Insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) has potential tumour-suppressive activity in human lung cancer

The expression of insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) is decreased in various tumours, but the role of IGFBP-rP1 in lung cancer is not yet clear. In this study, IGFBP-rP1 expression in lung cancer cell lines was evaluated and reduced expression of IGFBP-rP1 was found. In tissue microarrays containing 138 primary tumours and 20 normal lung tissues analysed by immunohistochemistry, 58 tumours (42%) exhibited no expression of IGFBP-rP1, while all 20 normal lung tissues showed high expression. In squamous cell lung cancer, low expression of IGFBP-rP1 was significantly linked to high-grade tumours. Treatment with 5-aza-2'-deoxycytidine restored the expression of IGFBP-rP1 in three of four lung cancer cell lines. Sequencing of PCR products of sodium bisulphite-treated genomic DNA from the three lung cancer cell lines revealed a heterogeneous methylation pattern in the region of exon 1 and intron 1. Stable transfection of IGFBP-rP1 full-length cDNA into the H2170 lung cancer cell line led to increased expression of IGFBP-rP1 protein. IGFBP-rP1-positive transfectants exhibited remarkably reduced colony-forming ability in soft agar, suppression of tumour growth rate in nude mice, and increased apoptotic cell number as well as activated caspase-3 expression level. The data suggest that IGFBP-rP1 is a tumour suppressor inactivated by DNA methylation in human lung cancer.     

A critical appraisal of prognostic and predictive factors for common lung cancers

The outlook for patients with lung cancer remains poor despite advances in the understanding of the pathology and biology of this disease. To optimize treatment protocols prognostic data are essential. The current era with molecular research on mRNA expression analysis and proteomics will lead to a plethora of new molecular markers, which are likely to be correlated, at least in part, with each other and with disease activity, progression and survival. However, although the number of prognostic factors analysed in published systematic reviews on lung cancer is large, the scope of these factors in individual studies is often narrow. In daily practice prognostic factors other than general TNM staging are not implemented. To assess the efficacy of new prognostic factors for the management of individual patients with non-small cell lung cancer, studies with clinically relevant modelling are required. In this review arguments are provided to use a model combining radiological and histopathological growth rate, histopathological diagnosis and molecular characteristics as markers for metastatic capacity, tumour volume doubling time and expected response to targeted therapy. This may reveal time-related predictive information useful for treatment guidance of the individual patient.     

与肺癌相关的靶基因研究简介

肺癌是目前全世界发病率最高的恶性肿瘤，其病死率也居于前列。因此，肺癌的早期诊断及早期治疗对于降低肺癌患者的病死率以及改善患者生存质量至关重要。近年来有关肺癌早期诊断、治疗及预后的分子标志物的研究愈来愈受到关注。在肺癌中，非小细胞肺癌(non-small cell lung cancer，NSCLC)占绝大多数。针对晚期NSCLC，肿瘤分子靶向治疗日趋重要。因此，从分子水平研究肺癌的发病机制和诊断，对肺癌的防治有重大意义。近些年，对基因水平方面的研究也取得了很大进展。现对与肺癌相关的靶基因最新研究进行展综述如下。     

Clinical significance of combined detection of interleukin-6 and tumour markers in lung cancer

Tumour markers play an important role in the early diagnosis and guidance of prognosis of lung cancer. This study focused on the significance of combined monitoring of interleukin (IL)-6 and tumour markers in improving the specificity and sensitivity of lung cancer diagnosis and disease. The expression of IL-6, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE) and cytokeratin 19 fragment antigen 21-1 (CYFRA21-1) in serum of patients with non-small cell lung cancer (NSCLC) (n?=?138) was significantly higher compared to patients with benign pulmonary lesions (BPL) (n?=?60) and was associated with the clinicopathological features of NSCLC patients. The simultaneous increase in the expression of IL-6 and tumour markers worsened the prognosis of patients. Lung cancer cells were grouped into the blank control group, IL-6 group, niclosamide group (IL-6 pathway inhibitor, NIC) and IL-6?+?NIC group. The expression of CEA, NSE, CYFRA21-1, p-Erk1/2 and p-AKT in the IL-6 group was significantly higher compared to the other groups. Therefore, the combined detection of IL-6 and tumour markers is critical to improve the specificity and sensitivity of lung cancer diagnosis. This in-depth study not only helped to elucidate the mechanism of how IL-6 promotes lung cancer but also provided new ideas and entry points to resolve the low specificity and sensitivity of lung cancer-related tumour markers.     

