SNORA5A regulates tumor-associated macrophage M1/M2 phenotypes via TRAF3IP3 in breast cancer

Small nucleolar RNAs (snoRNAs) have robust potential functions and therapeutic value in breast cancer. Herein, we investigated the role SNORA5A in breast cancer. Samples from The Cancer Genome Atlas (TCGA) were reviewed. The transcription matrix and clinical information were analyzed using R software and validated in clinical tissue samples. SNORA5A was significantly down-regulated in breast cancer, and high expression of SNORA5A correlated with a favorable prognosis. High expression of SNORA5A induced a high concentration of tumor-associated macrophages M1 and a low concentration of tumor-associated macrophages M2. Moreover, SNORA5A were clustered in terms related to cancer and immune functions. Possible downstream molecules of SNORA5A were identified, among which TRAF3IP3 was positively correlated with M1 and negatively correlated with M2. The function of TRAF3IP3 in tumor inhibition and its relationship with macrophages in clinical tissue samples were in accordance with bioinformatics analysis results. SNORA5A could regulate macrophage phenotypes through TRAF3IP3 and serves as a potential prognostic marker for breast cancer patients.

Cinobufacini inhibits the metastasis of colorectal cancer by regulating polarization of M2 macrophages / 安徽医科大学学报

Objective To investigate the effect of cinobufacini on inhibiting colorectal cancer metastasis by regula-ting the polarization of M2 macrophages.Methods THP-1 was induced into M0 type macrophages.The condi-tioned medium of HCT116 cells was collected to stimulate M0 type macrophages.The polarization of M2 type mac-rophages was observed by flow cytometry,real-time quantitative PCR and ELISA experiments.The conditioned me-dium of M0 type macrophages and HCT116-Mφ cells was collected to stimulate HCT116 cells.The ability of migra-tion and invasion was observed by wound healing assay and Transwell assay.The effect of cinobufacini on the via-bility of HCT116 cells was detected by CCK-8 assay.The conditioned medium of HCT116 and HCT116+cinobufa-cini was collected to stimulate M0 type macrophages.The polarization of M2 type macrophages was observed by flow cytometry,real-time quantitative PCR and ELISA experiments.The conditioned media of HCT116-Mφ cells and(HCT116+cinobufacini)-Mφ cells were collected to stimulate HCT116 cells.The changes of migration and inva-sion ability were observed by wound healing assay and Transwell assay.Results After stimulation of M0 type mac-rophages in HCT116 cell conditioned medium,the morphology of M0 macrophages turned into fusiform cells,the proportion of CD11b+CD206+cells increased,and the expression of M2 macrophage markers IL-10 and TGF-β in-creased.The migration and invasion ability of HCT116 cells were significantly enhanced after stimulation in the conditioned medium of HCT1 16-Mφ cells.After the addition of cinobufacini,not only the polarization proportion of M2 macrophages decreased,but also the metastatic effect mediated by M2 macrophages was inhibited.Conclusion HCT116 cells can induce the polarization of M2 macrophages,while cinobufacini can inhibit the tumor metastasis mediated by M2 macrophages by inhibiting the polarization of M2 macrophages.

Research progress in functional polarization of tumor-associated macrophages and targeting strategies / 中华微生物学和免疫学杂志

Tumor-associated macrophages (TAMs) are the predominant immune cells in the tumor microenvironment (TME). They have been shown to play an important immunosuppressive role in the development of TME and promote tumor immune escape, growth and metastasis. It is a current research hotspot to regulate the functional polarization of TAMs through trained immunity (metabolic reprogramming, epigenetic remodeling) to affect the occurrence and development of tumors. Therefore, in-depth research in this field not only presents a more comprehensive perspective on the pathogenesis of immune-mediated diseases, but also can provide new strategies for clinical anti-tumor immunotherapy. This paper outlines the origin of TAMs and the phenotypes and mechanisms of TAMs polarization, discusses the mechanisms by which metabolic reprogramming and epigenetic remodeling regulate TAMs, summarizes the regulation of TAMs activation and polarization by them, and provides an overview of the progress in TAMs at the current stage of clinical practice, hoping to provide reference for the development of new immunoprevention and treatment strategies.

