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.

CD86+/CD206+ tumor-associated macrophages predict prognosis of patients with intrahepatic cholangiocarcinoma

“…CD68 + TAMs had no prognostic value in predicting the outcome of surgically treated ICC patients, which may be attributed to the inability of CD68 to distinguish between M1 and M2 subsets. This was consistent with previous studies in HCC, colon cancer and gastric cancer (Dong et al, 2016;Hernandez et al, 2014;Zhang et al, 2015). Therefore, CD86 and CD206 immunostaining were further examined to distinguish between M1 and M2 subtypes.…”

“…In recent years, compelling evidence showed that M1 subtype macrophages expressed abundant CD86, CD38, Gpr18, Fpr2 and tumor necrosis factor a, whereas M2 subtype macrophages expressed high levels of CD206, CD163, Egr2 and c-Myc (Biswas & Mantovani, 2010;Olsson et al, 2015;Jablonski et al, 2015). Recent studies found that M1 subtype macrophages possessed high levels of CD86, while M2 subtype macrophages expressed high levels of CD206 in human gastrointestinal tumors tissues (Hernandez et al, 2014;Zhu et al, 2015).…”

CD86+/CD206+, Diametrically Polarized Tumor-Associated Macrophages, Predict Hepatocellular Carcinoma Patient Prognosis

“…This may attribute to functional counterbalance regulated by M1 and M2 macrophages. Previous studies in HCC, colon cancer and gastric cancer implied that the abundance of CD68 + TAMs infiltrated in tumor tissue was not associated with patient prognosis after curative cancer tissue resection [ 24 , 25 , 26 ]. However, other research reported that CD68 + TAMs in tumor stroma was an independent prognostic factor for poor OS and TTR in breast cancer, cholangiocarcinoma and Hodgkin lymphoma [ 27 , 28 , 29 ].…”

Prognostic Implication of M2 Macrophages Are Determined by the Proportional Balance of Tumor Associated Macrophages and Tumor Infiltrating Lymphocytes in Microsatellite-Unstable Gastric Carcinoma

“…The mechanism of our data that challenge the current theory regarding the prognostic role of CD163+ TAMs has not been entirely elucidated. However, several authors have argued that M2 macrophages have less deleterious effects in CRCs, which is attributed to the unique intestinal environment with numerous colonizing micro-organisms [ 18 , 35 , 36 ]. This less hazardous effect of M2 macrophages can be applied to GCs considering the fact that the vast majority of GCs arise in the stomach infected with Helicobacter pylori and that GCs have molecular mechanisms of carcinogenesis in common with CRCs.…”