CCR6, the sole receptor for the chemokine CCL20, promotes spontaneous intestinal tumorigenesis

PLoS One. 2014 May 27;9(5):e97566. doi: 10.1371/journal.pone.0097566. eCollection 2014.

Abstract

Interactions between the inflammatory chemokine CCL20 and its receptor CCR6 have been associated with colorectal cancer growth and metastasis, however, a causal role for CCL20 signaling through CCR6 in promoting intestinal carcinogenesis has not been demonstrated in vivo. In this study, we aimed to determine the role of CCL20-CCR6 interactions in spontaneous intestinal tumorigenesis. CCR6-deficient mice were crossed with mice heterozygous for a mutation in the adenomatous polyposis coli (APC) gene (APCMIN/+ mice) to generate APCMIN/+ mice with CCR6 knocked out (CCR6KO-APCMIN/+ mice). CCR6KO-APCMIN/+ mice had diminished spontaneous intestinal tumorigenesis. CCR6KO-APCMIN/+ also had normal sized spleens as compared to the enlarged spleens found in APCMIN/+ mice. Decreased macrophage infiltration into intestinal adenomas and non-tumor epithelium was observed in CCR6KO-APCMIN/+ as compared to APCMIN/+ mice. CCL20 signaling through CCR6 caused increased production of CCL20 by colorectal cancer cell lines. Furthermore, CCL20 had a direct mitogenic effect on colorectal cancer cells. Thus, interactions between CCL20 and CCR6 promote intestinal carcinogenesis. Our results suggest that the intestinal tumorigenesis driven by CCL20-CCR6 interactions may be driven by macrophage recruitment into the intestine as well as proliferation of neoplastic epithelial cells. This interaction could be targeted for the treatment or prevention of malignancy.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / pathology*
  • Chemokine CCL20 / genetics
  • Chemokine CCL20 / metabolism*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology*
  • Female
  • Fluorescent Antibody Technique
  • Genes, APC*
  • Humans
  • Immunoenzyme Techniques
  • Intestinal Neoplasms / etiology
  • Intestinal Neoplasms / metabolism
  • Intestinal Neoplasms / pathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, CCR6 / genetics
  • Receptors, CCR6 / metabolism*
  • Receptors, CCR6 / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • CCR6 protein, human
  • CCR6 protein, mouse
  • Chemokine CCL20
  • RNA, Messenger
  • Receptors, CCR6

Grant support

This work is supported by the Department of Veterans Affairs Office of Research and Development through a Career Development Award-2 to JSG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.