ACTIVATION OF C SRC IN PANCREATIC CANCER BY FGFR 1B

描述（申请人的描述）：胰腺癌是最常见的癌症之一。 医学上常见的致命肿瘤在诊断出这种情况后， 预期少于4%的患者存活超过5年。理解 胰腺肿瘤细胞恢复力需要阐明 机制 调节瘤形成过程中的细胞生长和转化。 该实验室和其他实验室正在进行的研究已经确定了增强的 FGF配体的出现，FGF受体的可变剪接同种型 （FGFR-1 β）iNOS和总硝基酪氨酸。初步 研究表明，通过FGFR-1 β激活的FGF信号可以促进 胰腺上皮细胞的生长和存活 化疗、放疗和过氧亚硝基阴离子（ONOO-）凋亡， 观察伴随着含有活化的c-Src的出现， 磷酸化和硝化的酪氨酸残基。 这些观察意味着 ONOO和FGF信号在肿瘤生长中的关键相互依赖作用 和转移行为。实验目标在框架内设计 临床上具有侵袭性的化疗和放射抵抗性的 胰腺癌的特点是相互依赖的后果， 活性氮物质和配体活化的FGFR-1 β向c- Src. 一个基本的主题包括量化生产和目标 对ONOO调节FGF/FGFR-1 β信号转导的分子应答 途径。 特定分子试剂的可用性， 技术，确定的人类和大鼠细胞群，相关啮齿动物模型， 和临床标本允许基本的机制研究，以阐明 负责因果关系的分子事件 氧化应激和FGF生物学之间的联系这些的详细特征 相互关系应提供监测这一点的诊断标准 毁灭性的疾病，并确定合理的战略，以打击胰腺癌 癌

DESCRIPTION (Applicant's Description): Pancreatic cancer is one of the most lethal tumors seen in medicine today. Following diagnosis of this condition, less than 4% of patients are expected to survive beyond 5 years. Understanding the resilience of pancreatic tumor cells will require elucidation of molecular mechanisms regulating cell growth anc transformation during neoplasia. Ongoing studies in this and other laboratories have identified the enhanced appearance of FGF ligands, an alteratively spliced isoform of the FGF receptor (FGFR-1beta) iNOS and total nitrotyrosine in target polypeptides. Preliminary studies demonstrate that FGF-activated signaling through FGFR-1beta promotes growth and the survival of pancreatic epithelial cells in response to chemotherapy, radiation treatment and peroxynitrite (ONOO-) apoptosis, an observation accompanied by the appearance of activated c-Src containing phosphorylated and nitrated tyrosine residues. These observations imply pivotal interdependent roles for ONOO and FGF signaling during tumor growth and metastatic behavior. Experimental aims are designed within the framework of the hypothesis that the clinically aggressive chemo- and radio-resistant features of pancreatic adenocarcinoma are the consequences of interdependent signaling of reactive nitrogen species and ligand-activated FGFR-1beta to c- Src. An underlying theme includes quantitating the production and targeted molecular responses to ONOO that modulate FGF/FGFR-1beta signal transduction pathways. The availability of specific molecular reagents, established techniques, defined human and rat cell populations, relevant rodent models, and clinical specimens permits fundamental mechanistic studies to elucidate molecular events responsible for the cause and effect interrelationship between oxidant stress and FGF biology. Detailed characteristics of these interrelationships should provide diagnostic criteria for monitoring this devastating disease and identify rational strategies to combat pancreatic cancer.