Progastrin represses the alternative activation of human macrophages and modulates their influence on colon cancer epithelial cells

PLoS One. 2014 Jun 5;9(6):e98458. doi: 10.1371/journal.pone.0098458. eCollection 2014.

Abstract

Macrophage infiltration is a negative prognostic factor for most cancers but gastrointestinal tumors seem to be an exception. The effect of macrophages on cancer progression depends on their phenotype, which may vary between M1 (pro-inflammatory, defensive) to M2 (tolerogenic, pro-tumoral). Gastrointestinal cancers often become an ectopic source of gastrins and macrophages present receptors for these peptides. The aim of the present study is to analyze whether gastrins can affect the pattern of macrophage infiltration in colorectal tumors. We have evaluated the relationship between gastrin expression and the pattern of macrophage infiltration in samples from colorectal cancer and the influence of these peptides on the phenotype of macrophages differentiated from human peripheral monocytes in vitro. The total number of macrophages (CD68+ cells) was similar in tumoral and normal surrounding tissue, but the number of M2 macrophages (CD206+ cells) was significantly higher in the tumor. However, the number of these tumor-associated M2 macrophages correlated negatively with the immunoreactivity for gastrin peptides in tumor epithelial cells. Macrophages differentiated from human peripheral monocytes in the presence of progastrin showed lower levels of M2-markers (CD206, IL10) with normal amounts of M1-markers (CD86, IL12). Progastrin induced similar effects in mature macrophages treated with IL4 to obtain a M2-phenotype or with LPS plus IFNγ to generate M1-macrophages. Macrophages differentiated in the presence of progastrin presented a reduced expression of Wnt ligands and decreased the number and increased cell death of co-cultured colorectal cancer epithelial cells. Our results suggest that progastrin inhibits the acquisition of a M2-phenotype in human macrophages. This effect exerted on tumor associated macrophages may modulate cancer progression and should be taken into account when analyzing the therapeutic value of gastrin immunoneutralization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Cell Count
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / metabolism*
  • Colonic Neoplasms / pathology
  • Female
  • Gastrins / metabolism*
  • Humans
  • Immunohistochemistry
  • Intestinal Mucosa / immunology*
  • Intestinal Mucosa / metabolism*
  • Intestinal Mucosa / pathology
  • Ligands
  • Macrophage Activation / immunology*
  • Macrophages / immunology*
  • Macrophages / metabolism*
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Phenotype
  • Protein Precursors / metabolism*
  • Wnt Proteins / metabolism

Substances

  • Gastrins
  • Ligands
  • Protein Precursors
  • Wnt Proteins
  • big gastrin

Grant support

This work was supported by Ministerio de Educación y Ciencia/FEDER [grant number SAF2007-064201], Ministerio de Ciencia e Innovacion [grant numbers SAF2010-20231, SAF2010-16030 and RYC-2011-09571], Ministerio de Sanidad y Consumo [grant number PI11/00327], CIBERehd [grant number CB06/04/0071] and Generalitat Valenciana [grant number PROMETEO/2010/060]. Carlos Hernandez acknowledges support from the ‘Ramon y Cajal’ program from Ministerio de Ciencia e Innovación of Spain (RYC-2011-09571). Jesús Cosín-Roger is supported by FPU fellowships from Ministerio de Educación, Cultura y Deporte. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.