feng Li

Impaired T cell function in malignant pleural effusion is caused by TGF‐β derived predominantly from macrophages

Malignant pleural effusion (MPE) is an indication of advanced cancer. Immune dysfunction often occurs in MPE. We aimed to identify the reason for impaired T cell activity in MPE from lung cancer patients and to provide clues toward potential immune therapies for MPE. The surface inhibitory molecules and cytotoxic activity of T cells in MPE and peripheral blood (PB) were analyzed using flow cytometry. Levels of inflammatory cytokines in MPE and PB were tested using ELISA. TGF‐β expression in tumor‐associated macrophages (TAMs) was also analyzed. The effect of TAMs on T cells was verified in vitro. Lastly, changes in T cells were evaluated following treatment with anti‐TGF‐β antibody. We found that expression levels of Tim‐3, PD‐1 and CTLA‐4 in T cells from MPE were upregulated compared with those from PB, but levels of IFN‐γ and Granzyme B were downregulated (p < 0.05). The amount of TGF‐β was significantly higher in MPE than in PB (p < 0.05). TGF‐β was mainly produced by TAMs in MPE. When T cells were co‐cultured with TAMs, expression levels of Tim‐3, PD‐1 and CTLA‐4 were significantly higher than controls, whereas levels of IFN‐γ and Granzyme B were significantly decreased, in a dose‐dependent manner (p < 0.05). In vitro treatment with anti‐TGF‐β antibody restored the impaired T cell cytotoxic activity in MPE. Our results indicate that macrophage‐derived TGF‐β plays an important role in impaired T cell cytotoxicity. It will therefore be valuable to develop therapeutic strategies against TGF‐β pathway for MPE therapy of lung cancer.

Association between metformin and the risk of gastric cancer in patients with type 2 diabetes mellitus: a meta-analysis of cohort studies

Objectives The objective of this study was to evaluate the association between metformin therapy and the incidence of gastric cancer (GC) in patients with type 2 diabetes mellitus (T2DM). Methods We systemically searched the following databases for studies published between the databases’ dates of inception and Nov. 2016: PubMed, Embase, the Cochrane Library, the Web of Science, and the China National Knowledge Infrastructure (CNKI). Hazard ratios (HR)and corresponding 95% confidence intervals (CIs) for the association between metformin therapy and the incidence of GC in patients with T2DM were the outcome measures assessed in this study. STATA 12.0 (Stata Corporation, College Station, Texas, USA) was used to conduct the statistical analysis. Results A total of seven cohort studies including 591,077 patients met all the criteria for inclusion in the analysis. Our data showed that metformin therapy was associated with a significantly lower incidence of GC in patients with T2DM than other types of therapy (HR=0.763, 95% CI: 0.642˜0.905). Subgroup analysis showed that patients living in Taiwan benefitted more from metformin therapy than patients living in any other region, as metformin significantly decreased the risk of GC in patients living in Taiwan but did not significantly decrease the risk of GC in patients living in other regions (HR=0.514, 95% CI: 0.384-0.688). The results of the present analysis support the idea that metformin facilitates reductions in the risk of T2DM-related GC. Conclusions The risk of GC among patients with T2DM is lower in patients receiving metformin therapy than in patients not receiving metformin therapy.

Transforming growth factor-beta1 promotes the migration and invasion of sphere-forming stem-like cell subpopulations in esophageal cancer

Esophageal cancer is one of the most lethal solid malignancies. Mounting evidence demonstrates that cancer stem cells (CSCs) are able to cause tumor initiation, metastasis and responsible for chemotherapy and radiotherapy failures. As CSCs are thought to be the main reason of therapeutic failure, these cells must be effectively targeted to elicit long-lasting therapeutic responses. We aimed to enrich and identify the esophageal cancer cell subpopulation with stem-like properties and help to develop new target therapy strategies for CSCs. Here, we found esophageal cancer cells KYSE70 and TE1 could form spheres in ultra low attachment surface culture and be serially passaged. Sphere-forming cells could redifferentiate and acquire morphology comparable to parental cells, when return to adherent culture. The sphere-forming cells possessed the key criteria that define CSCs: persistent self-renewal, overexpression of stemness genes (SOX2, ALDH1A1 and KLF4), reduced expression of differentiation marker CK4, chemoresistance, strong invasion and enhanced tumorigenic potential. SB525334, transforming growth factor-beta 1(TGF-β1) inhibitor, significantly inhibited migration and invasion of sphere-forming stem-like cells and had no effect on sphere-forming ability. In conclusion, esophageal cancer sphere-forming cells from KYSE70 and TE1 cultured in ultra low attachment surface possess cancer stem cell properties, providing a model for CSCs targeted therapy. TGF-β1 promotes the migration and invasion of sphere-forming stem-like cells, which may guide future studies on therapeutic strategies targeting these cells.

