EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis

• Published in: Oncogene 2017-07, Vol.36 (27), p.3807-3819
• Main Authors: Hardbower, D M, Coburn, L A, Asim, M, Singh, K, Sierra, J C, Barry, D P, Gobert, A P, Piazuelo, M B, Washington, M K, Wilson, K T
• Format: Article
• Language: English
• Subjects: 13/1; 13/51; 14/105; 14/63; 38/77; 38/90; 631/250/2504; 631/67/580; 631/67/70; 64/60; 96/21; Analysis; Angiogenesis; Animals; Apoptosis; Azoxymethane; Blood vessels; Bone marrow; Carcinogenesis; Carcinogenesis - immunology; Carcinogenesis - metabolism; Care and treatment; Cell activation; Cell Biology; Clonal deletion; Colitis; Colitis - pathology; Colon; Colon - immunology; Colon - pathology; Colonic Neoplasms - chemically induced; Colonic Neoplasms - immunology; Colonic Neoplasms - metabolism; Colorectal cancer; Dextran; Dextran Sulfate; Dysplasia; Epidermal growth factor; Epidermal growth factor receptors; Epithelial cells; ErbB Receptors - physiology; Gene expression; Growth factors; Human Genetics; Humans; Immunity, Innate; Inflammatory bowel disease; Inflammatory bowel diseases; Interferon; Interleukin 1; Interleukin 10; Interleukin 13; Internal Medicine; Intestine; Leukocytes (neutrophilic); Lymphocytes T; Macrophage Activation; Macrophages; Macrophages - physiology; Male; Medicine; Medicine & Public Health; Metastases; Mice, Inbred C57BL; Mice, Transgenic; Myeloid cells; Neovascularization, Pathologic - immunology; Neovascularization, Pathologic - metabolism; Oncology; original-article; Precancerous Conditions - immunology; Precancerous Conditions - metabolism; RNA; Rodents; Signal Transduction; Sodium sulfate; Tumor necrosis factor-TNF; Tumor necrosis factor-α; Tumorigenesis; Vascular endothelial growth factor; γ-Interferon
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2017.23

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.