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The prognostic impact of traditional Chinese medicine monomers on tumor-associated macrophages in non-small cell lung cancer

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Chinese Journal of Natural Medicines 2019年第10期17卷 729-737页

作者： WAN Liang-Qin TAN Yan JIANG Miao HUA Qian School of Acupuncture-Moxibustion and Tuina Beijing University of Chinese MedicineBeijing 100029China Dongzhimen Hospital Beijing University of Chinese MedicineBeijing 100029China

Non-small cell lung cancer(NSCLC) accounts for 80%-85% of all lung malignancies and good diagnosis and prognosis of NSCLC are critical to the increase of its survival rate. tumor-associated macrophages(TAM) abundantly present in numerous cancer types, and the role of TAMs in tumor biology and their prognostic value in cancer become major topics of interest. After various stimulations in the tumor microenvironment, TAMs develop into a M1(tumor-inhibitory) phenotype or M2(tumor-promoting) phenotype. Recent studies show that traditional Chinese medicine(TCM) monomers have markedly inhibitory actions for NSCLC through M1/M2 modulation. Due to the TCM monomers mainly covered five categories, i.e. terpenoids, flavonoids, polysaccharides, natural polyphenols, and alkaloids. Thus, we will discuss the regulation of TCM monomers on TAM involve in these five parts in this review. In addition, the potential role of TAMs as therapeutic targets will be discussed.

关键词： Lung cancer tumor microenvironment tumor-associated macrophages Traditional Chinese medicine (TCM) monomer Immunotherapy

tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

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Chinese Journal of Cancer Research 2020年第1期32卷 72-88页

作者： Zhu Wang Yang Yang Yancheng Cui Chao Wang Zhiyong Lai Yansen Li Wei Zhang Harri Mustonen Pauli Puolakkainen Yingjiang Ye Kewei Jiang Zhanlong Shen Shan Wang Department of Gastroenterological Surgery Peking University People’s HospitalBeijing 100044China Laboratory of Surgical Oncology Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment ResearchPeking University People’s HospitalBeijing 100044China Department of Surgery Helsinki University Central Hospitaland University of HelsinkiHelsinki 00290Finland

Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer(GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified.Methods: THP-1 monocytes were induced by PMA/interleukin(IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation(Ch IP) assay were used to investigate the mechanism of transforming growth factor β2(TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo.Results: We found that Kindlin-2 expression was upregulated at both m RNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo.Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.

关键词： Gastric cancer tumor-associated macrophage Kindlin-2 invasion and metastasis

Promotion of Sema4D expression by tumor-associated macrophages: Significance in gastric carcinoma

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World Journal of Gastroenterology 2018年第5期24卷 593-601页

作者： Han Li Jin-Shen Wang Lin-Jun Mu Ke-Shu Shan Le-Ping Li Yan-Bing Zhou Department of General Surgery Affiliated Hospital of Qingdao University Department of Gastrointestinal Surgery Shandong Provincial Hospital Affiliated to Shandong University Department of Emergency Surgery Weifang People’s Hospital

AIM To study the role of semaphorin 4 D(Sema4 D) expression promoted by tumor-associated macrophages(TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma.METHODS CD68 and Sema4 D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidinperoxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4 D level in the SGC-7901 cell supernatant were measured using an enzymelinked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively.RESULTS CD68 and Sema4 D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues(71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P associated with histological differentiation, TNM stage, and lymph node metastasis(P < 0.05), and their expression levels were positively correlated with one another(r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4 D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control(1224.13 ± 29.43 vs 637.15 ± 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays(P < 0.01).CONCLUSION TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4 D protein expression. Combined detection of TAM markers, CD68 and Sema4 D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression.

关键词： Gastric carcinoma CD68 Semaphorin 4D tumor-associated macrophages

Colorectal cancer vaccines: tumor-associated antigens vs neoantigens

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World Journal of Gastroenterology 2018年第48期24卷 5418-5432页

作者： Sandra Wagner Christina S Mullins Michael Linnebacher Section of Molecular Oncology and Immunotherapy General SurgeryUniversity Medical Center

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

关键词： Cancer vaccines Colorectal neoplasm Immunotherapy Neoplasm antigen tumor-associated antigens tumor-specific antigens Neoantigen(s)

Polarization of M1 tumor associated macrophage promoted by the activation of TLR3 signal pathway

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Asian Pacific Journal of Tropical Medicine 2016年第5期9卷 470-474页

作者： Bo Liu Xia Wang Tai-Zhong Chen Guang-Liang Li Chang-Chun Tan Yong Chen Shao-Qiang Duan Department of Pediatric Surgery Yongchuan hospital of chongqing medical university