Progress in antitumor effect of tumor-associated macrophages in co-culture system / 中华微生物学和免疫学杂志

Macrophages are important cells of the immune system. Tumor-associated macrophages are enriched macrophages near tumor cells or tissues. Their role is mainly to promote the construction of tumor inflammatory microenvironment and inhibit tumor immune response. Cell co-culture system is a symbiotic culture system formed by mimicking the internal environment of the body in vitro. The co-culture condition is relatively consistent with the environment in vivo, enabling better information exchange and material exchange between cells, which is a supplement to the monolayer cell culture and animal experiments. Tumor-associated macrophages and tumor cells co-exist in the tumor microenvironment. Thus, constructing a co-culture system for tumor-associated macrophages and tumor cells would be conducive to studying the antitumor effect of tumor-associated macrophages and developing new immunotherapy drugs. The co-culture system would provide a new direction for treating malignant tumors. This article mainly reviewed the co-culture patterns of macrophages and the antitumor effects of different phenotypes of macrophages, and highlighted the importance of using immunotherapy to treat malignant tumors in the tumor microenvironment.

Research progress of TAM in tumor immunotherapy / 肿瘤

TAM(tumor-associated macrophage)is a kind of immune cell in tumor microenvironment,which mainly exists in tumor matrix to mediate inflammatory reaction.Generally,TAM can be stimulated by different cytokines to polarize into M1 macrophage or M2 macrophage with different phenotypes.In the early stage of tumor,M1 macrophages in TAM exhibit pro-inflammatory and anti-tumor activities,while as tumor progresses,TAMs tend to polarize into M2 macrophages to play anti-inflammatory and tumor-promoting roles.A large number of studies have shown that TAM is closely related to tumor growth,invasion,metastasis and poor prognosis.Therefore,targeting TAM has become the focus of anti-tumor immunotherapy.This paper has summarized the origin of TAM,and introduced the specific roles of TAM in promoting tumor proliferation,angiogenesis,migration and invasion and the formation of immunosuppressive environment.At the same time,the research progress of TAM-targeted anti-tumor immu-notherapy in recent years was discussed from 3 aspects:inhibiting monocyte recruitment,promoting TAM apoptosis and reshaping TAM phenotype.

Research progress of the roles of tumor-associated macrophages in gallbladder cancer / 肿瘤

Gallbladder cancer(GBC)is a common malignancy of the biliary system with a poor diagnosis.The 5-year survival rate for patients with advanced GBC is less than 10％.Surgery is the only effective treatment for this disease.Tumor microenvironment(TME)plays an important role in GBC tumorigenesis,progression and prognosis.Tumor-associated macrophages(TAMs)are among the most abundant immune cells infiltrating the TME and are present in all stages of GBC progression.This paper has summarized the dynamic phenotypic transformation that macrophages undergo during GBC progression,discussed the impact that TAMs bring to GBC progression and the therapeutic potential of TAM-targeted strategies,and proposed the possible ways in which TAM are involved in the mechanism of GBC progression and are linked to the construction of the immunosuppressive TME.A generalization and analysis of the biological properties of TAM and their roles in GBC was carried out in the hope to provide reference for the development and innovation of GBC therapies.

