ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis.
Yang M,Liu J,Piao C,Shao J,Du J
Cell death & disease
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.
10.1038/cddis.2015.144
Ginsenoside RK3 inhibits glioblastoma by modulating macrophage M2 polarization via the PPARG/CCL2 axis.
Phytomedicine : international journal of phytotherapy and phytopharmacology
BACKGROUND:Glioblastoma is recognized as the most aggressive form of intracranial tumor, presenting significant challenges in treatment. Recent emphasis has been placed on the potential of traditional Chinese medicine (TCM) as an adjuvant treatment for cancer. METHODS:We employed a series of assays-including CCK8, EdU, Transwell, and neurosphere formation-to evaluate the impact of ginsenoside RK3 on the phenotype of GBM. The modulation of macrophage M2 polarization by ginsenoside RK3 was assessed through flow cytometry, immunohistochemistry, and Western blot analysis. Furthermore, we utilized sequencing analysis and network pharmacology to identify potential therapeutic targets. RESULTS:Our findings reveal that ginsenoside RK3 not only inhibits the phenotype of glioblastoma cells but also suppresses tumor progression in vivo while attenuating macrophage M2 polarization within the tumor immune microenvironment. Notably, ginsenoside RK3 down-regulates PPARG expression in tumor cells, leading to decreased secretion of CCL2, which subsequently diminishes macrophage M2 polarization. Additionally, we demonstrated that combining ginsenoside RK3 with temozolomide significantly enhances the inhibition of glioblastoma's malignant characteristics and progression. CONCLUSIONS:This study innovatively highlights the dual mechanism of ginsenoside RK3 in glioblastoma treatment: it impedes tumor progression by modulating the PPARG/CCL2 pathway and enhances the efficacy of temozolomide. Our research underscores the promising role of herbal medicine in the management of glioblastoma, paving the way for novel therapeutic strategies that integrate traditional approaches with conventional treatments.
10.1016/j.phymed.2024.156271
Exosome-derived FGD5-AS1 promotes tumor-associated macrophage M2 polarization-mediated pancreatic cancer cell proliferation and metastasis.
Cancer letters
Inflammatory molecules and exosomes are crucial for signal transduction between tumor-associated macrophages and tumor cells. IL-6, a key inflammatory molecule secreted by M2 macrophages after polarization, can mediate malignant progression of pancreatic cancer (PC). However, the functions and mechanisms of IL-6 and tumor-derived exosomes in tumor-associated macrophages and PC remain unclear. Transcriptome chip and quantitative reverse transcription PCR experiments indicated that FGD5-AS1 induced IL-6 and high FGD5-AS1 expression correlated with the poor prognosis in PC patients. RNA pulldown, mass spectrometry, and dual luciferase reporter assays were used to identify the mechanism of exosomal FGD5-AS1 in promoting PC progression and M2 macrophage polarization. FGD5-AS1 exerted cancer-promoting functions when co-cultured with M2 macrophages. PC-derived exosomal FGD5-AS1 stimulated M2 macrophage polarization by activating STAT3/NF-κB pathway. FGD5-AS1 interacts with p300, resulting in STAT3 acetylation, thus promoting nuclear localization and transcriptional activity of STAT3/NF-κB. These data indicated that PC cells generate FGD5-AS1-rich exosomes, which cause M2 macrophage polarization to promote the malignant behaviors of PC cells. Targeting exosomal FGD5-AS1 may provide a potential diagnosis and treatment strategy for PC.
10.1016/j.canlet.2022.215751
TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer.
Cell death & disease
Lung metastasis is the major cause of death in patients with triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in TNBC lung metastasis. Sohlh2 belongs to the basic helix-loop-helix transcription factor family. However, its role in macrophages polarization remains unknown, especially in TNBC progression. Here we demonstrated that Sohlh2 overexpression promoted M2 macrophage polarization. Moreover, high expression of Sohlh2 in M2-like macrophage enhanced TNBC cell growth, migration and lung metastasis in vivo and in vitro. Mechanistically, we revealed that Sohlh2 functioned through up-regulating LXRα, ABCA1, ABCG1 expression and disturbing the lipid homeostasis on the membrane of macrophages. Sohlh2 could directly bind to the promoter of LXRα and promote its transcription activity. E3 ubiquitin ligase TRIM21 promoted Sohlh2 ubiquitination and degradation, and suppressed M2 macrophage polarization and TNBC progression. Collectively, our findings suggested that Sohlh2 in macrophage could be a novel therapeutic target for TNBC metastatic treatment.
