Abstract
BackgroundThe interactions established between macrophages and cancer cells are largely dependent on instructions from the tumour microenvironment. Macrophages may differentiate into populations with distinct inflammatory profiles, but knowledge on their role on cancer cell activities is still very scarce. In this work, we investigated the influence of pro-inflammatory (LPS-stimulated) and anti-inflammatory (IL-10-stimulated) macrophages on gastric and colorectal cancer cell invasion, motility/migration, angiogenesis and proteolysis, and the associated molecular mechanisms.MethodsFollowing exposure of gastric and colon cancer cell lines to LPS- and IL-10-stimulated human macrophages, either by indirect contact or conditioned media, we analyzed the effect of the different macrophage populations on cancer cell invasion, migration, motility and phosphorylation status of EGFR and several interacting partners. Cancer-cell induced angiogenesis upon the influence of conditioned media from both macrophage populations was assessed using the chick embryo chorioallantoic membrane assay. MMP activities were evaluated by gelatin zymograhy.ResultsOur results show that IL-10-stimulated macrophages are more efficient in promoting in vitro cancer cell invasion and migration. In addition, soluble factors produced by these macrophages enhanced in vivo cancer cell-induced angiogenesis, as opposed to their LPS-stimulated counterparts. We further demonstrate that differences in the ability of these macrophage populations to stimulate invasion or angiogenesis cannot be explained by the EGFR-mediated signalling, since both LPS- and IL-10-stimulated macrophages similarly induce the phosphorylation of cancer cell EGFR, c-Src, Akt, ERK1/2, and p38. Interestingly, both populations exert distinct proteolytic activities, being the IL-10-stimulated macrophages the most efficient in inducing matrix metalloprotease (MMP)-2 and MMP-9 activities. Using a broad-spectrum MMP inhibitor, we demonstrated that proteolysis was essential for macrophage-mediated cancer cell invasion and angiogenesis.ConclusionsWe propose that IL-10- and LPS-stimulated macrophages distinctly modulate gastric and colorectal cancer cell behaviour, as result of distinct proteolytic profiles that impact cell invasion and angiogenesis.
Highlights
The interactions established between macrophages and cancer cells are largely dependent on instructions from the tumour microenvironment
We propose that IL-10- and LPS-stimulated macrophages distinctly modulate gastric and colorectal cancer cell behaviour, as result of distinct proteolytic profiles that impact cell invasion and angiogenesis
LPS- and IL-10-stimulated macrophages present distinct phenotypes To study the role of distinct macrophage populations on the modulation of cancer cell-related activities, primary human monocytes were first differentiated into macrophages, and left unstimulated or stimulated with 10 ng/ml of LPS (LPS-stimulated) or IL-10 (IL-10-stimulated), respectively
Summary
The interactions established between macrophages and cancer cells are largely dependent on instructions from the tumour microenvironment. We investigated the influence of pro-inflammatory (LPS-stimulated) and anti-inflammatory (IL-10-stimulated) macrophages on gastric and colorectal cancer cell invasion, motility/migration, angiogenesis and proteolysis, and the associated molecular mechanisms. Macrophages constitute a major component of the immune infiltrate in these tumours and are known to interact with cancer cells and to play a crucial role in distinct steps of cancer progression, such as survival, immune evasion, migration, invasion and metastasis [1,2,3,4]. Our own work recently reinforced these studies, describing that gastric and colorectal cancer cell motility, proteolysis and invasion are stimulated by macrophages and that epidermal growth factor (EGF) is a key molecule in this crosstalk [14]. Nothing was described about the putative impact of different macrophage subpopulations in gastric and colorectal cancer cell properties and signalling
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