title: EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis.
abstract: Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31+blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Hardbower
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Coburn
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M
authors.initials: M
authors.lastname: Asim
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: K
authors.initials: K
authors.lastname: Singh
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Sierra
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Barry
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Gobert
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M B
authors.initials: MB
authors.lastname: Piazuelo
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Washington
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, USA.|Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.|Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: K T
authors.initials: KT
authors.lastname: Wilson
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000276:immunology / Q000378:metabolism*; D003092:Colitis / Q000473:pathology*; D003106:Colon / Q000276:immunology / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D016264:Dextran Sulfate; D066246:ErbB Receptors / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D008262:Macrophage Activation; D008264:Macrophages / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000378:metabolism; D011230:Precancerous Conditions / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016264:Dextran Sulfate; C541485:EGFR protein, mouse; D066246:ErbB Receptors