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2017 ; 36
(27
): 3807-3819
Nephropedia Template TP
Hardbower DM
; Coburn LA
; Asim M
; Singh K
; Sierra JC
; Barry DP
; Gobert AP
; Piazuelo MB
; Washington MK
; Wilson KT
Oncogene
2017[Jul]; 36
(27
): 3807-3819
PMID28263971
show ga
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)-? and IL-1? 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.
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