GROWTH INHIBITION BY IL2 OF IL2R+ ORAL CARCINOMAS

说明(改编自《调查员摘要》)：应用程序为 旨在评估IL-2/IL-2R途径的作用，发现 在恶性肿瘤和正常组织中普遍表达，在生长中 口腔鳞癌(OSCC)细胞的调控。这些研究 在过去的三年中完成的表明IL-2是产生的，但 不分泌的，在人类口腔鳞癌可以检测到的ELISA水平上，而且它 肿瘤中生长激素和细胞凋亡保护因子的作用 细胞。这些细胞也表达功能性的IL-2R。外源性IL-2 NM浓度与其受体结合抑制口腔鳞癌生长 通过诱导细胞周期停滞于G0/G1期。其作用机制 负责内源性IL-2与 外源IL-2传递的负生长信号将被调查 用口腔鳞癌细胞系和小鼠口腔鳞状细胞癌异种移植模型进行体外和体内实验。 口腔鳞状细胞癌免疫抑制BALB/c裸鼠的建立 调查员的实验室。他们要检验的假设是 内源性IL-2通过下调IL-2在口腔鳞癌细胞中的作用 调控CDK细胞周期抑制因子的表达，同时外源性IL-2 通过破坏这一重要的内源性途径来干扰生长。 细胞周期蛋白、细胞周期蛋白激酶和细胞周期蛋白的表达、活性及转录调控 口腔鳞癌细胞中CDK抑制剂和Rb蛋白的磷酸化水平 反义IL-2或反义IL-2Rβ治疗组和未治疗组 对照细胞将被评估并与口腔鳞状细胞癌体内生长相关- 裸鼠异种移植。IL-2介导的肿瘤保护机制研究进展 通过调节Rb蛋白的状态防止细胞凋亡 将对磷酸化进行探讨。IL-2介导的细胞内途径 对肿瘤细胞的保护作用可能是通过调节 对Rb蛋白的磷酸化状态进行探讨。细胞内 白介素2和白介素2R的加工、定位和转运途径 肿瘤细胞将用共聚焦和免疫金电子技术进行研究 显微镜下确定外源性与内源性IL-2途径 在不同的细胞隔间中运行。对这一概念的理解 IL-2/IL-2R途径在肿瘤细胞中的调节作用 口腔鳞状细胞癌的新治疗干预机会不仅基于 论外源性IL-2对肿瘤生长的抑制作用 已知能够破坏IL-1的药物和/或生物制剂 2途径。

DESCRIPTION (Adapted from investigator's Abstract): The application is designed to evaluate the role of the IL-2/IL-2R pathway, found to be ubiquitously expressed in malignant and normal tissues, in growth regulation of oral squamous cell carcinoma (OSCC) cells. The studies completed in the last three years indicate that IL-2 is produced, but not secreted, at levels detectable in ELISA by human OSCC and that it functions as a growth hormone and apoptosis protection factor in tumor cells. These cells also express functional IL-2R. Exogenous IL-2 binding at nM concentrations to its receptor inhibits growth of OSCC cell lines by inducing cell cycle arrest in G0/G1. The mechanisms responsible for growth-promoting signals mediated by endogenous IL-2 vs. negative growth signals delivered by exogenous IL-2 will be investigated in vitro and in vivo, using both OSCC cell lines and xenograft model of OSCC immunosuppressed BALB/c nude mice established in the Prinicpal Investigator's laboratory. They hypothesis to be tested is that endogenous IL-2 acts as growth-promoting factor in OSCC cells by down- regulating expression of CDK cell cycle inhibitors, while exogenous IL-2 interferes with growth by disrupting this essential endogenous pathway. Expression, activity and transcriptional regulation of Cyclins, CDKs and CDK inhibitors and Rb protein phosphorylation levels in OSCC cells treated with antisense IL-2 or antisense IL-2Rbeta and in untreated control cells will be evaluated and related to growth in vivo in OSCC- xenografted nude mice. Mechanisms of IL-2 mediated protection of tumor cells from apoptosis possibly by regulation of the state of Rb protein phosphorylation will be probed. Intracellular pathways of IL-2 mediated protection of tumor cells from apoptosis possibly by regulation of the stat of Rb protein phosphorylation will be probed. Intracellular pathways of IL-2 and IL-2r processing, localization and trafficking in tumor cells will be studied by confocal and immunogold electron microscopy to determine whether exogenous vs. endogenous IL-2 pathways operate in distinct cellular compartments. Understanding of the regulatory role of the IL-2/IL-2R pathway in tumor cells provides opportunities for novel therapeutic interventions in OSCC based not only on arrest of tumor growth by exogenous IL-2 but also on the use of pharmacologic and/or biologic agents known to be able to disrupt the IL- 2 pathway.