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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA073992-15
Application #
8627125
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
15
Fiscal Year
2014
Total Cost
$279,869
Indirect Cost
$77,832
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Delker, Don A; McGettigan, Brett M; Kanth, Priyanka et al. (2014) RNA sequencing of sessile serrated colon polyps identifies differentially expressed genes and immunohistochemical markers. PLoS One 9:e88367
Samadder, N Jewel; Curtin, Karen; Tuohy, Thérèse M F et al. (2014) Characteristics of missed or interval colorectal cancer and patient survival: a population-based study. Gastroenterology 146:950-60
Tuohy, Therese M F; Rowe, Kerry G; Mineau, Geraldine P et al. (2014) Risk of colorectal cancer and adenomas in the families of patients with adenomas: a population-based study in Utah. Cancer 120:35-42
Stafforini, Diana M; McIntyre, Thomas M (2013) Determination of phospholipase activity of PAF acetylhydrolase. Free Radic Biol Med 59:100-7
Hammoud, Saher Sue; Cairns, Bradley R; Jones, David A (2013) Epigenetic regulation of colon cancer and intestinal stem cells. Curr Opin Cell Biol 25:177-83
Matsumiya, Tomoh; Xing, Fei; Ebina, Masayuki et al. (2013) Novel role for molecular transporter importin 9 in posttranscriptional regulation of IFN-ýý expression. J Immunol 191:1907-15
Sandoval, Imelda T; Manos, Elizabeth J; Van Wagoner, Ryan M et al. (2013) Juxtaposition of chemical and mutation-induced developmental defects in zebrafish reveal a copper-chelating activity for kalihinol F. Chem Biol 20:753-63
Teixeira-da-Cunha, Mariana G A; Gomes, Rachel N; Roehrs, Nathassia et al. (2013) Bacterial clearance is improved in septic mice by platelet-activating factor-acetylhydrolase (PAF-AH) administration. PLoS One 8:e74567
Xu, Changxin; Reichert, Ethan C; Nakano, Tomoyuki et al. (2013) Deficiency of phospholipase A2 group 7 decreases intestinal polyposis and colon tumorigenesis in Apc(Min/+) mice. Cancer Res 73:2806-16
Jasperson, Kory W; Kanth, Priyanka; Kirchhoff, Anne C et al. (2013) Serrated polyposis: colonic phenotype, extracolonic features, and familial risk in a large cohort. Dis Colon Rectum 56:1211-6

Showing the most recent 10 out of 82 publications