10.1038/s41419-023-06383-x
PAARH promotes M2 macrophage polarization and immune evasion of liver cancer cells through VEGF protein.
International journal of biological macromolecules
OBJECTIVE:This study aims to investigate the mechanism by which PAARH promotes M2 macrophage polarization and immune evasion of liver cancer cells through VEGF, in order to reveal its role in the progression of liver cancer. METHODS:The expressions of PAARH, VEGF, and HIF-1α in liver cancer cells were detected using qRT-PCR and Western blot. Flow cytometry was utilized to analyze the polarization status of macrophages and assess the impact on immune evasion-related markers. The relationship between PAARH and VEGF in macrophage polarization was further explored. Additionally, a tumor-bearing mouse model was established to observe tumor growth. RESULTS:The results show that PAARH is upregulated in liver cancer cells, and silencing PAARH significantly inhibits tumor malignancy progression. Under hypoxic conditions, overexpression of PAARH significantly increases VEGF expression, and PAARH regulates M2 macrophage polarization through VEGF. Overexpression of PAARH significantly promotes M2 macrophage polarization, increases levels of PD-L1 and Th2 immune response markers, and enhances cell proliferation, migration, and invasion; it also suppresses M1 macrophage polarization, decreases levels of PD-L2 and Th1 immune response markers, and inhibits cell apoptosis. Silencing VEGF reverses these effects. Silencing PAARH or overexpressing VEGF weakens the malignant phenotype of the cells and immune evasion. Results from the tumor-bearing mouse model indicate that silencing PAARH significantly reduces tumor size and weight, while overexpressing VEGF significantly increases tumor volume and weight. CONCLUSION:PAARH enhances the immune evasion capability of liver cancer cells by upregulating VEGF to promote M2 macrophage polarization, suggesting that PAARH may serve as a new therapeutic target for liver cancer.
10.1016/j.ijbiomac.2024.136580
Macrophage polarization in the tumor microenvironment: Emerging roles and therapeutic potentials.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
The tumor microenvironment (TME) is a combination of tumor cells and indigenous host stroma, which consists of tumor-infiltrating immune cells, endothelial cells, fibroblasts, pericytes, and non-cellular elements. Tumor-associated macrophages (TAMs) represent the major tumor-infiltrating immune cell type and are generally polarized into two functionally contradictory subtypes, namely classical activated M1 macrophages and alternatively activated M2 macrophages. Macrophage polarization refers to how macrophages are activated at a given time and space. The interplay between the TME and macrophage polarization can influence tumor initiation and progression, making TAM a potential target for cancer therapy. Here, we review the latest investigations on factors orchestrating macrophage polarization in the TME, how macrophage polarization affects tumor progression, and the perspectives in modulating macrophage polarization for cancer immunotherapy.
10.1016/j.biopha.2024.116930
Sorbitol dehydrogenase induction of cancer cell necroptosis and macrophage polarization in the HCC microenvironment suppresses tumor progression.