Research progress in drugs targeting tumor associated macrophage / 药学学报

Tumor brings great threat to human public health. In recent years, incidence rate and mortality of tumor were rapidly increased in the world. Anti-tumor therapies have undergone the development of cytotoxic therapy, targeted therapy, and immunotherapy. Among them, tumor immunotherapy is rapidly developed and becomes an important anti-tumor therapy in recent years, although it also brings some related side effects. Tumor microenvironment (TME) is composed of immune cells, vascular vessels, fibroblasts, the extracellular matrix, etc. TME significantly affects the efficacy of immunotherapy. Macrophages in the TME are named as tumor associated macrophages (TAMs). Recently, increasing studies have shown that TAMs play an important role in the regulation of tumor immunity, especially in tumor immune surveillance and immune escape. Currently, more and more anti-tumor immunotherapy strategies targeting TAMs are at the development stage. Based on the important role of TAMs in the TME and their potential as therapeutic targets in tumor immunotherapy, we first reviewed the subtypes and functions of TAMs, as well as the roles of TAMs in tumors. Furthermore, we summarized the research progress on anti-tumor strategies targeting TAMs and the current status of drug targeting TAMs. The current review will provide new ideas and novel insights for tumor immunotherapy.

Preparation and polarization activity research of astragalus polysaccharide-superparamagnetic iron oxide nanocomposite / 药学学报

Size and surface modification are the two key factors affecting the effect of macrophages polarization induced by superparamagnetic iron oxide nanoparticles (SPIONs). The smaller the particle size, the better the polarization effect of SPIONs. Besides, the reasonable SPIONs surface modification method can also be used to enhance the polarization effect. In this study, SPIONs was prepared by solvothermal method and optimized by Box-Benhnken center combination design and response surface method. Furthermore, astragalus polysaccharide-superparamagnetic iron oxide nanocomplex (APS-SPIONs) was successfully constructed by EDC/NHS esterification method. The structure of APS-SPIONs was confirmed by dynamic light scatter and infrared spectrometer, and the contents of iron and polysaccharide were characterized by spectrophotometry. The effect of APS-SPIONs on inducing mouse macrophages RAW264.7 polarization was investigated by flow cytometry. The RAW264.7 macrophages-HepG2 human hepatoma cancer cells Transwell co-culture system was established to investigate APS-SPIONs improve anti-tumor function of macrophages in vitro, and the proliferation activity of APS-SPIONs on RAW264.7 detected by cell counting kit-8 (CCK-8) method. The results showed that the average particle size and zeta potential of APS-SPIONs were (82.93 ± 1.47) nm and (-24.00 ± 0.47) mV. Polysaccharide and Fe content were 8.69% and 7.04%, respectively. APS-SPIONs effectively induced the polarization of RAW264.7 into M1 type in vitro, improving the anti-tumor ability of macrophages in a co-culture system, without effecting the proliferation of macrophages. Our study provides a drug development strategy and preliminary research results to educate macrophages and reshape the tumor immune microenvironment to achieve tumor-killing effects.

Tongxie Yaofang regulates tumor-associated macrophage polarization in colorectal cancer under chronic stress / 中国中药杂志