腺鳞癌转化在肺癌耐药中的功能和机制研究

肺癌是一种高致死率的疾病,具有高度的异质性和可塑性。基于病理学分型,肺癌可分为小细胞肺癌和非小细胞肺癌,后者又可细分为腺癌,鳞癌和大细胞癌。临床上可观察到同一个肿瘤内部混合腺癌和鳞癌(腺鳞癌),或小细胞肺癌混合腺癌或鳞癌(混合型小细胞肺癌)。其中,腺鳞癌在临床上占非小细胞肺癌的4%~10%。近几年越来越多的临床案例报道,肺腺癌患者经过化疗、靶向治疗或免疫治疗,肿瘤类型会从腺癌转变成鳞癌,并表现出耐药性。动物模型的研究发现,肝激酶B1(Lkb1)缺失会促进小鼠肺腺癌向鳞癌转化,而腺鳞癌是转化过程的中间态。从细胞起源来看,Club细胞和AT2(Alveolar Epithelial Type 2)来源的肺腺癌可以转化成鳞癌。从分子机制来看,肺腺癌向鳞癌转化的过程中,胞外基质重塑以及代谢重编程会导致细胞氧化应激异常,使得活性氧(Reactive Oxygen Species,ROS)水平急剧上升并诱导p63上调,最终导致腺鳞癌转化并伴随肿瘤耐药。本综述将总结近年来肺腺鳞癌转化领域的进展并阐述其与耐药的关系,以期为深入理解临床肺癌的可塑性奠定理论基础。     

Pathology and Pathogenesis of Ovine Pulmonary Adenocarcinoma

Ovine pulmonary adenocarcinoma (OPA), also known as jaagsiekte, is a transmissible lung tumour of sheep caused by jaagsiekte sheep retrovirus (JSRV). JSRV induces neoplastic transformation of alveolar and bronchiolar secretory epithelial cells and the resulting tumours can grow to occupy a significant portion of the lung. Tumour growth is frequently accompanied by the overproduction of fluid in the lung, which further compromises normal respiration. The period between infection and the appearance of clinical signs may be several months or years and many JSRV-infected sheep do not exhibit clinical signs at all during their lifespan. This allows the spread of OPA into new flocks through contact with infected but apparently normal animals. OPA was first described in the early 19th century; however, it has still not been possible to devise effective methods for controlling its spread and it remains an important problem in most countries where sheep are farmed. This is due in part to the absence of an immunological response to JSRV in infected animals, which has hindered the development of serological diagnostic tests and vaccines. In addition to its veterinary importance, OPA is regarded as a potential large animal model for human lung adenocarcinoma and this has stimulated research into the pathogenesis of the ovine disease. This work has produced some significant results, including the finding that one of the JSRV structural proteins is directly involved in oncogenesis. The recent advances in understanding JSRV and the pathogenesis of OPA should lead to novel strategies for diagnosis and control of this disease and for its exploitation as a comparative model for human lung cancer.     

Characterization of the cell of origin and propagation potential of the fibroblast growth factor 9‐induced mouse model of lung adenocarcinoma

Fibroblast growth factor 9 (FGF9) is essential for lung development and is highly expressed in a subset of human lung adenocarcinomas. We recently described a mouse model in which FGF9 expression in the lung epithelium caused proliferation of the airway epithelium at the terminal bronchioles and led to rapid development of adenocarcinoma. Here, we used this model to characterize the effects of prolonged FGF9 induction on the proximal and distal lung epithelia, and examined the propagation potential of FGF9‐induced lung tumours. We showed that prolonged FGF9 over‐expression in the lung resulted in the development of adenocarcinomas arising from both alveolar type II and airway secretory cells in the lung parenchyma and airways, respectively. We found that tumour cells harboured tumour‐propagating cells that were able to form secondary tumours in recipient mice, regardless of FGF9 expression. However, the highest degree of tumour propagation was observed when unfractionated tumour cells were co‐administered with autologous, tumour‐associated mesenchymal cells. Although the initiation of lung adenocarcinomas was dependent on activation of the FGF9–FGF receptor 3 (FGFR3) signalling axis, maintenance and propagation of the tumour was independent of this signalling. Activation of an alternative FGF–FGFR axis and the interaction with tumour stromal cells is likely to be responsible for the development of this independence. This study demonstrates the complex role of FGF–FGFR signalling in the initiation, growth and propagation of lung cancer. Our findings suggest that analysing the expressions of FGF–FGFRs in human lung cancer will be a useful tool for guiding customized therapy. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The challenge of classifying poorly differentiated tumours in the lung

