Modulation of EGFR signaling by lipid mediators in colon carcinogenesis

本项目主要研究肿瘤抑制因子APC通过前列腺素E{2}(PGE{2})和血小板活化因子(PAF)两个脂质信号轴影响表皮生长因子受体(EGFR)活化的机制。此外，我们将研究由这两个轴中的一个或两个所引发的EGFR信号如何影响结直肠癌的发生(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COX-2和EGFR在结直肠癌发生的小鼠模型中的有效性，该模型准确地反映了普通人群中的结直肠癌。这个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中存在癌基因突变的小鼠，KRAS是一种常见的突变基因，与突变的APC协同作用可以增加疾病的严重性。我们假设COX-2和EGFR在这种情况下对肿瘤的发生都是关键的，所以必须同时抑制它们才能有效地治疗复合突变小鼠的肿瘤。第三，我们将检验这样一种假设，即脂质信号来自激活的免疫细胞和/或癌症 利用体外和体内方法，细胞参与了结直肠癌的发病机制。我们将集中研究血小板激活因子受体(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，可以在相关系统中激活EGFR。我们推测，E-前列腺素受体和PAFR结合后产生的信号导致肠道内EGFR的反式激活，从而刺激细胞增殖。我们的具体目标是： 目的1：剖析连接APC和EGFR的信号通路。 目的2：在同时含有APC和KRAS突变的小鼠中，验证COX-2和EGFR在结直肠肿瘤发生中起关键作用的假设。 目的3：探讨血小板活化因子/氧化磷脂(PAF/OxPL)轴对肿瘤反应的影响。 目的4：确定PAF/OxPL信号增强是否影响体内结肠肿瘤的发生。

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.