This study aims to investigate the intervention effect and mechanism of Tongxie Yaofang in regulating tumor-associated macrophage polarization on colorectal cancer under chronic stress. BALB/C mice were randomized into blank, control, model, mifepristone, and low-, medium-, and high-dose Tongxie Yaofang groups. The other groups except the blank and model groups were subjected to chronic restraint stress and subcutaneous implantation of colon cancer cells for the modeling of colon cancer under stress. Du-ring this period, the body mass and tumor size of each group of mice were recorded. The degree of depression in mice was assessed by behavioral changes. Enzyme-linked immunosorbent assay was employed to determine the levels of cortisol(CORT), 5-hydroxytryptamine(5-HT), norepinephrine(NE), M1-associated inflammatory cytokines [interleukin(IL)-1β, IL-12, and tumor necrosis factor(TNF)-α], and M2-associated inflammatory cytokines(IL-4 and IL-10) in the serum. The tumor growth of mice in each group was regularly monitored by in vivo imaging. The histopathological changes of tumors in each group of mice were observed by hematoxylin-eosin staining. The proportions of CD86 and CD206 in the tumor tissue were detected by flow cytometry and immunofluorescence staining. Western blot was employed to determine the protein levels of Janus kinase(JAK)1, JAK2, JAK3, signal transducer and activator of transcription(STAT)3, and STAT6 in the tumor tissue. The results showed that chronic stress increased the immobility time of mice, elevated the serum levels of CORT, IL-4, and IL-10, lowered the levels of 5-HT, NE, IL-1β, IL-12, and TNF-α, and promoted the growth of subcutaneous tumors. The tumor cells in the tumor tissue grew actively, with obvious atypia and up-regulated protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and down-regulated protein level of CD86. The treatment with Tongxie Yaofang shortened the immobility time of mice, lowered the serum levels of CORT, IL-4, and IL-10, elevated the serum levels of 5-HT, NE, IL-1β, IL-12, and TNF-α, and inhibited the growth of subcutaneous tumors in mice. Moreover, the treatment caused different degrees of necrosis in the tumor tissues, down-regulated the protein levels of CD206, JAK1, JAK2, JAK3, STAT3, and STAT6, and up-regulated the protein level of CD86. In summary, Tongxie Yaofang can promote the transformation of M2 macrophages to M1 macrophages and change the tumor microenvironment under chronic stress to inhibit the development of colorectal cancer, which may be related to the JAK/STAT signaling pathway.

Immunosuppressive tumor microenvironment contributes to tumor progression in diffuse large B-cell lymphoma upon anti-CD19 chimeric antigen receptor T therapy / 医学前沿

Anti-CD19 chimeric antigen receptor (CAR)-T cell therapy has achieved 40%-50% long-term complete response in relapsed or refractory diffuse large B-cell lymphoma (DLBCL) patients. However, the underlying mechanism of alterations in the tumor microenvironments resulting in CAR-T cell therapy failure needs further investigation. A multi-center phase I/II trial of anti-CD19 CD28z CAR-T (FKC876, ChiCTR1800019661) was conducted. Among 22 evaluable DLBCL patients, seven achieved complete remission, 10 experienced partial remissions, while four had stable disease by day 29. Single-cell RNA sequencing results were obtained from core needle biopsy tumor samples collected from long-term complete remission and early-progressed patients, and compared at different stages of treatment. M2-subtype macrophages were significantly involved in both in vivo and in vitro anti-tumor functions of CAR-T cells, leading to CAR-T cell therapy failure and disease progression in DLBCL. Immunosuppressive tumor microenvironments persisted before CAR-T cell therapy, during both cell expansion and disease progression, which could not be altered by infiltrating CAR-T cells. Aberrant metabolism profile of M2-subtype macrophages and those of dysfunctional T cells also contributed to the immunosuppressive tumor microenvironments. Thus, our findings provided a clinical rationale for targeting tumor microenvironments and reprogramming immune cell metabolism as effective therapeutic strategies to prevent lymphoma relapse in future designs of CAR-T cell therapy.

The suppression of cervical cancer ferroptosis by macrophages: The attenuation of ALOX15 in cancer cells by macrophages-derived exosomes

Induction of cancer cell ferroptosis has been proposed as a potential treatment in several cancer types. Tumor-associated macrophages (TAMs) play a key role in promoting tumor malignant progression and therapy resistance. However, the roles and mechanisms of TAMs in regulating tumor ferroptosis is still unexplored and remains enigmatic. This study shows ferroptosis inducers has shown therapeutic outcomes in cervical cancer in vitro and in vivo. TAMs have been found to suppress cervical cancer cells ferroptosis. Mechanistically, macrophage-derived miRNA-660-5p packaged into exosomes are transported into cancer cells. In cancer cells, miRNA-660-5p attenuates ALOX15 expression to inhibit ferroptosis. Moreover, the upregulation of miRNA-660-5p in macrophages depends on autocrine IL4/IL13-activated STAT6 pathway. Importantly, in clinical cervical cancer cases, ALOX15 is negatively associated with macrophages infiltration, which also raises the possibility that macrophages reduce ALOX15 levels in cervical cancer. Moreover, both univariate and multivariate Cox analyses show ALOX15 expression is independent prognostic factor and positively associated with good prognosis in cervical cancer. Altogether, this study reveals the potential utility of targeting TAMs in ferroptosis-based treatment and ALOX15 as prognosis indicators for cervical cancer.

