scholarly journals A Novel Strategy for Inducing the Antitumor Effects of Triterpenoid Compounds: Blocking the Protumoral Functions of Tumor-Associated Macrophages via STAT3 Inhibition

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Yukio Fujiwara ◽  
Motohiro Takeya ◽  
Yoshihiro Komohara
Keyword(s):  
Anticancer Agents ◽  
Macrophage Polarization ◽  
Tumor Development ◽  
Natural Compounds ◽  
Target Cells ◽  
Tumor Associated Macrophages ◽  
Antitumor Effects ◽  
Clinical Prognosis ◽  
M2 Polarization ◽  
M2 Phenotype

There are many types of nontumor cells, including leukocytes, fibroblasts, and endothelial cells, in the tumor microenvironment. Among these cells, infiltrating macrophages have recently received attention as novel target cells due to their protumoral functions. Infiltrating macrophages are called tumor-associated macrophages (TAMs). TAMs polarized to the M2 phenotype are involved in tumor development and are associated with a poor clinical prognosis. Therefore, the regulation of TAM activation or M2 polarization is a new strategy for antitumor therapy. We screened natural compounds possessing an inhibitory effect on the M2 polarization of human macrophages. Among 200 purified natural compounds examined, corosolic acid (CA) and oleanolic acid (OA), both are categorized in triterpenoid compounds, inhibited macrophage polarization to M2 phenotype by suppressing STAT3 activation. CA and OA also directly inhibited tumor cell proliferation and sensitized tumor cells to anticancer drugs, such as adriamycin and cisplatin. Thein vivoexperiments showed that CA significantly suppressed subcutaneous tumor development and lung metastasis in a murine sarcoma model. The application of triterpenoid compounds, such as CA and OA, is a potential new anticancer therapy targeting macrophage activation, with synergistic effects with anticancer agents.

scholarly journals Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2006
Author(s):  
Hyeongjoo Oh ◽  
Sin-Hye Park ◽  
Min-Kyung Kang ◽  
Yun-Ho Kim ◽  
Eun-Jung Lee ◽  
...  
Keyword(s):  
High Glucose ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Macrophage Polarization ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Functional Transition ◽  
Functional Induction ◽  
M2 Phenotype ◽  
Functional Phenotype

Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes, and atherosclerosis. Macrophages responsiveness to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. J774A.1 murine macrophages were incubated with 40 ng/mL interleukin (IL)-4 or exposed to 33 mM glucose in the presence of 1-20 μΜ asaronic acid. In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163, and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF, and TGF-β. In glucose-loaded macrophages, there was cellular induction of IL-4, IL-4 Rα, arginase-1, and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes via an IL-4-IL-4Rα interaction. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6 pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A, SR-B1, and ABCG1 in diabetic macrophages with M2 phenotype polarity. These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization.

scholarly journals MicroRNA-720 suppresses M2 macrophage polarization by targeting GATA3

2016 ◽  
Vol 36 (4) ◽  
Author(s):  
Yan Zhong ◽  
Chun Yi
Keyword(s):  
Macrophage Polarization ◽  
Ectopic Expression ◽  
Tumour Microenvironment ◽  
M2 Macrophage ◽  
Breast Carcinomas ◽  
Downstream Target ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
And Function ◽  
M2 Phenotype

Macrophages are highly plastic cells with the ability to differentiate into both M1- and M2-polarized phenotypes. As a distinct M2-polarized population, tumour-associated macrophages (TAMs) promote tumorigenesis owing to their pro-angiogenic and immune-suppressive functions in tumour microenvironment. In the present study, we found that the microRNA-720 (miR-720) was down-regulated in TAMs isolated from breast carcinomas and M2-polarization macrophages. Overexpression of miR-720 attenuated M2 phenotype expression and thus inhibited M2 polarization. We further identified GATA binding protein 3 (GATA3), a transcriptional factor that plays an important role in M2 macrophage polarization, was the downstream target of miR-720. Ectopic expression of GATA3 restored the M2 phenotype in miR-720 overexpressed macrophages. Importantly, overexpression of miR-720 inhibited pro-migration behaviour and phagocytic ability of M2-polarized macrophages. Thus, our data suggest that miR-720 plays an important role in regulating M2 macrophage polarization and function.

