食管腺癌发生发展与慢性炎症的相关性研究

近年来,有不少关于食管腺癌发生发展的研究,其中以食管腺癌与慢性炎症反应的相关研究最为热门.相关研究证实各种刺激因素,如肥胖、反流胃酸等,诱发炎症细胞及免疫细胞在食管黏膜下浸润,其可释放相应炎症因子和活性氧(ROS),从而激活下游信号通路,促使细胞增殖和抑制细胞凋亡,导致组织癌变.此方面的研究将有利于人类更好地了解食管腺癌的致病机制,并希望能从中寻找更加有效预防和治疗食管腺癌的方法.此文就这方面的最新研究进展进行综述.     

Treating Multiple Myeloma in the Context of the Bone Marrow Microenvironment

The treatment landscape of multiple myeloma (MM) has evolved considerably with the FDA-approval of at least 15 drugs over the past two decades. Together with the use of autologous stem cell transplantation, these novel therapies have resulted in significant survival benefit for patients with MM. In particular, our improved understanding of the BM and immune microenvironment has led to the development of highly effective immunotherapies that have demonstrated unprecedented response rates even in the multiple refractory disease setting. However, MM remains challenging to treat especially in a high-risk setting. A key mediator of therapeutic resistance in MM is the bone marrow (BM) microenvironment; a deeper understanding is necessary to facilitate the development of therapies that target MM in the context of the BM milieu to elicit deeper and more durable responses with the ultimate goal of long-term control or a cure of MM. In this review, we discuss our current understanding of the role the BM microenvironment plays in MM pathogenesis, with a focus on its immunosuppressive nature. We also review FDA-approved immunotherapies currently in clinical use and highlight promising immunotherapeutic approaches on the horizon.     

白介素-17在肺癌发生及进展中的作用与机制研究进展

白介素-17(interleukin 17,IL-17)是一个重要的炎症因子,参与介导了机体的抗感染免疫及自身免疫性疾病相关的病理性炎症;此外,IL-17还与多种炎症相关的肿瘤有着密切联系.吸烟是导致肺癌的重要危险因素之一,而吸烟等因素所致的肺部慢性炎症反应伴有IL-17过表达,提示IL-17可能与肺癌的发生存在潜在联系;同时,IL-17还通过多种机制影响肺癌进展,本文对这一领域的相关研究进展进行了综述.     

Inactivation of Interferon Receptor Promotes the Establishment of Immune Privileged Tumor Microenvironment

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肿瘤浸润性免疫细胞在肺癌微环境中的作用

摘 要：肺癌细胞与包括肿瘤浸润性免疫细胞在内的基质细胞共同构成了肺癌微环境。肿瘤浸润性免疫细胞主要包括四类,肿瘤浸润性淋巴细胞、肿瘤相关巨噬细胞、树突状细胞和骨髓来源的抑制性细胞。肺癌微环境中的肿瘤浸润性免疫细胞能够调控肿瘤的生长、转移和血管生成,对肿瘤的发展起到重要的调节作用。全文就肿瘤浸润性免疫细胞对肺部肿瘤的发展发挥的作用作一综述。     

Risk Analysis of Environmental Chemicals on Lung Carcinogenesis

Lung cancer is one of the most common cancers in the world, and the incidence of lung cancer is increasing.Risk analysis of environmental chemicals on lung carcinogenesis is particularly important. Detection of chemopreventive agents of lung carcinogenesis is also important to reduce our risk of lung cancer. For that purpose, it is necessary to establish reliable in vivo animal models of lung carcinogenesis. The A/J mouse is a mouse strain sensitive to lung carcinogens, and also develops spontaneous lung tumors without any chemical treatment. We have demonstrated that a treatment of 4-(methylnitrosamino)-1-(3-pyridyle)-1-butanone (NNK), a tobacco specific nitrosamine, or 2-amino-1-methyl-6-phenylimidazo [4,5-b]pyridine (MeIQx), a heterocyclic amine, induced lung tumors in the female A/J mouse in 16 and 32 weeks. The lung tumors developed in the A/J mouse are histopathologically classified as adenocarcinomas, adenomas, and alveolar cell hyperplasias. Some of these types of lung cancer are similar to those of human lung cancer. We also investigated the chemopreventive effects of bovine LF (bLF) on different phases of NNK-induced lung tumorigenesis in A/J mice. The A/J mouse is very useful mouse strain as a reliable in vivo model, which can be used for risk analysis of lung carcinogenesis.     

Higher Serum C-reactive Protein Level Represents the Immunosuppressive Tumor Microenvironment in Patients With Clear Cell Renal Cell Carcinoma

Introduction

C-reactive protein (CRP), a representative inflammatory marker, could serve as a biomarker in renal cell carcinoma because CRP is an important prognostic factor. However, its detailed mechanism remains unknown. This study showed that higher CRP levels correlated with the tumor immune microenvironment, which leads to a worse prognosis. These findings can help to clarify the underlying mechanisms between the presence of systemic inflammatory reaction and prognosis. The aim of this study is to investigate the association between tumor immune microenvironment and CRP in patients with renal cell carcinoma (RCC) to explore the underlying mechanisms between CRP level and prognosis.

