title: Progastrin represses the alternative activation of human macrophages and modulates their influence on colon cancer epithelial cells.
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.
authors.affiliation: FISABIO, Hospital Dr. Peset, Valencia, Spain; Unidad Mixta de Investigación en Biomedicina y Farmacología FISABIO - Hospital Dr.Peset - UVEG, Valencia, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Hernández
authors.affiliation: 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.
authors.forename: María Dolores
authors.initials: MD
authors.lastname: Barrachina
authors.affiliation: 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.
authors.forename: Jesús
authors.initials: J
authors.lastname: Cosín-Roger
authors.affiliation: 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.
authors.forename: Dolores
authors.initials: D
authors.lastname: Ortiz-Masiá
authors.affiliation: 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.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Álvarez
authors.affiliation: Hospital de Manises, Valencia, Spain.
authors.forename: Liria
authors.initials: L
authors.lastname: Terrádez
authors.affiliation: Hospital de Manises, Valencia, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Nicolau
authors.affiliation: Hospital de Manises, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Alós
authors.affiliation: 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.
authors.forename: Juan Vicente
authors.initials: JV
authors.lastname: Esplugues
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Calatayud
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002452:Cell Count; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005755:Gastrins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008024:Ligands; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010641:Phenotype; D011498:Protein Precursors / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D005755:Gastrins; D008024:Ligands; D011498:Protein Precursors; D051153:Wnt Proteins; C013706:big gastrin