Cancer letters
Hepatocellular carcinoma (HCC) is among the most common malignant cancers worldwide, with an increasing incidence associated with an increase in deaths due to liver cancer. HCC is typically detected at an advanced stage in patients with underlying liver dysfunction, resulting in high mortality. The identification of HCC-specific targets represents a desired but unmet need for liver cancer treatment. To identify potentially novel HCC therapeutic targets, we performed a secretome analysis using HCC spheroids. Sorbitol dehydrogenase (SORD) was identified as uniquely enriched in the secretomes and lysates derived from HCC spheroids, and high SORD expression in HCC tissues was associated with favorable effects on overall survival among patients with liver cancer. We found that the introduction of excess SORD in HCC cells inhibited tumor growth and stemness by enhancing necroptosis signal and bypassing energy-yielding pathways through regulation of lactate dehydrogenase A (LDHA) expression and mitochondrial dynamics. Treatment with human recombinant SORD (hrSORD) controlled HCC cell growth and regulated macrophage polarization in the tumor microenvironment. These results demonstrate that SORD plays critical functional roles in HCC suppression through polyol pathway-independent mechanisms, suggesting that targeting SORD expression might represent a promising therapeutic strategy for liver cancer therapy.
10.1016/j.canlet.2022.215960
Exosomal AP000439.2 from clear cell renal cell carcinoma induces M2 macrophage polarization to promote tumor progression through activation of STAT3.
Cell communication and signaling : CCS
BACKGROUND:Tumorigenic phenotype of M2 tumor-associated macrophages promote tumor progression in response to exosomes cues imposed by tumor cells. However, the effect and underlying mechanisms of clear cell renal cell carcinoma (ccRCC)-derived exosomes (ccRCC-exo) on instructing macrophages phenotype remains unclear. METHODS:Macrophages were cocultured with ccRCC-exo and then evaluate the polarization of macrophages and migration of ccRCC cells. The effect and mechanism of lncRNA AP000439.2 overexpressed or deleted exosomes on macrophages M2 polarization were examined. Xenograft tumor mice model was used for in vivo validation. RESULTS:The ccRCC-exo significantly activated macrophages to M2 phenotype presented by increased expression of transforming growth factor-beta (TGF-β) and interleukin 10 (IL-10) at mRNA and protein levels, and these M2 macrophages in turn facilitating the migration of ccRCC cells. LncRNA AP000439.2 was highly enriched in the ccRCC-exo. Overexpression of exosomal AP000439.2 promoted M2 macrophage polarization whereas AP000439.2-deficient exosome had the opposite effects. Nuclear-localized AP000439.2 directly interacted with signal transducer and activator of transcription 3 (STAT3) proteins and phosphorylated STAT3 in macrophages. RNA-Seq results showed overexpression of AP000439.2 activated NF-κB signaling pathway. Silencing of STAT3 suppressed overexpression of AP000439.2-induced up-regulation of TGF-β and IL-10 expression, and p65 phosphorylation. AP000439.2-deleted exosome inhibited tumor growth in vivo. CONCLUSION:Exosomes from ccRCC deliver AP000439.2 to promote M2 macrophage polarization via STAT3, thus enhancing ccRCC progression, indicating exosomal AP000439.2 might be a novel therapeutic target in ccRCC. Video Abstract.
10.1186/s12964-022-00957-6
Andrographolide suppresses breast cancer progression by modulating tumor-associated macrophage polarization through the Wnt/β-catenin pathway.
Phytotherapy research : PTR
Andrographolide(ADE) has been demonstrated to inhibit tumor growth through direct cytotoxicity on tumor cells. However, its potential activity on tumor microenvironment (TME) remains unclear. Tumor-associated macrophages (TAMs), composed mainly of M2 macrophages, are the key cells that create an immunosuppressive TME by secretion of cytokines, thus enhancing tumor progression. Re-polarized subpopulations of macrophages may represent vital new therapeutic alternatives. Our previous studies showed that ADE possessed anti-metastasis and anoikis-sensitization effects. Here, we demonstrated that ADE significantly suppressed M2-like polarization and enhanced M1-like polarization of macrophages. Moreover, ADE inhibited the migration of M2 and tube formation in HUVECs under M2 stimulation. In vivo studies showed that ADE restrained the growth of MDA-MB-231 and HCC1806 human breast tumor xenografts and 4T-1 mammary gland tumors through TAMs. Wnt5a/β-catenin pathway and MMPs were particularly associated with ADE's regulatory mechanisms to M2 according to RNA-seq and bioinformatics analysis. Moreover, western blot also verified the expressions of these proteins were declined with ADE exposure. Among the cytokines released by M2, PDGF-AA and CCL2 were reduced. Our current findings for the first time elucidated that ADE could modulate macrophage polarization and function through Wnt5a signaling pathway, thereby playing its role in inhibition of triple-negative breast cancer.