The lung is a common site for primary carcinomas as well as a wide range of metastatic carcinomas and other rarer primary and secondary tumours that clinically and radiologically may mimic lung cancer. The World Health Organization classification of lung tumours is based on the morphological appearances in resected specimens. This provides a widely applicable system for classification, which, although complex, can be applied universally. The vast majority of patients with lung cancer, however, do not have their tumours resected, and the application of the same classification system to small biopsy specimens is problematic due in large part to sampling. Recognition of this has led to the widespread use of the term 'non-small cell carcinoma'. Future developments in our understanding of lung cancer and the development of novel targeted therapies may mean that in the future classification will become based more on the molecular features of tumours that predict response to therapies and prognosis rather than simple morphology. The predictive validity of such an approach using small biopsy or cytology specimens, however, still requires to be established. The problem of tumour heterogeneity, which is problematic for morphological classification, may also pose similar challenges for molecular approaches.     

The clonal relationships between pre‐cancer and cancer revealed by ultra‐deep sequencing

The study of the relationships between pre‐cancer and cancer and identification of early driver mutations is becoming increasingly important as the value of molecular markers of early disease and personalised drug targets is recognized, especially now the extent of clonal heterogeneity in fully invasive disease is being realized. It has been assumed that pre‐cancerous lesions exhibit a fairly passive progression to invasive disease; the degree to which they, too, are heterogeneous is unknown. We performed ultra‐deep sequencing of thousands of selected mutations, together with copy number analysis, from multiple, matched pre‐invasive lesions, primary tumours and metastases from five patients with oral cancer, some with multiple primary tumours presenting either synchronously or metachronously, totalling 75 samples. This allowed the clonal relationships between the samples to be observed for each patient. We expose for the first time the unexpected variety and complexity of the relationships between this group of oral dysplasias and their associated carcinomas and, ultimately, the diversity of processes by which tumours are initiated, spread and metastasize. Instead of a series of genomic precursors of their adjacent invasive disease, we have shown dysplasia to be a distinct dynamic entity, refuting the belief that pre‐cancer and invasive tumours with a close spatial relationship always have linearly related genomes. We show that oral pre‐cancer exhibits considerable subclonal heterogeneity in its own right, that mutational changes in pre‐cancer do not predict the onset of invasion, and that the genomic pathway to invasion is neither unified nor predictable. Sequence data from this study have been deposited in the European Nucleotide Archive, Accession No. PRJEB6588. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

结直肠癌肝转移预测及预后的影像组学综述

结直肠癌在国内外都是高发病率和高死亡率的肿瘤疾病，肝脏是结直肠癌血行转移最主要的靶器官，尽早准确地预测结直肠癌肝转移的发生以及监测患者治疗的预后反应，对患者的诊断和治疗尤为关键。新兴的影像组学为精准预测结直肠癌肝转移以及评估预后提供新的可能。对现有的结直肠癌肝转移影像组学研究进行综述，首先介绍结直肠癌肝转移研究的临床意义以及现有研究存在的缺陷，然后阐述结直肠癌肝转移影像组学的分析流程，接着对结直肠癌肝转移影像组学的4个研究方向展开综述，包括肝转移病理生长模式预测、隐匿性肝转移预测、肝转移疗效预后评估、肝转移患者生存期预后评估；阐明各个方向的最新研究进展及存在的缺陷性；最后对结直肠癌肝转移影像组学的未来发展趋势进行展望。     

Exosomes carrying immunoinhibitory proteins and their role in cancer

Recent emergence of exosomes as information carriers between cells has introduced us to a new previously unknown biological communication system. Multi‐directional cross‐talk mediated by exosomes carrying proteins, lipids and nucleic acids between normal cells, cells harbouring a pathogen or cancer and immune cells has been instrumental in determining outcomes of physiological as well as pathological conditions. Exosomes play a key role in the broad spectrum of human diseases. In cancer, tumour‐derived exosomes carry multiple immunoinhibitory signals, disable anti‐tumour immune effector cells and promote tumour escape from immune control. Exosomes delivering negative signals to immune cells in cancer, viral infections, autoimmune or other diseases may interfere with therapy and influence outcome. Exosomes can activate tissue cells to produce inhibitory factors and thus can suppress the host immune responses indirectly. Exosomes also promise to be non‐invasive disease biomarkers with a dual capability to provide insights into immune dysfunction as well as disease progression and outcome.     

