PDGF-A. We have further shown that T antigen-immortalized human mesothelial cells become tumorigenic after transfection with an expression vector for PDGF-A. A mechanistic understanding of this tumorigenic conversion became problematic when it was reported that the PDGF-alpha receptor was not expressed in mesothelioma cell lines. We have investigated the expression of the two receptors for PDGF. Results show that the PDGFR-alpha is expressed in mesotheliomas but at a level much below that of normal mesothelial cells. Furthermore, in experiments with normal mesothelial cells which express the PDGF-alpha receptor at high levels, we showed that treatment with PDGF-A, as expected, decreased receptor expression. Initial experiments using suramin to block cell surface ligand-receptor interactions in mesothelioma suggest that this is part of the explanation for the down regulation of this receptor. The finding that residual receptor is expressed suggests that this amount of receptor, when fully activated by autocrine ligand, may contribute significantly to oncogenic pathways of signal transduction. In additional experiments, we are treating mesothelial cells, in vitro, with asbestos. We have repeated the finding that this treatment generates mesothelial cell populations with extended life span. We are characterizing these populations with respect to genes which have recently been implicated in senescence and immortalization and are lost in mesothelioma.

该项目的目标是确定如何交互 间皮细胞与纤维致癌物石棉会导致 间皮瘤的发展。我们之前已经证明间皮瘤 过度表达PDGF-A。我们进一步证明T抗原永生化 人间皮细胞转染后可致瘤 PDGF-A的表达载体。对此的机械理解 当有报道称，致瘤性转化成为问题 PDGF-α受体在间皮瘤细胞系中不表达。我们 研究了PDGF 的两种受体的表达。结果 表明 PDGFR-α 在间皮瘤中表达，但表达水平 远低于正常间皮细胞。此外，在实验中 与表达 PDGF-α 受体的正常间皮细胞 高水平，我们表明用 PDGF-A 治疗，正如预期的那样， 受体表达减少。初步实验使用苏拉明 间皮瘤中阻断细胞表面配体-受体相互作用表明 这是该下调的部分解释 受体。残余受体表达的发现表明 当自分泌配体完全激活时，这一数量的受体可能 对信号转导的致癌途径有显着贡献。 在其他实验中，我们正在体外治疗间皮细胞， 与石棉。我们重复了这一发现，这种治疗 产生寿命延长的间皮细胞群。我们是 描述这些群体的基因特征 最近因衰老和永生而失落 在间皮瘤中。