Characterization and Purification of an Immunosuppressive Factor Produced by a Small Cell Lung Cancer Cell Line

The present study was undertaken to determine whether small cell lung cancer (SCLC) cell lines produce immunosuppressive factors and, if they do, to characterize the factors. The supernatants of SCLG cell lines, H69 and N857, inhibited not only the blastogenic response of human peripheral blood lymphocytes (PBL) to phytohemagglutinin or concanavalin A, but also the cytotoxic activity of lymphokine-activated killer cells. Neither was inhibited by supernatants from non-SCLC cell lines PC9, QG56, and A549. The immunosuppressive activity of H69 supernatant was stable upon heating to 56°C for 60 min, but labile when heated to 70°C for 10 min. The activity was abolished after dialysis at pH 2.0 or pH 11.0, but not at pH 4.5 or pH 9.0. Digestion with trypsin or proteinase eliminated the immunosuppressive activity, whereas treatment with neuraminidase, mixed glycosidase, DNase or RNase had no effect, suggesting that the immunosuppressive activity in H69 supernatant is due to a protein factor. This H69-derived immunosuppressive factor was isolated by ion exchange chromatography using a gradient of 0.04 to 0.08 M NaCl solution. Gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed the factor to have molecular weights of 98 kD and 102 kD, respectively. These results suggest that SCLC cells produce a potent immunosuppressive factor which may account for the immune deficiency in SCLC patients.     

Possible Chemopreventive Effects of Bovine Lactoferrin on Esophagus and Lung Carcinogenesis in the Rat

A milk component, bovine lactoferrin (bLF), previously shown by us to be a strong chemopreventive of colon carcinoma development, was examined for its influence on other organs using a rat multi-organ carcinogenesis model. Male F344 rats, aged 6 weeks, were treated sequentially with diethylnitrosamine (DEN, i.p.), dihydroxy-di- N -propylnitrosamine (DHPN, in drinking water) and N -nitrosomethylbenzylamine (NMBA, s.c.) during the first 8 weeks (DDN treatment), and then bLF was administered in the basal diet, at a dose of 2, 0.2, 0.02 or 0.002%. Other groups were given DDN treatment or bLF alone as controls. All surviving animals were killed at week 41, and major organs were examined histopathologically for neoplastic lesions. In the esophagus, a tendency for reduction in development of papillomas was evident in the bLF-treated animals, along with a significant suppression of relatively large-sized papillomas (more than 50 mm³ volume) at the 0.2% dose ( P <0.05, 11% of the control). The multiplicity of tumors (adenomas and carcinomas) in the lung was also decreased in animals fed 0.02% bLF (1.98±0.41 per cm² lung tissue section, P <0.05) compared to the control group (3.48±0.33). No enhancing or inhibitory effects of bLF on tumor development in other organs were noted. The present results indicate that bLF exerts chemopreventive effects in the esophagus and lung in addition to the colon.     

大鼠肺鳞癌癌变过程中基因组甲基化水平动态研究

背景与目的:研究大鼠肺鳞癌癌变各阶段基因组DNA甲基化水平动态变化趋势.材料与方法:支气管灌注3-甲基胆蒽(MCA)及二乙基亚硝胺(DEN)碘油溶液诱发Wistar大鼠肺鳞癌模型.采用免疫组化法检测大鼠肺鳞癌癌变各阶段基因组DNA甲基化水平,利用图像分析系统测量其平均光密度值和积分光密度值.结果:经支气管灌注MCA及DEN碘油溶液,诱发Wistar大鼠肺鳞癌模型,共获取癌变各阶段标本154例,其中增生25例,鳞状化生组织27例,不典型增生组织37例,原位癌组织30例,浸润癌组织25例.大鼠肺鳞癌癌变各阶段基因组DNA甲基化水平按上述顺序呈递减的趋势,癌变各阶段甲基化水平与正常对照组比较,差异具有统计学意义(P＜0.01),正常和癌变支气管上皮基底层甲基化水平高于腔细胞层,差异亦具有统计学意义(P＜0.01).结论:大鼠肺鳞癌癌变过程中基因组DNA甲基化水平的降低,可能是介导其癌变的重要表遗传学机制.     

PIG11 is Involved in Hepatocellular Carcinogenesis and Its Over-expression Promotes Hepg2 Cell Apoptosis

PIG11 (p53-induced gene 11) is a p53 target gene and candidate tumour suppressor gene. In this study, the expression of PIG11 protein was detected in human hepatocellular carcinoma (HCC) and normal liver tissues with an immunohistochemical method. Compared with expression in human normal liver tissues, the expression of PIG11 protein was significantly down-regulated in human HCC tissues. In addition, a recombinant pLXSN-PIG11 retroviral vector was constructed and transfected into HepG2 cells (human hepatocellular carcinoma cell line) and the role of PIG11 in apoptosis was analyzed. The percentage (18.60%) of apoptotic cells transfected with pLXSN-PIG11 was higher than that in cells transfected with pLXSN only (6.03%) or the vehicle control (3.81%) (P < 0.01). DNA gel electrophoresis showed a clear DNA ladder in pLXSN-PIG11-infected HepG2 cells. Our results suggested that the PIG11 gene is involved in carcinogenesis and development of hepatocarcinoma. Therefore, PIG11 is considered to be a new candidate liver tumour suppressor gene, and may play an important role in tumour suppression through promotion of cell apoptosis.     

