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

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

Author information

1
FISABIO, Hospital Dr. Peset, Valencia, Spain; Unidad Mixta de Investigación en Biomedicina y Farmacología FISABIO - Hospital Dr.Peset - UVEG, Valencia, Spain.
2
Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; Unidad Mixta de Investigación en Biomedicina y Farmacología FISABIO - Hospital Dr.Peset - UVEG, Valencia, Spain.
3
Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; Unidad Mixta de Investigación en Biomedicina y Farmacología FISABIO - Hospital Dr.Peset - UVEG, Valencia, Spain; Fundación General Universidad de Valencia, Valencia, Spain.
4
Hospital de Manises, Valencia, Spain.
5
Departamento de Farmacología and CIBER, Facultad de Medicina, Universidad de Valencia, Valencia, Spain; FISABIO, Hospital Dr. Peset, Valencia, Spain; Unidad Mixta de Investigación en Biomedicina y Farmacología FISABIO - Hospital Dr.Peset - UVEG, Valencia, Spain.

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.

PMID:
24901518
PMCID:
PMC4047028
DOI:
10.1371/journal.pone.0098458
[Indexed for MEDLINE]
Free PMC Article

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