CD39/CD73 upregulation on myeloid-derived suppressor cells via TGF-β-mTOR-HIF-1 signaling in patients with non-small cell lung cancer

ABSTRACT CD39/CD73-adenosine pathway has been recently defined as an important tumor-induced immunosuppressive mechanism. We here documented a fraction of CD11b+CD33+ myeloid-derived suppressor cells (MDSCs) in peripheral blood and tumor tissues from non-small cell lung cancer (NSCLC) patients expressed surface ectonucleotidases CD39 and CD73. Tumor TGF-β stimulated CD39 and CD73 expression, thereby inhibited T cell and NK cell activity, and protected tumor cells from the cytotoxic effect of chemotherapy through ectonucleotidase activity. Mechanistically, TGF-β triggered phosphorylation of mammalian target of rapamycin, and subsequently activated hypoxia-inducible factor-1α (HIF-1α) that induced CD39/CD73 expression on MDSCs. CD39 and CD73 on MDSCs, therefore, link their immunosuppressive and chemo-protective effects to NSCLC progression, providing novel targets for chemo-immunotherapeutic intervention.

Target of obstructive sleep apnea syndrome merge lung cancer: based on big data platform

Based on our hospital database, the incidence of lung cancer diagnoses was similar in obstructive sleep apnea Syndrome (OSAS) and hospital general population; among individual with a diagnosis of lung cancer, the presence of OSAS was associated with an increased risk for mortality. In the gene expression and network-level information, we revealed significant alterations of molecules related to HIF1 and metabolic pathways in the hypoxic-conditioned lung cancer cells. We also observed that GBE1 and HK2 are downstream of HIF1 pathway important in hypoxia-conditioned lung cancer cell. Furthermore, we used publicly available datasets to validate that the late-stage lung adenocarcinoma patients showed higher expression HK2 and GBE1 than early-stage ones. In terms of prognostic features, a survival analysis revealed that the high GBE1 and HK2 expression group exhibited poorer survival in lung adenocarcinoma patients. By analyzing and integrating multiple datasets, we identify molecular convergence between hypoxia and lung cancer that reflects their clinical profiles and reveals molecular pathways involved in hypoxic-induced lung cancer progression. In conclusion, we show that OSAS severity appears to increase the risk of lung cancer mortality.

‘Repair’ Treg Cells in Tissue Injury

Studies in mice and humans have elucidated an important role for Tregs in promoting tissue repair and restoring tissue integrity. Emerging evidence has revealed that Tregs promoted wound healing and repair processes at multiple tissue sites, such as the heart, liver, kidney, muscle, lung, bone and central nervous system. The localization of repair Tregs in the lung, muscle and liver exhibited unique phenotypes and functions. Epidermal growth factor receptor, amphiregulin, CD73/CD39 and keratinocyte growth factor are important repair factors that are produced or expressed by repair Tregs; these factors coordinate with parenchymal cells to limit injury and promote repair. In addition, repair Tregs can be modulated by IL-33/ST2, TCR signals and other cytokines in the context of injured microenvironment cues. In this review, we provide an overview of the emerging knowledge about Treg-mediated repair in damaged tissues and organs.

Metformin-Induced Reduction of CD39 and CD73 Blocks Myeloid-Derived Suppressor Cell Activity in Patients with Ovarian Cancer

Metformin is a broadly prescribed drug for type 2 diabetes that exerts antitumor activity, yet the mechanisms underlying this activity remain unclear. We show here that metformin treatment blocks the suppressive function of myeloid-derived suppressor cells (MDSC) in patients with ovarian cancer by downregulating the expression and ectoenzymatic activity of CD39 and CD73 on monocytic and polymononuclear MDSC subsets. Metformin triggered activation of AMP-activated protein kinase α and subsequently suppressed hypoxia-inducible factor α, which was critical for induction of CD39/CD73 expression in MDSC. Furthermore, metformin treatment correlated with longer overall survival in diabetic patients with ovarian cancer, which was accompanied by a metformin-induced reduction in the frequency of circulating CD39+CD73+ MDSC and a concomitant increase in the antitumor activities of circulating CD8+ T cells. Our results highlight a direct effect of metformin on MDSC and suggest that metformin may yield clinical benefit through improvement of antitumor T-cell immunity by dampening CD39/CD73-dependent MDSC immunosuppression in ovarian cancer patients.Significance: The antitumor activity of an antidiabetes drug is attributable to reduced immunosuppressive activity of myeloid-derived tumor suppressor cells. Cancer Res; 78(7); 1779-91. ©2018 AACR.

