Modulation of EGFR signaling by lipid mediators in colon carcinogenesis

结肠癌发生过程中脂质介质对 EGFR 信号传导的调节

• 批准号: 8234101
• 负责人: MATTHEW KENT TOPHAM
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8234101
• 关键词: Adenomatous Polyposis Coli; Affect; Cell Proliferation; Cells; Clinical; Clinical Research; Colon; Colon Carcinoma; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Disease; Disease model; Enzymes; Epidermal Growth Factor Receptor; Event; G-Protein-Coupled Receptors; Gene Mutation; General Population; Genes; Genetically Engineered Mouse; Goals; Growth; Human Cell Line; Immune; In Vitro; Inflammation; Intestines; KRAS2 Gene Mutation; KRAS2 gene; Laboratories; Lead; Ligands; Link; Lipids; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Oncogenic; PTGS2 gene; Pathogenesis; Pathway interactions; Phospholipids; Platelet Activating Factor; Production; Prostaglandins; Prostaglandins E; Public Health; Receptor Activation; Receptor Inhibition; Receptor Signaling; Recruitment Activity; Severity of illness; Signal Pathway; Signal Transduction; Site; System; Testing; Transactivation; Tretinoin; Tumor Suppressor Proteins; Zebrafish; base; cancer cell; carcinogenesis; colon carcinogenesis; in vivo; lipid mediator; mouse model; novel; platelet activating factor receptor; receptor; response; therapeutic target; tumor; tumor growth; tumorigenesis

This project is centered on the characterization of the mechanisms by which the tumor suppressor APC impacts epidermal growth factor receptor (EGFR) activation through two lipid signaling axes¿prostaglandin E{2} (PGE{2}) and platelet-activating factor (PAF). Additionally, we will study how EGFR signals elicited by one or both of these axes affect colorectal carcinogenesis (CRC). Our first goal is to assess whether APC mutations activate EGFR through the PGE{2} axis. Our second goal is to determine the efficacy of combined inhibition of COX-2 and EGFR in a mouse model of colorectal tumorigenesis that accurately reflects CRC in the general population. This sub-aim mirrors our clinical study in Project 1. We will use mice that harbor oncogenic mutations in APC and also in KRAS, a commonly mutated gene that synergizes with mutated APC to increase disease severity. We hypothesize that both COX-2 and EGFR are critical for tumorigenesis in this context, so both of them must be inhibited in order to effectively treat tumors in the compound mutant mice. Third, we will test the hypothesis that lipid signals derived from activated immune cells and/or cancer cells participate in the pathogenesis of CRC, using in vitro and in vivo approaches. We will focus our studies on events mediated by phospholipid ligands of the platelet-activating factor (PAF) receptor (PAFR), a G protein-coupled receptor controlled by APC and that can activate EGFR in related systems. We hypothesize that signals generated following engagement of E-Prostanoid receptors and PAFR result in intestinal transactivation of EGFR, leading to the stimulation of cellular proliferation. Our Specific Aims are: Aim 1: Dissect the signaling pathways linking APC to EGFR. Aim 2: Test the hypothesis that COX-2 and EGFR are critical for colorectal tumorigenesis in mice that harbor mutations in both APC and KRAS. Aim 3: Assess the impact of the platelet-activating factor/oxidized phospholipid (PAF/OxPL) axis on oncogenic responses. Aim 4: Determine if enhanced signaling by PAF/OxPL affects colon tumorigenesis in vivo.

该项目的重点是肿瘤抑制剂APC通过两个脂质信号轴？前列腺素E{2}（PGE{2}）和血小板活化因子（PAF）影响表皮生长因子受体（EGFR）活化的机制的表征。此外，我们将研究EGFR信号如何引起的一个或两个轴影响结直肠癌（CRC）。我们的第一个目标是评估APC突变是否通过PGE{2}轴激活EGFR。我们的第二个目标是确定联合抑制考克斯-2和EGFR在结直肠肿瘤发生的小鼠模型中的疗效，该模型准确地反映了一般人群中的CRC。该子目标反映了我们在项目1中的临床研究。我们将使用在APC和KRAS中携带致癌突变的小鼠，KRAS是一种常见的突变基因，与突变的APC协同作用，增加疾病的严重程度。我们假设，在这种情况下，考克斯-2和EGFR都是肿瘤发生的关键，因此必须抑制它们两者才能有效地治疗复合突变小鼠的肿瘤。第三，我们将测试来自激活的免疫细胞和/或癌症的脂质信号的假设， 细胞参与CRC的发病机制，使用体外和体内方法。我们将集中研究血小板活化因子（PAF）受体（PAFR）的磷脂配体介导的事件，PAFR是一种由APC控制的G蛋白偶联受体，可以激活相关系统中的EGFR。我们推测，E-前列腺素受体和PAFR参与后产生的信号导致EGFR在肠道的反式激活，导致细胞增殖的刺激。我们的具体目标是： 目的1：研究APC与EGFR之间的信号通路。 目的2：检验考克斯-2和EGFR对APC和KRAS突变小鼠的结直肠肿瘤发生至关重要的假设。 目的3：评估血小板活化因子/氧化磷脂（PAF/OxPL）轴对致癌反应的影响。 目的4：确定PAF/OxPL增强的信号传导是否影响体内结肠肿瘤发生。