Objective: To investigate the correlation between activation of toll-like receptors 3(TLR3) signaling pathway and tumor-associated macrophage and its effect on the tumor growth. Methods: The mice Lewis lung cancer cell lines 3LL and melanoma B16H10 were used to construct the subcutaneous transplantation tumor models and then they were treated with Poly-ICLC. The curative effect was observed and then the T cell and macrophage phenotypes infiltrated in local tumor were detected by flow cytometry. After the in vitro culture of mouse bone marrow-derived macrophage, the real-time PCR and western blot were applied to detect the expression of macrophage activation markers and the activation of intracellular signaling pathways. Results: The survival time of mice with brown tumor treated with Poly-ICLC significantly increased and the tumor growth was inhibited. The ratio of local tumor-infiltrated Treg decreased, while the ratio of CD8+ T cell increased significantly. The macrophages surface CD206 expression was down-regulated while the expression of i NOS increased. The Poly-ICLC could promote the expression of M1 markers(IL-1毬, TNF-α毩 and i NOS) in bone marrow-derived macrophage and inhibited the expression of M2 molecules(Arg-1, YM-1 and CD206). The phosphorylation level of downstream p65, TBK1 and IRF3 increased significantly. Conclusions: The Poly-ICLC can activate the TLR3 downstream signaling pathway to induce a M1 polarization of tumor associated macrophage, thereby inhibiting the tumor growth.

关键词： tumor-associated macrophage TLR3 Poly-ICLC M1

tumor-associated macrophages (TAMs) as biomarkers for gastric cancer:A review

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Chronic Diseases and Translational Medicine 2018年第3期4卷 156-163页

作者： Meri R.Raiha Pauli A.Puolakkainen Department of Surgery Helsinki University Hospital and University of HelsinkiHelsinki 00014Finland

Gastric adenocarcinoma is one of the most common types of cancer worldwide, with an incidence of a million new cases annually. In addition to having a high mortality rate due to often delayed detection and its poor response to cancer therapy, it also spreads aggressively. Inflammation has been shown to play a role in carcinogenesis. Consequently, macrophages are important in phagocytosis, antigen presenting and producing cytokines and growth factors. As a response to microenvironmental signals, they may polarize into tumor resisting M1 or tumor promoting M2 macrophages. Recently, studies have indicated that M2-type macrophage resembling tumor-associated macrophages (TAMs) might be used as an independent prognostic factor for gastric cancer. This review will discuss the possible use of TAMs as prognostic tools for gastric cancer and whether they are suitable for use in clinical environment.

关键词： Gastric cancer tumor-associated macrophages Biomarkers Prognosis Diagnosis

Update on a tumor-associated NADH oxidase in gastric cancer cell growth

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World Journal of Gastroenterology 2016年第10期22卷 2900-2905页

作者： Hsiao-Ling Cheng Yi-Hui Lee Tein-Ming Yuan Shi-Wen Chen Pin-Ju Chueh Institute of Biomedical Sciences National Chung Hsing University Department of Surgery FengYuan HospitalMinistry of Health and Welfare Graduate Institute of Basic Medicine China Medical University Department of Medical Research China Medical University Hospital Department of Biotechnology Asia University

Gastric cancer is one of the most common human malignancies, and its prevalence has been shown to be well-correlated with cancer-related deaths worldwide. Regrettably, the poor prognosis of this disease is mainly due to its late diagnosis at advanced stages after the cancer has already metastasized. Recent research has emphasized the identification of cancer biomarkers in the hope of diagnosing cancer early and designing targeted therapies to reverse cancer progression. One member of a family of growth-related nicotinamide adenine dinucleotide(NADH or hydroquinone) oxidases is tumor-associated NADH oxidase(t NOX; ENOX2). Unlike its counterpart CNOX(ENOX1), identified in normal rat liver plasma membranes and shown to be stimulated by growth factors and hormones, t NOX activity purified from rat hepatoma cells is constitutively active. Its activity is detectable in the sera of cancer patients but not in those of healthy volunteers, suggesting its clinical relevance. Interestingly, t NOX expression was shown to be present in an array of cancer cell lines. More importantly, inhibition of t NOX was well correlated with reduced cancer cell growth and induction of apoptosis. RNA interference targeting t NOX expression in cancer cells effectively restored non-cancerous phenotypes, further supporting the vital role of t NOX in cancer cells. Here, we review the regulatory role of t NOX in gastric cancer cell growth.