Strategies for targeting and remodeling tumor microenvironment / 药学学报

Tumor microenvironment (TME) is composed of abnormal tumor vasculature, extracellular matrix components, endothelial cells, pericytes, tumor associated fibroblasts, smooth muscle cells and immune cells, which is characterized by hypoxia, acidosis and high interstitial fluid pressure. Hypoxia and acidosis within the TME trigger an adjustment of the extracellular matrix (ECM), a response from neighbor stromal cells (e.g., fibroblasts) and immune cells (lymphocytes and macrophages), inducing tumor growth, angiogenesis, and ultimately, resulting in metastasis. What's more, the components of TME including abnormal tumor vasculature, rich composition of the ECM, and abundant stroma cells impair tumoral distribution and penetration of the drugs. At the same time, this stromal microenvironment plays a vital role in creating an immunosuppressive environment.Over the past years, more and more researches focus on targeting and remolding TME to improve therapeutic effects against tumors. Herein, we reviewed current strategies developed to target and remodel TME, including modulating tumor hypoxia, tumor vasculature, tumor associated fibroblasts, extracellular matrix components, tumor associated macrophage phenotypes and dendritic cells. Also, potential problems and future directions are pointed out in this review.

The effect of HOXC10 gene on biological behaviors of glioma cells and mechanism in tumor microenvironment / 中华肿瘤杂志

