Inhibition of Fas-apoptosis in Gastric Cancer

逃避细胞凋亡或程序性细胞死亡的能力是在所有人类癌症中发现的六个特征之一。 凋亡抗性允许细胞绕过监测癌基因表达或基因组表达的常规检查点。 不稳定性，促进基因突变的积累，促进对放射性和化疗的抵抗， 疗法胃癌细胞凋亡抵抗的机制研究较少。内进行工程 在我的培训/过渡补助金CA 90518的时间定义了Fas信号转导在我们的良好建立的 螺杆菌感染/胃癌小鼠模型。我们确定了Fas介导的凋亡在细胞丢失中的作用， 和萎缩，并将获得性抵抗定义为化生和发育不良进展到胃粘膜， 腺癌实验诱导的Fas缺陷中的螺杆菌感染迅速导致侵袭性 胃腺癌证实了获得性耐药在癌症发生和发展中的作用。 这一发现引导我们研究胃粘膜细胞获得Fas的机制 阻力我们已经确定了胃粘膜中3种不同水平的获得性Fas抗性， 细胞凋亡并赋予化学抗性。这一提议的中心假设是Fas抵抗 介导的凋亡有助于胃腺癌的形成。在第一个具体目标中，我们将 使用体外和体内方法的组合来确定表面受体的需求 在决定线粒体依赖性和线粒体非依赖性Fas凋亡信号转导中的丰度， 定义MHCII分子和Fas通路之间的相互作用，强调脂质的完整性 筏结构和启动PKC和P13-K信号。在第二个具体目标中，我们将研究 决定FLICE/FLICE与FLIP/FLICE二聚体形成的细胞因子， DISC上的蛋白质，其激活Erk 1/2和NF-κ B并分析p38信号传导抑制。在我们的第三 具体的目的，我们将研究废除和/或恢复Fas凋亡信号在一个小组， 胃癌细胞株，并测试恢复Fas凋亡途径对肿瘤生长的体内意义 和对化疗的反应本提案中概述的研究将确定 胃粘膜细胞获得性Fas抵抗的机制。这些研究将提供关键的 深入了解旨在恢复肿瘤细胞内Fas敏感性的新型预防和抗癌策略 并为癌症治疗提供了新的方向。

The ability to evade apoptosis or programmed cell death is one of six traits found in all human cancers. Apoptosis resistance allows cells to bypass usual checkpoints that monitor oncogene expression or genomic instability, facilitating the accumulation of genetic mutations and promoting resistance to radio- and chemo- therapy. Mechanism of apoptosis resistance in gastric cancer are poorly studied. Work carried out during the time of my training/transition grant CA90518 defined a critical role for Fas signaling in our well established Helicobacter infection/gastric cancer mouse model. We defined a role for Fas mediated apoptosis in cell loss and atrophy, and defined an acquired resistance as metaplasia and dysplasia progressed to gastric adenocarcinoma. Helicobacter infection in experimentally induced Fas deficiency rapidly leads to invasive gastric adenocarcinoma substantiating a role for acquired resistance in cancer initiaiton and progression. This finding lead us to investigate the mechanisms through which gastric mucosal cells acquire Fas resistance. We have identified 3 distinct levels of acquired Fas resistance in the gastric mucosa which inhibit apoptosis and confer chemoresistance. The central hypothesis of this proposal is resistance to Fas mediated apoptosis contributes to gastric adenocarcinoma formation. In the first specific aim, we will use a combination of in vitro and in vivo approaches to define the requirement of surface receptor abundance in determining mitochondrial dependant and mitochondrial independent Fas apoptotic signaling, define the interaction between MHCII molecules and the Fas pathway, with an emphasis on integrity of lipid raft structures and initiation of PKC and P13-K signaling. In the second specific aim, we will investigate the cellular factors determining FLICE/FLICE vs FLIP/FLICE dimmer formation, the recruitment of adaptor proteins at the DISC which activate Erk1/2 and NF-KB and analyze p38 inhibitiion of signaling. In our third specific aim, we will investigate the abrogation and/or restoration of Fas-apoptotic signaling in a panel of gastric cancer cell lines and test the vivo significance of restoring the Fas apoptotic pathway on tumor growth and response to chemotherapy. The studies outlined in this proposal will determine the signaling mechanisms involved in acquired Fas resistance in gastric mucosal cells. These studies will provide critical insight into novel preventive, and anti-cancer strategies aimed at restoring Fas sensitivity within tumor cells and provide a new direction for cancer treatment.