THBS4 Promotes the Metastasis of Hepatocellular Carcinoma Cells by Inducing M2 Polarization of Tumor-associated Macrophages / 中国生物化学与分子生物学报

Thrombospondin 4 (THBS4), a member of the THBS family, is a protein secreted by the extracellular matrix and is involved in regulating various physiological processes, such as cell proliferation, adhesion and angiogenesis. Recent studies have shown that the inflammation stimulates THBS4 production and induces the adhesion and accumulation of macrophages. Our previous study confirmed that THBS4 acts as an oncogene in hepatocellular carcinoma (HCC), the effect of THBS4 on the immune microenvironment of HCC remains unclear. This study aims to analyze the role of THBS4 in promoting the metastasis of HCC cells by inducing M2-type polarization of tumor-associated macrophages. We simulate the tumor microenvironment through HCC conditioned medium (HCM) and found that the expression of THBS4 in macrophages increased in a time-dependent manner under the action of HCM (P<0.05); THBS4 knockdown promotes the expression of M1 macrophages markers IL-1β and CD86 (P<0.01), while the expression of M2-type markers IL-10 and CD206 were decreased (P<0.01). Transwell co-culture assay was used to further detect the effect of THBS4-induced M2-type macrophages on HCC metastasis. Results from co-culture of THBS4-downregulated M2 macrophages with HepG2 cells showed that THBS4-downregulated M2-TAMs significantly inhibited the invasion and migration ability of HepG2 cells (all P < 0.01). In conclusion, the tumor microenvironment promotes the expression of THBS4 in macrophages, and THBS4 may promote the invasion and metastasis of HCC cells by inducing M2-type polarization of macrophages. This study provides some new experimental basis for exploring the establishment of THBS4-induced HCC immune microenvironment.

Role of Tumor Associated Macrophages in Chemotherapy Resistance and Intervention with Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

The tumor incidence goes up with every passing year. Chemotherapy， as one of the main treatment methods， is faced with a major challenge of drug resistance in clinical practice. Tumor-associated macrophages （TAMs） are the key factors inducing chemotherapy resistance of tumors. TAMs are inflammatory cells with the largest number in the tumor microenvironment， which are widely distributed in such epithelial tissues as large intestine and stomach in the immune environment and closely associated with multiple common cancers like breast cancer and colorectal cancer. TAMs can be divided into two phenotypes， with M2-polarized TAMs into the tumor-promoting phenotype that affects the oncogenesis and progression and promotes drug resistance via immune escape， angiogenesis and other ways. At the same time， the frequently utilized chemotherapeutic agents will increase the recruitment of TAMs and trigger the secretion of cytokines， leading to the excessive polarization of macrophages to M2 type， followed by tumor drug resistance. The molecular mechanism of chemotherapy resistance is complex， which is becoming an urgent problem in the field of chemotherapy. Traditional Chinese medicine （TCM） has exhibited unique advantages in resisting tumor drug resistance. It has been proved efficient and safe in improving tumor microenvironment and regulating TAMs by acting on multiple targets via multiple ways， thus adjusting tumor progression and improving drug resistance. Based on related articles published in recent years， this paper reviewed the drug resistance-promoting effect of TAMs via regulating the immune microenvironment and interacting with tumor stem cells and the driving effect of chemotherapeutic agents on drug resistance to figure out the role of TAMs in chemotherapy resistance. Besides， it summarized the mechanisms of TCM in regulating related cytokines， proteins， activity， and the polarization direction of TAMs to expound the effective components of TCM in the intervention of drug resistance. The aim of this paper was to provide reference for further research on the biological mechanism of chemotherapy resistance and its targeted intervention with TCM.

2-Hexyl-4-Pentylenic Acid (HPTA) Stimulates the Radiotherapy-induced Abscopal Effect on Distal Tumor through Polarization of Tumor-associated Macrophages / 生物医学与环境科学（英文）

Objective@#The aim of this study was to explore the effects of 2-hexyl-4-pentylenic acid (HPTA) in combination with radiotherapy (RT) on distant unirradiated breast tumors.@*Methods@#Using a rat model of chemical carcinogen (7,12-dimethylbenz[a]anthracene,DMBA)-induced breast cancer, tumor volume was monitored and treatment response was evaluated by performing HE staining, immunohistochemistry, immunofluorescence, qRT-PCR, and western blot analyses.@*Results@#The results demonstrated that HPTA in combination with RT significantly delayed the growth of distant, unirradiated breast tumors. The mechanism of action included tumor-associated macrophage (TAM) infiltration into distant tumor tissues, M1 polarization, and inhibition of tumor angiogenesis by IFN-γ.@*Conclusion@#The results suggest that the combination of HPTA with RT has an abscopal effect on distant tumors

Study of Fusobacterium nucleatum -related bacterial biofilm promoting M2 polarization of macrophages and chemoresistance in colon cancer / 上海交通大学学报（医学版）

Objective: To investigate whether and how Fusobacterium nucleatum-related bacterial biofilm modulates the infiltration of tumor-associated macrophages into tumor microenvironment and the response to chemotherapy in colon cancer patients. Methods: Both biofilm-based F.n-culture medium (BF-CM) and planktonic F.n-culture medium, (P-CM) Fusobacterium nucleatum was cultured, and the culture-medium was collected to coculture with CRC cell lines and macrophages. Quantified real time PCR( qRT-PCR) was used to measure genes related to chemoresistance, CCK8 assay was conducted to measure proliferation inhibition rate of chemicals to cancer cells, qRT-PCR was used to measure the expression of genes related to macrophage polarization. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were conducted to evaluate existence of bacterial biofilm and infiltration of macrophages in tumor tissues of colon cancer. Results: Expression of chemoresistance-related genes(e.g. MDR1/Abcb1a/ Abcb1b) were higher in BF-CM treated CRC cells than those in P-CM treated cells. CRC cell inhibition level via LOHP/5-FU were reduced with F.n culture medium(metabolites) co-culture, and much lower in BF-CM group. Expression of M2-polarization markers were also higher after BF-CM treated macrophages than P-CM. Biofilm positivity was higher in recurrent(confirmed by PET-CT, CT, or colonoscopy) colon cancer patients with post-resection adjuvant chemotherapy, than that in non-recurrent ones; correlated with infiltration rate of M2 macrophages. Conclusion: Fusobacterium nucleatumrelated bacterial biofilm can induce M2-polarization of intratumor macrophages and could promote chemoresistance to chemicals in CRC cells, which may contribute to prognosis of colon cancer patients.

A study on correlation of tumor-associated macrophages infiltration, MMP-2 expression and angiogenesis in colon carcinoma / 中国免疫学杂志

Objective:To study the correlation of tumor-associated macrophages infiltration , MMP-2 expression and angiogenesis in colon carcinoma by testing the MMP-2 through immunological methods ,and counting of macrophages and distributing of vessels in colonic adenocarcinoma at different differential degrees .Methods: Analyze the infiltration of tumor-associated macrophages (TAMs),and count blood capillaries in 79 patients with colon carcinoma by immunohistochemical staining ,detect the expression of MMP-2 in macrophages by immunological methods .Analyze the relationship among numbers of macrophages and vessels , clinical pathology and expression of MMP-2.Results: Macrophages in colon carcinoma were labeled to brown yellow by murine monoclonal antibody to human.The number of macrophages was markedly higher than normal group (F=412.04,P<0.05); Variance of macrophages number had statistical significance in differentiatial degrees and Duck ′s staging of colon carcinoma ( t=10.80 and F=412.04,P<0.05);variance of microvessel density(MVD) had statistical significance in Duck′s staging of colon carcinoma(t=7.35, P<0.05 ) ,MVD in colon carcinoma patients with lymphatic metastasis was higher than patients without lymphatic metastasis ( t=6.77 , P<0.05).Expression of MMP-2 in colon carcinoma showed strong positive.Expression of MMP-2 in patients with lymphatic metastasis was higher than patients without lymphatic metastasis ( t=10.91 , P<0.05 ) . There was a positive relationship among MMP-2 expression,number of tumor-associated macrophages(TAMs) and MVD(r=0.451,0.672,P<0.05,respectively).Conclusion:MMP-2 and TAMs correlated closely with the development of colon carcinoma .TAMs in colon carcinoma can promote the angiogenesis ,growth and metastasis of the tumor by up-regulating the expression of MMP-2.