EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis.
Authors Hardbower DM, Coburn LA, Asim M, Singh K, Sierra JC, Barry DP, Gobert AP,
Piazuelo MB, Washington MK, Wilson KT
Submitted By Submitted Externally on 7/27/2017
Status Published
Journal Oncogene
Year 2017
Date Published 7/1/2017
Volume : Pages 36 : 3807 - 3819
PubMed Reference 28263971
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)-?, tumor necrosis factor (TNF)-a and IL-1ß 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.