scholarly journals Cathepsin S-mediated autophagic flux in tumor-associated macrophages accelerate tumor development by promoting M2 polarization

2014 ◽  
Vol 13 (1) ◽  
pp. 43 ◽  
Author(s):  
Min Yang ◽  
Jingwei Liu ◽  
Jianghua Shao ◽  
Yanwen Qin ◽  
Qunsheng Ji ◽  
...  
Keyword(s):  
Tumor Development ◽  
Cathepsin S ◽  
Autophagic Flux ◽  
Tumor Associated Macrophages ◽  
M2 Polarization

scholarly journals Asaronic Acid Inhibited Glucose-Triggered M2-Phenotype Shift Through Disrupting the Formation of Coordinated Signaling of IL-4Rα-Tyk2-STAT6 and GLUT1-Akt-mTOR-AMPK

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 766-766
Author(s):  
Hyeongjoo Oh ◽  
Young-Hee Kang
Keyword(s):  
High Glucose ◽  
Metabolic Diseases ◽  
Therapeutic Potential ◽  
Macrophage Polarization ◽  
Funding Sources ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Inflammatory State ◽  
Functional Induction ◽  
M2 Phenotype

Abstract Objectives Macrophage polarization has been implicated in the pathogenesis of metabolic diseases such as obesity, diabetes and atherosclerosis. Macrophages responsive to polarizing signals can result in their functional phenotype shifts. This study examined whether high glucose induced the functional transition of M2 macrophages, which was inhibited by asaronic acid, one of purple perilla constituents. Methods J774A.1 murine macrophages were incubated with 40 ng/ml interleukin(IL)-4 or 33 mM glucose in the absence and presence of 1–20 μΜ asaronic acid, which led to M2 or diabetic inflammatory state at 48 h. TheM2 macrophage biomarkers were estimated by conducting Western blot analysis, IHC and ELISA with specific antibodies. Results In macrophages treated with IL-4 for 48 h, asaronic acid further accelerated cellular induction of the M2 markers of IL-10, arginase-1, CD163 and PPARγ via increased IL-4-IL-4Rα interaction and activated Tyk2-STAT6 pathway. Asaronic acid promoted angiogenic and proliferative capacity of M2-polarized macrophages, through increasing expression of VEGF, PDGF and TGF-β. In glucose-loaded macrophages there was cellular induction of IL-4, IL-4 Rα, arginase-1 and CD163, indicating that high glucose skewed naïve macrophages toward M2 phenotypes. However, asaronic acid inhibited M2 polarization in diabetic macrophages in parallel with inactivation of Tyk2-STAT6pathway and blockade of GLUT1-mediated metabolic pathway of Akt-mTOR-AMPKα. Consequently, asaronic acid deterred functional induction of COX-2, CTGF, α-SMA, SR-A and SR-B1in diabetic macrophages with M2 phenotype. Conclusions These results demonstrated that asaronic acid allayed glucose-activated M2-phenotype shift through disrupting coordinated signaling of IL-4Rα-Tyk2-STAT6 in parallel with GLUT1-Akt-mTOR-AMPK pathway. Thus, asaronic acid has therapeutic potential in combating diabetes-associated inflammation, fibrosis, and atherogenesis through inhibiting glucose-evoked M2 polarization. Funding Sources This work was supported by the Hallym University Research Fund, 2019 (HRF-201,910–007) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2019R1A2C1003218).

