title: Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma.
abstract: OBJECTIVE
  Substantial evidence indicates that inflammation is a critical component of tumor progression. Hepatocellular carcinoma (HCC) is usually derived from inflamed cirrhotic liver with extensive leukocyte infiltration. Neutrophils are the common inflammatory infiltrate in tumors, but their nature and regulation in human cancers remain elusive.
  
  
  METHODS
  A total of 238 HCC patients were enrolled randomly. Immunohistochemistry and SuperArray Real-Time PCR were used to analyze the distribution and clinical relevance of neutrophils in different microanatomical areas. The regulation and function of neutrophils were assessed by both in vitro and in vivo studies.
  
  
  RESULTS
  Neutrophils were enriched predominantly in peritumoral stroma of HCC tissues and their levels could serve as a powerful predictor for poor survival in HCC patients. Proinflammatory IL-17 is a critical mediator of the recruitment of neutrophils into peritumoral stroma of HCC tissues by epithelial cell-derived CXC chemokines. The accumulated peritumoral neutrophils were the major source of matrix metalloproteinase-9 in HCC tissues; this secreted protein stimulated proangiogenic activity in hepatoma cells. Accordingly, high infiltration of peritumoral neutrophils was positively correlated with angiogenesis progression at tumor-invading edge of HCC patients. Furthermore, we found that selective depletion of neutrophils effectively inhibited tumor angiogenesis and growth, in vivo.
  
  
  CONCLUSIONS
  These data provide direct evidence supporting the critical role of neutrophils in human tumor progression and reveal a fine-tuned collaborative action between cancer cells and immune cells in distinct tumor milieu, which reroutes the inflammatory response into a tumor-promoting direction.
authors.affiliation: State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou, PR China.
authors.forename: Dong-Ming
authors.initials: DM
authors.lastname: Kuang
authors.forename: Qiyi
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Chen
authors.initials: C
authors.lastname: Peng
authors.forename: Jianen
authors.initials: J
authors.lastname: Wang
authors.forename: Zhenqun
authors.initials: Z
authors.lastname: Xu
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Yin
authors.forename: Limin
authors.initials: L
authors.lastname: Zheng
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000276:immunology / Q000401:mortality; D018450:Disease Progression; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005647:Fucosyltransferases / Q000378:metabolism; D006505:Hepatitis / Q000276:immunology / Q000401:mortality / Q000473:pathology; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D016256:Lewis X Antigen / Q000378:metabolism; D008103:Liver Cirrhosis / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008113:Liver Neoplasms / Q000098:blood supply / Q000276:immunology / Q000401:mortality; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000401:mortality / Q000473:pathology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011237:Predictive Value of Tests; D015398:Signal Transduction / Q000276:immunology; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020381:Interleukin-17; D016256:Lewis X Antigen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C066693:FUT4 protein, human; D005647:Fucosyltransferases; D020780:Matrix Metalloproteinase 9