title: Activation of Epidermal Growth Factor Receptor in Macrophages Mediates Feedback Inhibition of M2 Polarization and Gastrointestinal Tumor Cell Growth.
abstract: EGF receptor (EGFR) in tumor cells serves as a tumor promoter. However, information about EGFR activation in macrophages in regulating M2 polarization and tumor development is limited. This study aimed to investigate the effects of EGFR activation in macrophages on M2 polarization and development of gastrointestinal tumors. IL-4, a cytokine to elicit M2 polarization, stimulated release of an EGFR ligand, HB-EGF, and transactivation and down-regulation of EGFR in Raw 264.7 cells and peritoneal macrophages from WT mice. Knockdown of HB-EGF in macrophages inhibited EGFR transactivation by IL-4. IL-4-stimulated STAT6 activation, Arg1 and YM1 gene expression, and HB-EGF production were further enhanced by inhibition of EGFR activity in Raw 264.7 cells using an EGFR kinase inhibitor and in peritoneal macrophages from Egfr(wa5) mice with kinase inactive EGFR and by knockdown of EGFR in peritoneal macrophages from Egfr(fl/fl) LysM-Cre mice with myeloid cell-specific EGFR deletion. Chitin induced a higher level of M2 polarization in peritoneal macrophages in Egfr(fl/fl) LysM-Cre mice than that in Egfr(fl/fl) mice. Accordingly, IL-4-conditioned medium stimulated growth and epithelial-to-mesenchymal transition in gastric epithelial and colonic tumor cells, which were suppressed by that from Raw 264.7 cells with HB-EGF knockdown but promoted by that from Egfr(wa5) and Egfr(fl/fl) LysM-Cre peritoneal macrophages. Clinical assessment revealed that the number of macrophages with EGFR expression became less, indicating decreased inhibitory effects on M2 polarization, in late stage of human gastric cancers. Thus, IL-4-stimulated HB-EGF-dependent transactivation of EGFR in macrophages may mediate inhibitory feedback for M2 polarization and HB-EGF production, thereby inhibiting gastrointestinal tumor growth.
authors: From the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the Department of Gastrointestinal Cancer Biology, National Clinical Cancer Research Center, Tianjin Cancer Institute and Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
authors: Gang
authors: G
authors: Zhao
authors: From the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors: Liping
authors: L
authors: Liu
authors: the Departments of Medicine and Cancer Biology, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232.
authors: Richard M
authors: RM
authors: Peek
authors: the Department of Gastrointestinal Cancer Biology, National Clinical Cancer Research Center, Tianjin Cancer Institute and Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.
authors: Xishan
authors: X
authors: Hao
authors: the Departments of Pediatrics and Biochemistry and Molecular Biology, Children's Hospital Los Angeles and University of Southern California Keck School of Medicine, Los Angeles, California 90027, and the Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027 dbpolk@chla.usc.edu.
authors: D Brent
authors: DB
authors: Polk
authors: the Department of Gastrointestinal Cancer Biology, National Clinical Cancer Research Center, Tianjin Cancer Institute and Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China, lihui@tjmuch.com.
authors: Hui
authors: H
authors: Li
authors: From the Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee 37232, fang.yan@vanderbilt.edu.
authors: Fang
authors: F
authors: Yan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D005770:Gastrointestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D066257:Heparin-binding EGF-like Growth Factor / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000067996:RAW 264.7 Cells; D015533:Transcriptional Activation
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; C508598:IL4 protein, human; D015847:Interleukin-4; C512478:EGFR protein, human; C541485:EGFR protein, mouse; D066246:ErbB Receptors
keywords: HB-EGF; M2 polarization; STAT6; colonic tumor; epidermal growth factor receptor (EGFR); epithelial-mesenchymal transition (EMT); gastric cancer; macrophage; tumor microenvironment