10.1002/ptr.7578
Renal cell carcinoma-derived exosomes deliver lncARSR to induce macrophage polarization and promote tumor progression via STAT3 pathway.
International journal of biological sciences
Tumor-derived exosomes play a pivotal role in regulating tumor progression by mediating crosstalk between tumor cells and immune cells such as macrophages within the tumor microenvironment. Macrophages can adopt two distinct polarization statuses and switch between M1 or M2 activation phenotypes in response to the different external stimuli. However, the role of tumor derived exosomes in the macrophage phenotypic switch and tumor development have not been elucidated in renal cell carcinoma (RCC). Here we found that high macrophage infiltration was associated with worse prognosis in RCC patients, therefore we propose our hypothesis that RCC derived exosomes might directly influence macrophage polarization and thus promote tumor progression. Both cell-based models and orthotopic transplantation tumor models were constructed and ELISA, flow cytometry, and macrophage functional studies were performed to investigate whether and how RCC-derived exosomes regulate macrophage polarization and tumor growth. The results found that these exosomes promote macrophage polarization, cytokine release, phagocytosis, angiogenesis, and tumor development. Further study revealed high amount of a recently discovered lncRNA called lncARSR in RCC-derived exosomes. Overexpression of lncARSR induced phenotypic and functional changes of macrophages and promoted tumor growth , while knockdown of lncARSR by siRNA disrupted the exosomes-mediated macrophage polarization. LncARSR interacts directly with miR-34/miR- 449 to increase STAT3 expression and mediate macrophage polarization in RCC cells. Together, RCC-derived exosomes facilitate the development of tumor through inducing macrophage polarization via transferring lncARSR, suggesting that RCC-derived exosomes, lncARSR and STAT3 are the potential therapeutic targets for treatment of RCC.
10.7150/ijbs.70289
VDR promotes pancreatic cancer progression in vivo by activating CCL20-mediated M2 polarization of tumor associated macrophage.
Cell communication and signaling : CCS
BACKGROUND:Activation of VDR pathway was a promising anti-tumor therapy strategy. However, numerous clinical studies have demonstrated the effect of activating VDR is limited, which indicates that VDR plays a complex role in vivos. METHODS:We analyzed the TCGA database to examine the association between VDR expression and immune cell infiltration in pancreatic adenocarcinoma (PAAD). Western blot, ELISA, ChIP, and dual-luciferase reporter assays were performed to determine the mechanism of VDR regulating CCL20. Migration assay and immunofluorescence were used to investigate the role of CCL20 in M2 macrophage polarization and recruitment. We employed multiplexed immunohistochemical staining and mouse models to validate the correlation of VDR on macrophages infiltration in PAAD. Flow cytometry analysis of M2/M1 ratio in subcutaneous graft tumors. RESULTS:VDR is extensively expressed in PAAD, and patients with elevated VDR levels exhibited a significantly reduced overall survival. VDR expression in PAAD tissues was associated with increased M2 macrophages infiltration. PAAD cells overexpressing VDR promote macrophages polarization towards M2 phenotype and recruitment in vitro and vivo. Mechanistically, VDR binds to the CCL20 promoter and up-regulates its transcription. The effects of polarization and recruitment on macrophages can be rescued by blocking CCL20. Finally, the relationship between VDR and M2 macrophages infiltration was evaluated using clinical cohort and subcutaneous graft tumors. A positive correlation was demonstrated between VDR/CCL20/CD163 in PAAD tissues and mouse models. CONCLUSION:High expression of VDR in PAAD promotes M2 macrophage polarization and recruitment through the secretion of CCL20, which activates tumor progression. This finding suggests that the combination of anti-macrophage therapy may improve the efficacy of VDR activation therapy in PAAD.
10.1186/s12964-024-01578-x