title: Tumor-derived GM-CSF promotes inflammatory colon carcinogenesis via stimulating epithelial release of VEGF.
abstract: Chronic inflammation is a major driving force for the development of colitis-associated cancer (CAC). Elevated production of granulocyte macrophage colony-stimulating factor (GM-CSF) has been observed in mucosa of patients with inflammatory bowel disease. Its actions in the progression from colitis to cancer, however, remain poorly understood. Herein, we demonstrated that colonic epithelial cells (CEC) were a major cellular source of GM-CSF and its production was significantly augmented when CAC model was established by administration of azoxymethane and dextran sulfate sodium. Furthermore, we showed that GM-CSF was a driver for VEGF release by CEC in autocrine and/or paracrine manners through the extracellular signal-regulated kinase (ERK)-dependent pathway. Blocking GM-CSF activity in vivo significantly decreased epithelial release of VEGF, thereby abrogating CAC formation. In vitro treatment of transformed CEC with recombinant GM-CSF dramatically augmented its invasive potentials, largely in VEGF-dependent fashion. Furthermore, commensal microbiota-derived lipopolysaccharides were identified as a trigger for GM-CSF expression in CEC, as antibiotics treatment or Toll-like receptor 4 ablation considerably impaired its epithelial expression. Overall, these findings may have important implications for the understanding of mechanisms underlying CAC pathogenesis and the therapeutic potentials of regimens targeting GM-CSF or VEGF in clinic.
authors.affiliation: Authors' Affiliations: Department of Immunology, Institute of Basic Medical Sciences, Beijing; Department of Immunology, School of Basic Medical Sciences, Central South University, Changsha; Center of Molecular Biology, Inner Mongolia Medical College, Hohhot, People's Republic of China; and Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.forename: Gencheng
authors.initials: G
authors.lastname: Han
authors.forename: Ke
authors.initials: K
authors.lastname: Wang
authors.forename: Guijun
authors.initials: G
authors.lastname: Liu
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.forename: Xinying
authors.initials: X
authors.lastname: Li
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hou
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.forename: Renfeng
authors.initials: R
authors.lastname: Guo
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Guojiang
authors.initials: G
authors.lastname: Chen
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002908:Chronic Disease; D003092:Colitis / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D003110:Colonic Neoplasms / Q000209:etiology; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D051197:Toll-Like Receptor 4; D042461:Vascular Endothelial Growth Factor A; D016178:Granulocyte-Macrophage Colony-Stimulating Factor