A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans.
OBJECTIVE
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.
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Gerold
G
Bongers
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Luciana R
LR
Muniz
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Michelle E
ME
Pacer
Division of Gastrointestinal Pathology, Department of Pathology, The Mount Sinai Medical Center, New York, New York.
Alina C
AC
Iuga
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Nanthakumar
N
Thirunarayanan
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Erik
E
Slinger
Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Faculty of Sciences, VU University Amsterdam, Amsterdam, The Netherlands.
Martine J
MJ
Smit
Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York.
E Premkumar
EP
Reddy
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Lloyd
L
Mayer
Immunology Institute, Mount Sinai School of Medicine, New York, New York.
Glaucia C
GC
Furtado
Division of Gastrointestinal Pathology, Department of Pathology, The Mount Sinai Medical Center, New York, New York.
Noam
N
Harpaz
Immunology Institute, Mount Sinai School of Medicine, New York, New York. Electronic address: sergio.lira@mssm.edu.
Sergio A
SA
Lira
D000236:Adenoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D015153:Blotting, Western; D018938:Caco-2 Cells; D003113:Colonoscopy; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D007417:Intestinal Polyps / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D018631:ras Proteins / Q000235:genetics
C587883:HBEGF protein, human; C587884:Hbegf protein, mouse; C587885:Hbegf protein, rat; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; C117307:KRAS protein, human; D008024:Ligands; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins