A Role for the Epidermal Growth Factor Receptor Signaling in Development of Intestinal Serrated Polyps in Mice and Humans

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 143; no. 3; pp. 730 - 740
• Main Authors: Bongers, Gerold, Muniz, Luciana R, Pacer, Michelle E, Iuga, Alina C, Thirunarayanan, Nanthakumar, Slinger, Erik, Smit, Martine J, Reddy, E. Premkumar, Mayer, Lloyd, Furtado, Glaucia C, Harpaz, Noam, Lira, Sergio A
• Format: Journal Article
• Language: English
• Published: United States 01-09-2012
• Subjects: Adenoma - genetics; Adenoma - metabolism; Adenoma - pathology; Adenoma - prevention & control; Animals; Blotting, Western; Caco-2 Cells; Colonoscopy; Enzyme Activation; Gastroenterology and Hepatology; Heparin-binding EGF-like Growth Factor; Humans; Hyperplasia; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intestinal Mucosa - drug effects; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestinal Neoplasms - genetics; Intestinal Neoplasms - metabolism; Intestinal Neoplasms - pathology; Intestinal Neoplasms - prevention & control; Intestinal Polyps - genetics; Intestinal Polyps - metabolism; Intestinal Polyps - pathology; Intestinal Polyps - prevention & control; Ligands; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Mutation; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - metabolism; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Recombinant Fusion Proteins - metabolism; Signal Transduction - drug effects; Transfection; hyperplastic polyps; intestinal epithelial cells; HB-EGF; mutL homolog 1; HPP; mRNA; mitogen-activated protein kinase kinase 1; ERBB; EGFR; GFP; mitogen-activated protein kinase; messenger RNA; Colon Cancer; qPCR; SSA/P; WT; G protein-coupled receptor; TSA; MGMT; v-raf murine sarcoma viral oncogene homolog B1; epidermal growth factor receptor; IEC; quantitative polymerase chain reaction; BRAF; receptor tyrosine-protein kinase erbB; O-6-methylguanine-DNA methyltransferase; traditional serrated adenomas; MAPK; MLH1; green fluorescent protein; Neoplasm; MEK; p-ERK1/2; bromodeoxyuridine; Heparin-binding EGF-like growth factor; v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; GPCR; KRAS; wild type; Colorectal Tumorigenesis; phospho-ERK1/2; BrdU; sessile serrated adenoma/polyps
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2012.05.034

Background & Aims Epithelial cancers can be initiated by activating mutations in components of the mitogen-activated protein kinase signaling pathway such as v-raf murine sarcoma viral oncogene homolog B1 (BRAF), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), or epidermal growth factor receptor (EGFR). Human intestinal serrated polyps are a heterogeneous group of benign lesions, but some progress to colorectal cancer. Tumors that arise from these polyps frequently contain activating mutations in BRAF or KRAS, but little is known about the role of EGFR activation in their development. Methods Polyp samples were obtained from adults during screening colonoscopies at Mount Sinai Hospital in New York. We measured levels of EGFR protein and phosphorylation in human serrated polyps by immunohistochemical and immunoblot analyses. We generated transgenic mice that express the ligand for EGFR, Heparin-binding EGF-like growth factor (HB-EGF), in the intestine. Results EGFR and the extracellular-regulated kinases (ERK)1/2 were phosphorylated in serrated areas of human hyperplastic polyps (HPPs), sessile serrated adenomas, and traditional serrated adenomas. EGFR and ERK1/2 were phosphorylated in the absence of KRAS or BRAF activating mutations in a subset of HPP. Transgenic expression of the EGFR ligand HB-EGF in the intestines of mice promoted development of small cecal serrated polyps. Mice that expressed a combination of HB-EGF and US28 (a constitutively active, G-protein–coupled receptor that increases processing of HB-EGF from the membrane) rapidly developed large cecal serrated polyps. These polyps were similar to HPPs and had increased phosphorylation of EGFR and ERK1/2 within the serrated epithelium. Administration of pharmacologic inhibitors of EGFR or MAPK to these transgenic mice significantly reduced polyp development. Conclusions Activation of EGFR signaling in the intestine of mice promotes development of serrated polyps. EGFR signaling also is activated in human HPPs, sessile serrated adenomas, and traditional serrated adenomas.