The Next Generation of Pattern Recognition Receptor Agonists: Improving Response Rates in Cancer Immunotherapy

2020 ◽  
Vol 27 (34) ◽  
pp. 5654-5674 ◽  
Author(s):  
Daniel H. O’ Donovan ◽  
Yumeng Mao ◽  
Deanna A. Mele
Keyword(s):  
Pattern Recognition ◽  
Immune System ◽  
Cancer Immunotherapy ◽  
Anticancer Agents ◽  
Adaptive Immune System ◽  
Antitumor Effects ◽  
Tlr Agonists ◽  
Recent Success ◽  
Promising Target ◽  
Tumor Types

The recent success of checkpoint blocking antibodies has sparked a revolution in cancer immunotherapy. Checkpoint inhibition activates the adaptive immune system leading to durable responses across a range of tumor types, although this response is limited to patient populations with pre-existing tumor-infiltrating T cells. Strategies to stimulate the immune system to prime an antitumor response are of intense interest and several groups are now working to develop agents to activate the Pattern Recognition Receptors (PRRs), proteins which detect pathogenic and damageassociated molecules and respond by activating the innate immune response. Although early efforts focused on the Toll-like Receptor (TLR) family of membrane-bound PRRs, TLR activation has been associated with both pro- and antitumor effects. Nonetheless, TLR agonists have been deployed as potential anticancer agents in a range of clinical trials. More recently, the cytosolic PRR Stimulator of IFN Genes (STING) has attracted attention as another promising target for anticancer drug development, with early clinical data beginning to emerge. Besides STING, several other cytosolic PRR targets have likewise captured the interest of the drug discovery community, including the RIG-Ilike Receptors (RLRs) and NOD-like Receptors (NLRs). In this review, we describe the outlook for activators of PRRs as anticancer therapeutic agents and contrast the earlier generation of TLR agonists with the emerging focus on cytosolic PRR activators, both as single agents and in combination with other cancer immunotherapies.

Engineering “Antimicrobial Peptides” and Other Peptides to Modulate Protein-Protein Interactions in Cancer

2020 ◽  
Vol 20 (32) ◽  
pp. 2970-2983
Author(s):  
Samuel J.S. Rubin ◽  
Nir Qvit
Keyword(s):  
Antimicrobial Peptides ◽  
Protein Interactions ◽  
Anticancer Agents ◽  
Cancer Therapeutics ◽  
Target Cells ◽  
Protein Protein Interactions ◽  
Peptide Backbone ◽  
Modified Peptides ◽  
Selective Death ◽  
Drug Leads

Antimicrobial peptides (AMPs) are a class of peptides found across a wide array of organisms that play key roles in host defense. AMPs induce selective death in target cells and orchestrate specific or nonspecific immune responses. Many AMPs exhibit native anticancer activity in addition to antibacterial activity, and others have been engineered as antineoplastic agents. We discuss the use of AMPs in the detection and treatment of cancer as well as mechanisms of AMP-induced cell death. We present key examples of cathelicidins and transferrins, which are major AMP families. Further, we discuss the critical roles of protein-protein interactions (PPIs) in cancer and how AMPs are well-suited to target PPIs based on their unique drug-like properties not exhibited by small molecules or antibodies. While peptides, including AMPs, can have limited stability and bioavailability, these issues can be overcome by peptide backbone modification or cyclization (e.g., stapling) and by the use of delivery systems such as cellpenetrating peptides (CPPs), respectively. We discuss approaches for optimizing drug properties of peptide and peptidomimetic leads (modified peptides), providing examples of promising techniques that may be applied to AMPs. These molecules represent an exciting resource as anticancer agents with unique therapeutic advantages that can target challenging mechanisms involving PPIs. Indeed, AMPs are suitable drug leads for further development of cancer therapeutics, and many studies to this end are underway.

scholarly journals Kdm2a deficiency in macrophages enhances thermogenesis to protect mice against HFD-induced obesity by enhancing H3K36me2 at the Pparg locus

2021 ◽  
Author(s):  
Longmin Chen ◽  
Jing Zhang ◽  
Yuan Zou ◽  
Faxi Wang ◽  
Jingyi Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
High Fat Diet ◽  
Macrophage Polarization ◽  
Fatty Acid Uptake ◽  
Chromatin Accessibility ◽  
Acid Uptake ◽  
High Fat ◽  
M2 Polarization ◽  
Adipose Tissue Macrophages ◽  
Cold Challenge