Objective: To study the effects of Homeobox C10 (HOXC10) on biological characteristics such as migration, invasion and proliferation of glioma cancer cells and to explore the role of HOXC10 gene in glioma microenvironment. Methods: The expression level of HOXC10 in high grade glioma (glioblastoma) and low grade glioma and its effect on patient survival were analyzed by using The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) database. Hoxc10-siRNA-1, HOXC10-siRNA-2 and siRNA negative control (NC) were transfected into U251 cells according to the operation instructions of HOXC10-siRNA transfection. 100 ng/ mL recombinant protein chemokine ligand 2 (reCCL2) was added into the transfection group, and was labeled as HOXC10-siRNA-1+ reCCL2 and HOXC10-siRNA-2+ reCCL2 groups. The expressions of HOXC10 mRNA and target protein in each group was detected by real-time fluorescence quantitative polymerase chain reaction (qRT-PCR) and western blot. The proliferation ability of cells in each group was detected by cell counting kit 8 (CCK8) method. The migration ability of cells was detected by Transwell assay and Nick assay, and cell apoptosis was detected by flow cytometry. The expression of chemokines in each group was detected by multiple factors. Co-incubation assays were performed to determine the role of HOXC10 and chemokine ligand 2 (CCL2) in recruiting and polarizing tumor-associated macrophages (M2-type macrophages). Results: The median expression level of HOXC10 in high grade gliomas was 8.51, higher than 1.00 in low grade gliomas (P<0.001) in TCGA database. The median expression level of HOXC10 in high grade gliomas was 0.83, higher than 0.00 in low grade gliomas (P=0.002) in CGGA database. The 5-year survival rate of patients with high HOXC10 expression in TCGA database was 28.2%, lower than 78.7% of those with low HOXC10 expression (P<0.001), and the 5-year survival rate of patients with high HOXC10 expression in CGGA database was 20.3%, lower than 58.0% of those with low HOXC10 expression (P<0.001). The numbers of cell migration in HOXC10-siRNA-1 group and HOXC10-siRNA-2 group were (45±3) and (69±4) respectively, lower than (159±3) in NC group (P<0.05). The cell mobility of HOXC10-siRNA-1 group and HOXC10-siRNA-2 group at 48 hours were (15±2)% and (28±4)% respectively, lower than (80±5)% of NC group (P<0.05). The expressions of vimentin in HOXC10-siRNA-1 group and HOXC10-siRNA-2 group were (141 740.00±34 024.56) and (94 655.00±5 687.97), N-cadherin were (76 810.00±14.14) and (94 254.00±701.45), β-catenin were (75 786.50±789.84) and (107 296.50±9 614.53), lower than (233 768.50±34 114.37), (237 154.50±24 715.50) and (192 449.50±24 178.10) of NC group (P<0.05). The A value of HOXC10-siRNA-1 group and HOXC10-siRNA-2 group were (0.44±0.05) and (0.32±0.02) at 96 hours, lower than 0.92±0.12 of NC group (P<0.05). The apoptosis rates of HOXC10-siRNA-1 group and HOXC10 siRNA-2 group were (10.23±1.24)% and (13.81±2.16)%, higher than (4.60±0.07)% of NC group (P<0.05). The expression levels of CCL2 in U251 cells in HOXC10-siRNA-1 and HOXC10-siRNA-2 groups were (271.63±44.27) and (371.66±50.21), lower than (933.93±29.84) in NC group (P<0.05). The expression levels of CCL5 (234.81±5.95 and 232.62±5.72), CXCL10 (544.13±48.14 and 500.87±15.65) and CXCL11 (215.75±15.30 and 176.18±16.49) in HOXC10-siRNA-1 and HOXC10-siRNA-2 groups were higher than those in NC group (9.98±0.71, 470.54±18.84 and 13.55±0.73, respectively, P<0.05). The recruited numbers of CD14(+) THP1 in HOXC10-siRNA-1 and HOXC10-siRNA-2 groups were (159.33±1.15) and (170.67±1.15), respectively, lower than (360.00±7.81) in NC group (P<0.05), while addition of reCCL2 promoted the recruitment of CD14(+) THP1 cells (287.00±3.61 and 280.67±2.31 in HOXC10-siRNA-1+ reCCL2 group and HOXC10-siRNA-2+ reCCL2 group, respectively, P<0.05). The expressions level of M2-type macrophage-related gene TGF-β in HOXC10-siRNA-1 group and HOXC10-siRNA-2 group were (0.30±0.02) and (0.28±0.02), respectively, lower than (1.06±0.10) in NC group (P<0.05). The expressions level of M1-related gene NOS2 in HOXC10-siRNA-1 and HOXC10-siRNA-2 were (11 413.95±1 911.85) and (5 894.00±945.21), respectively, higher than (13.39±4.32) in NC group (P<0.05). Conclusions: The expression of HOXC10 in glioma is high and positively correlated with the poor prognosis of glioma patients. Knockdown of HOXC10 can inhibit the proliferation, migration and metastasis of human glioma U251 cells. HOXC10 may play an immunosuppressive role in glioma microenvironment by promoting the expression of CCL2 and recruiting and polarizing tumor-associated macrophages (M2 macrophages).

Advances in Tumor-associated Macrophages in Cancer Radiotherapy / 肿瘤防治研究

Tumor-associated macrophages (TAMs) are one of the most abundant immune cells in the tumor microenvironment. As a heterogenous cell population, TAMs usually affect tumor growth, metastasis, and therapeutic resistance. Currently, TAM has attracted wide attention as a promising therapy target for human cancers. As one of the basic treatments of malignant tumors, radiotherapy can regulate the phenotypes and functions of TAM. Meanwhile, TAM can affect the response of cancer cells to radiation. This paper reviews the research advances of TAM in cancer radiotherapy.

