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.
Colorectal cancer is a major public health problem and we propose to investigate how events such as inflammation and a gene mutation that is common in this disease affect the initiation and progression of colorectal cancer through a growth promoting receptor called EGFR.
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