AbstractKdm2a catalyzes H3K36me2 demethylation to play an intriguing epigenetic regulatory role in cell proliferation, differentiation, and apoptosis. Herein we found that myeloid-specific knockout of Kdm2a (LysM-Cre-Kdm2af/f, Kdm2a−/−) promoted macrophage M2 program by reprograming metabolic homeostasis through enhancing fatty acid uptake and lipolysis. Kdm2a−/− increased H3K36me2 levels at the Pparg locus along with augmented chromatin accessibility and Stat6 recruitment, which rendered macrophages with preferential M2 polarization. Therefore, the Kdm2a−/− mice were highly protected from high-fat diet (HFD)-induced obesity, insulin resistance, and hepatic steatosis, and featured by the reduced accumulation of adipose tissue macrophages and repressed chronic inflammation following HFD challenge. Particularly, Kdm2a−/− macrophages provided a microenvironment in favor of thermogenesis. Upon HFD or cold challenge, the Kdm2a−/− mice manifested higher capacity for inducing adipose browning and beiging to promote energy expenditure. Collectively, our findings demonstrate the importance of Kdm2a-mediated H3K36 demethylation in orchestrating macrophage polarization, providing novel insight that targeting Kdm2a in macrophages could be a viable therapeutic approach against obesity and insulin resistance.

scholarly journals Iron Released after Cryo-Thermal Therapy Induced M1 Macrophage Polarization, Promoting the Differentiation of CD4+ T Cells into CTLs

2021 ◽  
Vol 22 (13) ◽  
pp. 7010
Author(s):  
Shicheng Wang ◽  
Man Cheng ◽  
Peng Peng ◽  
Yue Lou ◽  
Aili Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Immunity ◽  
Macrophage Polarization ◽  
Thermal Therapy ◽  
High Plasticity ◽  
Antitumor Effects ◽  
M1 Macrophages ◽  
Splenic Macrophages ◽  
M1 Macrophage

Macrophages play critical roles in both innate and adaptive immunity and are known for their high plasticity in response to various external signals. Macrophages are involved in regulating systematic iron homeostasis and they sequester iron by phagocytotic activity, which triggers M1 macrophage polarization and typically exerts antitumor effects. We previously developed a novel cryo-thermal therapy that can induce the mass release of tumor antigens and damage-associated molecular patterns (DAMPs), promoting M1 macrophage polarization. However, that study did not examine whether iron released after cryo-thermal therapy induced M1 macrophage polarization; this question still needed to be addressed. We hypothesized that cryo-thermal therapy would cause the release of a large quantity of iron to augment M1 macrophage polarization due to the disruption of tumor cells and blood vessels, which would further enhance antitumor immunity. In this study, we investigated iron released in primary tumors, the level of iron in splenic macrophages after cryo-thermal therapy and the effect of iron on macrophage polarization and CD4+ T cell differentiation in metastatic 4T1 murine mammary carcinoma. We found that a large amount of iron was released after cryo-thermal therapy and could be taken up by splenic macrophages, which further promoted M1 macrophage polarization by inhibiting ERK phosphorylation. Moreover, iron promoted DC maturation, which was possibly mediated by iron-induced M1 macrophages. In addition, iron-induced M1 macrophages and mature DCs promoted the differentiation of CD4+ T cells into the CD4 cytolytic T lymphocytes (CTL) subset and inhibited differentiation into Th2 and Th17 cells. This study explains the role of iron in cryo-thermal therapy-induced antitumor immunity from a new perspective.

scholarly journals Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 903
Author(s):  
Xiao-Mei Zhang ◽  
De-Gao Chen ◽  
Shengwen Calvin Li ◽  
Bo Zhu ◽  
Zhong-Jun Li
Keyword(s):  
Metabolic Regulation ◽  
Transcriptional Profiling ◽  
Tumor Development ◽  
Metabolic Reprogramming ◽  
Cancer Therapies ◽  
Functional Heterogeneity ◽  
Tumor Associated Macrophages ◽  
Metabolic Remodeling ◽  
And Function ◽  
Mapping Models

Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous “camouflage” in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages’ ontogeny in macrophages’ functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs’ origins may help understand the classification of TAMs’ population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.

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