Integrated analysis profiles of long non-coding RNAs reveal potential biomarkers of drug resistance in lung cancer

Lung cancer is one of the leading causes of cancer-related death. Resistance to chemotherapy and molecularly targeted therapies is a major problem that can contribute substantially to high mortality. The roles of long non-coding RNAs (lncRNAs) in drug resistance of lung cancer are insufficiently understood. Here, we identified a distinct drug resistance-related transcriptional signature and constructed a functional lncRNA-mRNA co-expression network. We found that 34 lncRNAs and 103 mRNAs have differential expression in drug resistance of lung cancer, in which 10 lncRNAs were down regulated and 24 up regulated; 49 mRNAs were down regulated and 54 up regulated. LncRNAs-mRNAs expression network analysis revealed a role for lncRNAs in modulating cancer-related pathways. We also found that two pair lncRNAs and their subnetworks were highly related to drug resistance. NR_028502.1/NR_028505.1 were found differentially co-expressed with nine mRNAs, and highly correlated with better clinical outcome. NR_030725.1/NR_030726.1 co-expressed with eleven mRNAs, and were associated with poor survival in patients with lung cancer. Our work comprehensively identified expression signature of resistance-associated lncRNAs and their inter-regulated mRNAs in lung cancer.Lung cancer is one of the leading causes of cancer-related death. Resistance to chemotherapy and molecularly targeted therapies is a major problem that can contribute substantially to high mortality. The roles of long non-coding RNAs (lncRNAs) in drug resistance of lung cancer are insufficiently understood. Here, we identified a distinct drug resistance-related transcriptional signature and constructed a functional lncRNA-mRNA co-expression network. We found that 34 lncRNAs and 103 mRNAs have differential expression in drug resistance of lung cancer, in which 10 lncRNAs were down regulated and 24 up regulated; 49 mRNAs were down regulated and 54 up regulated. LncRNAs-mRNAs expression network analysis revealed a role for lncRNAs in modulating cancer-related pathways. We also found that two pair lncRNAs and their subnetworks were highly related to drug resistance. NR_028502.1/NR_028505.1 were found differentially co-expressed with nine mRNAs, and highly correlated with better clinical outcome. NR_030725.1/NR_030726.1 co-expressed with eleven mRNAs, and were associated with poor survival in patients with lung cancer. Our work comprehensively identified expression signature of resistance-associated lncRNAs and their inter-regulated mRNAs in lung cancer.

Construction of an oesophageal cancer-specific ceRNA network based on miRNA, lncRNA, and mRNA expression data

AIM To explore the expression profiles of microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and mRNAs in oesophageal squamous cell carcinoma (ESCC) in order to construct an oesophageal cancer-specific competing endogenous RNA (ceRNA) network. METHODS In this work, the expression data of miRNAs, lncRNAs, and mRNAs in ESCC were obtained. An oesophageal cancer-specific ceRNA network was then constructed and investigated. RESULTS CeRNAs have the ability to reduce the targeting activity of miRNAs, leading to the de-repression of specific mRNAs with common miRNA response elements. CeRNA interactions have a critical effect in gene regulation and cancer development. CONCLUSION This study suggests a novel perspective on potential oesophageal cancer mechanisms as well as novel pathways for modulating ceRNA networks for treating cancers.

Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis

ABSTRACT Purpose: Tumor development has been closely linked to tumor microenvironment, particularly in terms of myeloid-derived suppressive cells (MDSCs), a heterogeneous population of immature myeloid cells that protect tumors from elimination by immune cells. Approaches aimed at blocking MDSC accumulation could improve cancer clinical outcome. Experimental Design: We investigated that metformin suppressed MDSC migration to inhibit cancer progression. Primary tumor tissues were incubated with metformin, and proinflammatory chemokine production was measured. To study MDSC chemotaxis in vivo, BALB/C nude mice were injected subcutaneously with TE7 cells and treated with metformin. Migration of adoptively transferred MDSCs was analyzed using flow cytometry and immunohistochemistry. Results: The frequency of tumor-infiltrated polymorphonuclear (PMN)-MDSCs was increased compared to their circulating counterparts. There was a significant correlation between PMN-MDSCs accumulation in tumors and ESCC prognosis. Moreover, PMN-MDSCs displayed immunosuppressive activity in vitro. Treatment with metformin reduced MDSC migration in patients. Metformin inhibited CXCL1 secretion in ESCC cells and tumor xenografts by enhancing AMPK phosphorylation and inducing DACH1 expression, leading to NF-κB inhibition and reducing MDSC migration. Knockdown of AMPK and DACH1 expression blocked the effect of metformin on MDSC chemotaxis. Conclusions: A novel anti-tumor effect of metformin, which is mediated by reducing PMN-MDSC accumulation in the tumor microenvironment via AMPK/DACH1/CXCL1 axis.