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

Carlos Hernández,María Dolores Barrachina,Rafael Alós,María Jesús Nicolau,Dolores Ortiz-Masiá,Liria Terrádez,Sara Calatayud,Ángeles Álvarez,Jesús Cosín-Roger,Juan Vicente Esplugues,Joseph Najbauer

doi:10.1371/journal.pone.0098458

Carlos Hernández, María Dolores Barrachina + Show 9 more

Open Access

https://doi.org/10.1371/journal.pone.0098458

Copy DOI

Journal: PloS one	Publication Date: Jun 5, 2014
Citations: 39	License type: CC BY 4.0

Affiliation: University of Valencia

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.

Highlights

Macrophages are a significant component of tumors and display a variety of functions depending on the local environment
M2 macrophage number is increased in the tumoral area We first analyzed the amount and phenotype of macrophages in the non-tumor and tumor areas of colorectal cancer patients
The number of macrophages was similar in tumor and normal surrounding tissue, but the number of M1 and M2 macrophages was significantly different between the two areas (Figure 1)

Summary

Introduction

Macrophages are a significant component of tumors and display a variety of functions depending on the local environment They can be pro-inflammatory and help to generate adaptive immune responses (classically activated macrophages, M1) or tolerogenic/ anti-inflammatory (alternatively activated macrophages, M2) [1,2]. In patients with colorectal or gastric cancers a higher macrophage infiltration correlates with a better prognosis [3] The reasons for this differential role of macrophages in these particular diseases is far from clear, but from the current knowledge one can infer that the colorectal/gastric tumor microenvironment marks a different equilibrium in the function of infiltrated M1 and M2 macrophages, with M2 macrophages exerting a defective opposition to the accompanying M1phagocytes [4,5].

Objectives

Methods

Results

Discussion

Conclusion