Microenvironment Analysis of Prognosis and Molecular Signature of Immune-Related Genes in Lung Adenocarcinoma

There is growing evidence on the clinical significance of tumor microenvironment (TME) cells in predicting prognosis and therapeutic effects. However, cell interactions in tumor microenvironments have not been thoroughly studied or systematically analyzed so far. In this study, 22 immune cell components in the lung adenocarcinoma (LUAD) TME were analyzed using gene expression profile from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The TME-based molecular subtypes of LUAD were defined to evaluate further the relationship between molecular subtypes, prognosis, and clinical characteristics. A TME risk score model was constructed by using the differentially expressed genes (DEGs) of molecular subtypes. The relationship between the TME score and clinical characteristics and genomic mutations was compared to identify the genes that have significant associations with the TME. The comprehensive analysis of the TME characteristics may be helpful in revealing the response of LUAD patients to immunotherapy, providing a new strategy for immunotherapy.Key words: Tumor microenvironment, Lung adenocarcinoma, The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Immunotherapy     

Microenvironment Analysis of Prognosis and Molecular Signature of Immune-Related Genes in Lung Adenocarcinoma

There is growing evidence on the clinical significance of tumor microenvironment (TME) cells in predicting prognosis and therapeutic effects. However, cell interactions in tumor microenvironments have not been thoroughly studied or systematically analyzed so far. In this study, 22 immune cell components in the lung adenocarcinoma (LUAD) TME were analyzed using gene expression profile from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The TME-based molecular subtypes of LUAD were defined to evaluate further the relationship between molecular subtypes, prognosis, and clinical characteristics. A TME risk score model was constructed by using the differentially expressed genes (DEGs) of molecular subtypes. The relationship between the TME score and clinical characteristics and genomic mutations was compared to identify the genes that have significant associations with the TME. The comprehensive analysis of the TME characteristics may be helpful in revealing the response of LUAD patients to immunotherapy, providing a new strategy for immunotherapy.     

The Role of Inflammation in the Pathogenesis of Non-small Cell Lung Cancer

The link between chronic immune activation and tumorigenesis is well established. Compelling evidence has accumulated that histologic assessment of infiltration patterns of different host immune response components in non-small cell lung cancer specimens helps identify different prognostic patient subgroups. This review provides an overview of recent insights gained in the understanding of the role played by chronic inflammation in lung carcinogenesis. The usefulness of quantification of different populations of lymphocytes, natural killer cells, macrophages, and mast cells within the tumor microenvironment in non-small cell lung cancer is also discussed. In particular, the importance of assessment of inflammatory cell microlocalization within both the tumor islet and surrounding stromal components is emphasized.     

Circulating Inflammation Proteins Associated With Lung Cancer in African Americans

IntroductionLung cancer incidence is higher among African Americans (AAs) compared with European Americans (EAs) in the United States. We and others have previously shown a relationship between immune and inflammation proteins with lung cancer in EAs. Our aim was to investigate the etiologic relationship between inflammation and lung cancer in AAs.MethodsWe adopted a two-stage, independent study design (discovery cases, n = 316; control cases, n = 509) (validation cases, n = 399; control cases, n = 400 controls) and measured 30 inflammation proteins in blood using Meso Scale Discovery V- PLEX multiplex assays.ResultsWe identified and validated 10 proteins associated with lung cancer in AAS, some that were common between EAs and AAs (C-reactive proteins [OR: 2.90; 95% confidence interval (CI): 1.99–4.22], interferon γ [OR: 1.55; 95% CI: 1.10–2.19], interleukin 6 [OR: 6.28; 95% CI: 4.10–9.63], interleukin 8 [OR: 2.76; 95% CI: 1.92–3.98]) and some that are only observed among AAs (interleukin 10 [OR: 1.69; 95% CI: 1.20–2.38], interleukin 15 [OR: 2.83; 95% CI: 1.96–4.07], interferon gamma-induced protein 10 [OR: 1.54; 95% CI: 1.09–2.18], monocyte chemotactic protein-4 [OR: 0.54; 95% CI: 0.38–0.76], macrophage inflammatory protein-1 alpha [OR: 1.57; 95% CI: 1.12–2.21], and tumor necrosis factor β [OR: 0.52; 95% CI: 0.37–0.74]). We did not find evidence that either menthol cigarette smoking or global genetic ancestry drove these population differences.ConclusionsOur results highlight a distinct inflammation profile associated with lung cancer in AAs compared with EAs. These data provide new insight into the etiology of lung cancer in AAs. Further work is needed to understand what drives this relationship with lung cancer and whether these proteins have utility in the setting of early diagnosis.