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ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis.

ABSTRACT: Efficient clearance of apoptotic cells (efferocytosis) can profoundly influence tumor-specific immunity. Tumor-associated macrophages are M2-polarized macrophages that promote key processes in tumor progression. Efferocytosis stimulates M2 macrophage polarization and contributes to cancer metastasis, but the signaling mechanism underlying this process is unclear. Intercellular cell adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein member of the immunoglobulin superfamily, which has been implicated in mediating cell-cell interaction and outside-in cell signaling during the immune response. We report that ICAM-1 expression is inversely associated with macrophage infiltration and the metastasis index in human colon tumors by combining Oncomine database analysis and immunohistochemistry for ICAM-1. Using a colon cancer liver metastasis model in ICAM-1-deficient (ICAM-1(-/-)) mice and their wild-type littermates, we found that loss of ICAM-1 accelerated liver metastasis of colon carcinoma cells. Moreover, ICAM-1 deficiency increased M2 macrophage polarization during tumor progression. We further demonstrated that ICAM-1 deficiency in macrophages led to promotion of efferocytosis of apoptotic tumor cells through activation of the phosphatidylinositol 3 kinase/Akt signaling pathway. More importantly, coculture of ICAM-1(-/-) macrophages with apoptotic cancer cells resulted in an increase of M2-like macrophages, which was blocked by an efferocytosis inhibitor. Our findings demonstrate a novel role for ICAM-1 in suppressing M2 macrophage polarization via downregulation of efferocytosis in the tumor microenvironment, thereby inhibiting metastatic tumor progression.

SUBMITTER: Yang M

PROVIDER: S-EPMC4669827 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis.

Yang M M Liu J J Piao C C Shao J J Du J J

Cell death & disease 20150611

Efficient clearance of apoptotic cells (efferocytosis) can profoundly influence tumor-specific immunity. Tumor-associated macrophages are M2-polarized macrophages that promote key processes in tumor progression. Efferocytosis stimulates M2 macrophage polarization and contributes to cancer metastasis, but the signaling mechanism underlying this process is unclear. Intercellular cell adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein member of the immunoglobulin superfamily, which has be ...[more]

PMID: 26068788

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Project description:BACKGROUND: Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-?B. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. METHODS: Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-?) and low (TNF-?) expression in M2 macrophages, and molecules in NF-?B pathway (IKK? and I?-B) were evaluated by RT-qPCR or western blot. RESULTS: EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-? and increased TNF-?. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKK? suppression and concomitant I-?B accumulation; increase of IL-6 and TGF-?; and, decrease of TNF-?. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-?B pathway elicited by EGCG-treated exosomes. CONCLUSIONS: Our data demonstrate that EGCG up-regulates miR-16 in tumor cells, which can be transferred to TAM via exosomes and inhibits TAM infiltration and M2 polarization. We suggest a novel mechanism by which EGCG exerts anti-tumor activity via regulation of TAM in tumor microenvironment.

Project description:BackgroundScar tissue formation at the tendon-bone interface caused by excessive inflammation leads to insufficient healing strength, while the phagocytic clearance of dying cells (efferocytosis) has profound consequences on macrophage polarisation and the inflammatory response. Modulating the inflammatory microenvironment may have satisfactory curative effects in patients with anterior cruciate ligament reconstruction (ACLR).MethodsBone marrow-derived macrophages (BMDMs) and polymorphonuclear leukocytes (PMNs) were harvested from bone marrow. The effects of milk fat globulin protein E8 (MFG-E8) on macrophage polarisation were compared with those of M1 and M2 macrophages induced by conventional methods. The BMDMs and apoptotic PMNs co-culture system was used to assess the efficiency of efferocytosis. The biological functions of MFG-E8 in tendon-bone healing by regulating macrophage efferocytosis and polarisation were further investigated using a rat ACLR model.ResultsBMDMs and PMNs were successfully isolated. Compared to conventional induction methods, MFG-E8 alone did not significantly induce macrophage M1 or M2 polarisation, but it could partially reverse the expression of inducible nitric oxide synthase (iNOS) in M1 macrophages. In vitro studies revealed that appropriate dosing of MFG-E8 could significantly promote the efficiency of macrophage efferocytosis and subsequently increase M2 polarisation. More importantly, significantly increased peri-tunnel new bone formation, tighter connected interface and better mechanical properties were observed after ACLR when treated with MFG-E8 in vivo. We further demonstrated that MFG-E8 remarkably facilitated the clearance of apoptotic cells and increased the number of M2 macrophages at the interface between the tendon graft and bone tunnel in the early postoperative stage.ConclusionMFG-E8 promoted tendon-bone healing histologically and biomechanically, probably by the regulation of inflammatory processes via macrophage efferocytosis and M2 polarisation.The translational potential of this article: Regulation of macrophage efferocytosis and M2 polarization by MFG-E8 is expected to be a therapeutic strategy for promoting tendon-bone healing in patients undergoing ACLR.

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ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis.

Publications

ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis.

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