Basic and clinical treatments target tumor-associated macrophages in liver cancer / 西安交通大学学报(医学版)

Hepatocellular carcinoma （HCC） most often develops in patients with liver disease characterized by chronic non-resolving inflammation. The inflammatory response is mainly derived from innate immune cells， and tumor-associated macrophages （TAMs） play an important role in the development of tumors．It is usually chemotactic from mononuclear progenitor cells in the blood to tumor tissue， then is induced by the tumor microenvironment and further develops into TAMs. They play an important role in promoting tumor growth，angiogenesis and tumor invasion and inducing tumor tissues to form an environment without inhibition mechanisms. As the relationship between TAMs and malignant tumors becomes clearer， TAMs are beginning to be seen as therapeutic targets. The heterogeneity of TAM subtypes and their origin and dynamic phenotype during the initiation and progression of HCC has been partially unraveled. It further forms the base for developing therapeutic agents by decreasing the population of TAMs via blocking recruitment of bone marrow-derived monocytes and functionally reprograms TAMs to anti-tumoral behavior. This review focuses on the preclinical evolution and hitherto clinical trials for TAM-targeted therapy in HCC.

Tumor-associated macrophages in osteosarcoma / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Osteosarcoma (OS) is the most common primary bone tumor in children and adolescents. It is an aggressive tumor with a tendency to spread to the lung, which is the most common site of metastasis. Patients with advanced OS with metastases have poor prognoses despite the application of chemotherapy, thus highlighting the need for novel therapeutic targets. The tumor microenvironment (TME) of OS is confirmed to be essential for and supportive of tumor growth and dissemination. The immune component of the OS microenvironment is mainly composed of tumor-associated macrophages (TAMs). In OS, TAMs promote tumor growth and angiogenesis and upregulate the cancer stem cell-like phenotype. However, TAMs inhibit the metastasis of OS. Therefore, much attention has been paid to investigating the mechanism of TAMs in OS development and the progression of immunotherapy for OS. In this article, we aim to summarize the roles of TAMs in OS and the major findings on the application of TAMs in OS treatment.

MicroRNAs in tumor immunity: functional regulation in tumor-associated macrophages / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are critical for cancer initiation and progression. MicroRNAs (miRNAs) could notably influence the phenotype of TAMs through various targets and signal pathways during cancer progression due to their post-transcriptional regulation. In this review, we discuss mainly the regulatory function of miRNAs on macrophage differentiation, functional polarization, and cellular crosstalk. Firstly, during the generation process, miRNAs take part in the differentiation from myeloid cells to mature macrophages, and this maturation process directly influences their recruitment into the TME, attracted by tumor cells. Secondly, macrophages in the TME can be either tumor-promoting or tumor-suppressing, depending on their functional polarization. Large numbers of miRNAs can influence the polarization of macrophages, which is crucial for tumor progression, including tumor cell invasion, intravasation, extravasation, and premetastatic site formation. Thirdly, crosstalk between tumor cells and macrophages is essential for TME formation and tumor progression, and miRNAs can be the mediator of communication in different forms, especially when encapsulated in microvesicles or exosomes. We also assess the potential value of certain macrophage-related miRNAs (MRMs) as diagnostic and prognostic markers, and discuss the possible development of MRM-based therapies.

MicroRNAs in tumor immunity: functional regulation in tumor-associated macrophages / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME) and are critical for cancer initiation and progression. MicroRNAs (miRNAs) could notably influence the phenotype of TAMs through various targets and signal pathways during cancer progression due to their post-transcriptional regulation. In this review, we discuss mainly the regulatory function of miRNAs on macrophage differentiation, functional polarization, and cellular crosstalk. Firstly, during the generation process, miRNAs take part in the differentiation from myeloid cells to mature macrophages, and this maturation process directly influences their recruitment into the TME, attracted by tumor cells. Secondly, macrophages in the TME can be either tumor-promoting or tumor-suppressing, depending on their functional polarization. Large numbers of miRNAs can influence the polarization of macrophages, which is crucial for tumor progression, including tumor cell invasion, intravasation, extravasation, and premetastatic site formation. Thirdly, crosstalk between tumor cells and macrophages is essential for TME formation and tumor progression, and miRNAs can be the mediator of communication in different forms, especially when encapsulated in microvesicles or exosomes. We also assess the potential value of certain macrophage-related miRNAs (MRMs) as diagnostic and prognostic markers, and discuss the possible development of MRM-based therapies.