关键词： Apoptosis Capsaicin Gastric cancer cells Protein expression tumor-associated NADH oxidase

tumor-associated Autoantibodies: Re-Optimization of EarlyCDT-Lung Diagnostic Performance and Its Application to Indeterminate Pulmonary Nodules

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Journal of Cancer Therapy 2017年第5期8卷 506-517页

作者： Graham F. Healey Isabel K. Macdonald Chris Reynolds Jared Allen Andrea Murray Oncimmune Holdings plc Nottingham City Hospital Nottingham UK

Background: Low-dose computed tomography (CT) screening reduces lung cancer mortality but costs are prohibitive for most healthcare budgets due to high false positive rates. An adjunctive test able to distinguish malignant from benign pulmonary nodules would be hugely beneficial. EarlyCDT-Lung measures serum autoantibodies to tumor-associated antigens and has found clinical acceptance to aid early detection of lung cancer for high risk patients. However performance was optimized for screening. The construction of a receiver-operating characteristic (ROC) curve would enable optimization of performance for alternative settings, including nodule malignancy. Methods: A Monte-Carlo search method was used to construct a ROC curve using a case-control cohort, enabling high and low specificity versions of EarlyCDT-Lung to be determined. These were used for a theoretical evaluation of a nodule cohort, and positive predictive value (PPV) was calculated under the assumption of independence of risk source. Patients or their nodules are typically classified into three risk groups: low (0% - 10%), intermediate (10% - 65%) and high (>65%) risk of malignancy. The predicted shift in risk group by application of the high and low specificity versions, along with the current commercial EarlyCDT-Lung, was then estimated. Results: The ROC curve, with an area under the curve of 0.743, was constructed. The high specificity (98%), low specificity (49%) and current commercial (91% specificity) versions of EarlyCDT-Lung re-classified 27%, 23% and 26% of intermediate nodules, respectively, to either a higher (10%, 8% and 10%) or lower (17%, 15% and 16%) risk group. Conclusion: A ROC curve was constructed to allow performance prediction of EarlyCDT-Lung at different specificities in the indeterminate nodule setting. This enabled risk re-classification of intermediate risk nodules, and could therefore facilitate alternative more appropriate intervention. We have shown how a multivariate biomarker test can add to the interpretation of pulmonar

关键词： tumor-associated Autoantibodies Indeterminate Pulmonary Nodules Diagnostic Screening Computed Tomography ROC Curve

Risk factors of interstitial lung diseases in clinically amyopathic dermatomyositis

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Chinese Medical Journal 2020年第6期133卷 644-649页

作者： Yu-Zhou Gan Li-Hua Zhang Lin Ma Feng Sun Yu-Hui Li Yuan An Zhan-Guo Li Hua Ye Department of Rheumatology Immunology and Beijing Key Laboratory for Rheumatism and Immune Diagnosis(BZ0135) Peking University People's HospitalBeijing 100044China Center of Clinical Immunology Peking UniversityBeijing 100044China Department of Rheumatology Hulunbeier People's HospitalHulunbeierInner Mongolia 021008China Department of Rheumatology Hebei Hospital of Traditional Chinese MedicineShijiazhuangHebei 050200China

Background:Clinically amyopathic dermatomyositis(CADM)is a unique sub-type of idiopathic inflammatory myopathies with a high prevalence of interstitial lung disease(ILD).Poor prognosis of the patients was strongly associated with rapid progressive ILD.The aim of this study was to identify risk factors for prediction of different types of ILD in CADM.Methods:In this study,data of 108 inpatients with CADM were collected,including 87 with ILD.The baseline clinical data and laboratory parameters,including myositis-specific and associated antibodies and tumor-associated antigens were analyzed to identify risk factors for acute or subacute interstitial pneumonitis(A/SIP)and chronic interstitial pneumonitis(CIP).Results:In 87 patients with CADM-ILD,39(36.1%)were A/SIP,and 48(44.4%)were CIP.There were 22(20.4%)patients with asymptomatic ILD who were detected by routine high resolution computed tomography.Cytokeratin-19 fragment(CYFRA21-1)was significantly higher in CADM-ILD than that in CADM patients without ILD;carcinoembryonic antigen and neuron-specific enolase were significantly elevated in A/SIP than that in CIP.Patients with A/SIP had a higher positive rate of anti-melanoma differentiation-associated gene 5(MDA5),while patients with CIP had a higher positive rate of anti PL-12 and anti-Ro-52.Logistic regression analysis indicated that elevation of CYFRA21-1 was a risk factor for ILD,higher titer of anti-MDA5 indicated increased likelihood for A/SIP,and higher titer of anti-Ro-52 was also clearly associated with CIP.Conclusions:This study indicated that the prevalence of ILD was high in CADM.Asymptomatic ILD has been previously underestimated.Anti-MDA5 was a risk factor for the presence of A/SIP,and CYFRA21-1 was a risk factor for ILD.

关键词： Clinically amyopathic dermatomyositis Interstitial lung diseases Myositis autoantibodies tumor-associated antigen