A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans

Gastroenterology. 2012 Sep;143(3):730-740. doi: 10.1053/j.gastro.2012.05.034. Epub 2012 May 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenoma / metabolism*
  • Adenoma / pathology
  • Adenoma / prevention & control
  • Animals
  • Blotting, Western
  • Caco-2 Cells
  • Colonoscopy
  • Enzyme Activation
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • 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)
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction* / drug effects
  • Transfection
  • ras Proteins / genetics


  • HBEGF protein, human
  • Hbegf protein, mouse
  • Hbegf protein, rat
  • Heparin-binding EGF-like Growth Factor
  • Intercellular Signaling Peptides and Proteins
  • KRAS protein, human
  • Ligands
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Receptors, G-Protein-Coupled
  • Recombinant Fusion Proteins
  • EGFR protein, human
  • EGFR protein, mouse
  • ErbB Receptors
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • MAPK1 protein, human
  • Mapk1 protein, mouse
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins