Crucial involvement of tumor-associated neutrophils in the regulation of chronic colitis-associated carcinogenesis in mice

PLoS One. 2012;7(12):e51848. doi: 10.1371/journal.pone.0051848. Epub 2012 Dec 18.

Abstract

Ulcerative colitis (UC) is a major form of chronic inflammation that can frequently progress to colon cancer. Several studies have demonstrated massive infiltration of neutrophils and macrophages into the lamina propria and submucosa in the progression of UC-associated colon carcinogenesis. Macrophages contribute to the development of colitis-associated colon cancer (CAC). However, the role of neutrophils is not well understood. To better understand the involvement of tumor-associated neutrophils (TANs) in the regulation of CAC, we used a mouse CAC model produced by administering azoxymethane (AOM), followed by repeated dextran sulfate sodium (DSS) ingestion. This causes severe colonic inflammation and subsequent development of multiple tumors in mice colon. We observed that colorectal mucosal inflammation became increasingly severe with AOM and DSS treatment. Macrophages infiltrated the lamina propria and submucosa, together with a marked increase in neutrophil infiltration. The chemokine CXCL2 increased in the lamina propria and submucosal regions of the colons of the treated mice, together with the infiltration of neutrophils expressing CXCR2, a specific receptor for CXCL2. This process was followed by neoplastic transformation. After AOM and DSS treatment, the mice showed enhanced production of metalloproteinase (MMP)-9 and neutrophil elastase (NE), accompanied by excessive vessel generation and cell proliferation. Moreover, CXCL2 promoted neutrophil recruitment and induced neutrophils to express MMP-9 and NE in vitro. Furthermore, administration of neutrophil-neutralizing antibodies after the last DSS cycle markedly reduced the number and size of tumors and decreased the expression of CXCR2, CXCL2, MMP-9, and NE. These observations indicate a crucial role for TANs in the initiation and progression of CAC and suggest that the CXCL2-CXCR2 axis might be useful in reducing the risk of UC-associated colon cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / administration & dosage
  • Antibodies, Monoclonal / immunology
  • Antigens, Ly / immunology
  • Cell Proliferation
  • Cell Transformation, Neoplastic* / immunology
  • Chemokine CXCL2 / genetics
  • Chemokine CXCL2 / metabolism
  • Chronic Disease
  • Colitis / complications*
  • Colitis / immunology*
  • Colitis, Ulcerative / complications
  • Colitis, Ulcerative / immunology
  • Colonic Neoplasms / etiology*
  • Colonic Neoplasms / pathology*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation, Neoplastic
  • Leukocyte Elastase / genetics
  • Leukocyte Elastase / metabolism
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Neovascularization, Pathologic
  • Neutrophil Infiltration / immunology
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Proliferating Cell Nuclear Antigen / genetics
  • Proliferating Cell Nuclear Antigen / metabolism
  • Receptors, Interleukin-8B / genetics
  • Receptors, Interleukin-8B / metabolism

Substances

  • Antibodies, Monoclonal
  • Antigens, Ly
  • Chemokine CXCL2
  • Ly6G antigen, mouse
  • Proliferating Cell Nuclear Antigen
  • Receptors, Interleukin-8B
  • Leukocyte Elastase
  • Matrix Metalloproteinase 9

Grant support

This study supported by funding from The National Science Foundation of China (NSFC) (30973476) and Shanghai Pujiang Program (10PJ1402100). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.