Effect of tumor-associated macrophages on malignant biological behaviors of gastric cancer MGC-803 cells / 中国肿瘤生物治疗杂志

@# Objective: To investigate the effects of tumor-associated macrophages (TAM) on proliferation, migration, invation and apoptosis of gastric cancer MGC-803 cells and the possible mechanisms. Methods: Human monocyte THP-1 was cultured in vitro. After being added with PMA and IL-4, the levels of interleukin-12 (IL-12) and interleukin-10 (IL-10) in cell supernatant were detected by enzyme-linked immunosorbent assay (ELISA). MGC-803 cells at logarithmic phase and M2-type TAM cells were divided into single cell culture group, non-contact co-culture group and contact co-culture group according to different culture methods. MTT assay was used to detect the proliferation of MGC-803 cells, Transwell assay was used to detect cell migration and invasion, andAnnexin V-FITC/ PI staining flow cytometry was used to examine the apoptosis and cell cycle changes of MGC-803 cells; In addition, the mRNAand protein expressions of matrix metalloproteinase-9 (MMP-9) and MMP-2 were detected by Real-time fluorescence quantitative PCR (qPCR) and Western blotting. Results: Compared with PMA group, the level of IL-12 in cell supernatant of PMA+IL-4 group decreased significantly while the level of IL-10 increased significantly (all P<0.05), indicating THP-1 cells were successfully induced to differentiate into M2-type TAM. Compared with the single cell culture group, the non-contact co-culture group and the contact co-culture group exhibited: (1) significantly increased proliferation rate of MGC-803 cells (P<0.05)； (2) increased number of migrated and invaded cells (all P < 0.05)； (3) significantly decreased apoptotic rate (P<0.05)； (4) increased proportion of S, G2 phase cells and decreased proportion of G1 phase cells (all P<0.05)；and (5) significantly increased mRNA and protein expressions of MMP-9 and MMP-2 (all P<0.05). Conclusion: TAM can promote the proliferation, migration and invasion of gastric cancer MGC-803 cells, relieve G1 phase arrest and reduce cell apoptosis, which may be related to the up-regulation of MMP-9 and MMP-2 expression in gastric cancer cells.

Biomimetic albumin-modified gold nanorods for photothermo-chemotherapy and macrophage polarization modulation

Nanotechnology-based photothermal therapy has attracted great attention in the past decade. Nevertheless, photothermal therapy has some inherent drawbacks, such as the uneven heat production and limited laser penetration, often leading to insufficient treatment outcomes. Here, we developed a combination strategy to improve cancer therapy. The biomimetic albumin-modified gold nanorods (AuNRs) were prepared with incorporation of paclitaxel (PTX). This therapeutic system was characterized by several features. First, the albumin modification enhanced the biocompatibility and colloidal stability. Second, the surface-coated albumin promoted cellular uptake the albumin-binding protein pathway. Third, PTX was incorporated hydrophobic interaction between PTX and the albumin lipophilic domain. Fourth, the system can be used for combined photothermo-chemotherapy for yielding synergistic effects. The antitumor activity of the system was evaluated both and using the HCT116 colon cancer cell and tumor model. The combination therapy was found with an enhanced treatment efficiency and no obvious side effect. Most importantly, the thermal effect was also discovered with the ability to modulate the tumor microenvironments and suppress the macrophages polarization towards the M2 pro-tumor phenotype. It could be a mechanism for photothermal immunotherapy. The combination strategy and the system provide a potential method for cancer therapy.