Cellular landscape of tumour microenvironment in prostate cancer

Prostate cancer is still a public health priority in men and the impact of this disease will be more pronounced with the ageing of the world's population. Clinical heterogeneity of prostate cancer is reflected in spatial and clonal genomic diversity. Accumulating evidence demonstrates that the malignant behaviour of cancer is not only attributed to cancer cells but also fundamentally affected by stromal activity and controlled by various mechanisms of the tumour microenvironment. Data on prostate cancer in this study was derived from seven GEO datasets and the TCGA database. We analyzed the tumour microenvironment of prostate cancer in terms of clinical process, T stage and Gleason score using EPIC and xCell algorithms. We also analyzed the common immune checkpoints. In this study, we confirmed remarkable tumour tissue remodelling in the development of prostate cancer and further demonstrated the importance of cancer-related fibroblasts in the biochemical recurrence and metastasis for patients with prostate cancer undergoing radical radiotherapy or prostatectomy. In addition, we found that NRP1, CD200, TNFSF18 and CD80 might be the potential targets for prostate cancer.     

Antibody combinations for optimized staining of macrophages in human lung tumours

The analysis of tumour-associated macrophages (TAMs) has a high potential to predict cancer recurrence and response to immunotherapy. However, the heterogeneity of TAMs poses a challenge for quantitative and qualitative measurements. Here, we critically evaluated by immunohistochemistry and flow cytometry two commonly used pan-macrophage markers (CD14 and CD68) as well as some suggested markers for tumour-promoting M2 macrophages (CD163, CD204, CD206 and CD209) in human non–small cell lung cancer (NSCLC). Tumour, non-cancerous lung tissue and blood were investigated. For immunohistochemistry, CD68 was confirmed to be a useful pan-macrophage marker although careful selection of antibody was found to be critical. The widely used anti-CD68 antibody clone KP-1 stains both macrophages and neutrophils, which is problematic for TAM quantification because lung tumours contain many neutrophils. For TAM counting in tumour sections, we recommend combined labelling of CD68 with a cell membrane marker such as CD14, CD163 or CD206. In flow cytometry, the commonly used combination of CD14 and HLA-DR was found to not be optimal because some TAMs do not express CD14. Instead, combined staining of CD68 and HLA-DR is preferable to gate all TAMs. Concerning macrophage phenotypic markers, the scavenger receptor CD163 was found to be expressed by a substantial fraction (50%-86%) of TAMs with a large patient-to-patient variation. Approximately 50% of TAMs were positive for CD206. Surprisingly, there was no clear overlap between CD163 and CD206 positivity, and three distinct TAM sub-populations were identified in NSCLC tumours: CD163⁺CD206⁺, CD163⁺CD206⁻ and CD163⁻CD206⁻. This work should help develop macrophage-based prognostic tools for cancer.     

Malignant effusions: from diagnosis to biology

Serous effusions are a frequently encountered clinical manifestation of metastatic disease, with breast, ovarian, and lung carcinomas and malignant mesothelioma (MM) leading the list. Recently, extensive research has resulted in expansion of the antibody panel that is available for effusion diagnosis, thereby reducing the risk for error. Despite this progress, relatively little has been done in way of understanding the biology of cancer cells in effusions, especially those of nonovarian origin. The diagnosis of a malignant effusion signifies disease progression and is associated with a worse prognosis regardless of the tumor site of origin. However, survival is much more variable with ovarian cancer compared with other tumors. Furthermore, cancer cells of different origins differ considerably in their biology and have unique phenotypic and genotypic characteristics. This review summarizes the current knowledge in this field and presents a model for the study of tumor metastasis and disease progression, through large comparative studies of malignant cells in effusions, primary tumors, and solid metastases. The case also is made for potential applications of this rapidly evolving body of knowledge in the diagnosis, classification, and prediction of biological behavior of processes resulting in cryptic effusions at the clinical level.     

血清MCP-1蛋白水平对肺癌及肺结核患者诊断的临床意义

目的 探讨MCP-1蛋白表达在肺癌及肺结核患者中的临床意义。方法 选取2017年1月~2018年12月我院呼吸科收治的40例肺癌及40例肺结核患者为研究对象,同时选取同期在我院体检健康人群40例为对照组,对比三组血清及PBMC上清液中MCP-1浓度及不同期、不同病理类型肺癌患者血清及PBMC上清液中MCP-1浓度和初治和复治肺结核血清及PBMC上清液中MCP-1浓度。结果 肺结核组及肺癌组血清及PBMC上清液中MCP-1浓度高于对照组,且肺结核组高于肺癌组,差异有统计学意义（P＜0.05）;晚期肺癌患者血清及PBMC上清液中MCP-1浓度分别为（152.71±12.56）pg/ml、（419.52±33.93）pg/ml,均高于早期肺癌患者的（73.21±7.90）pg/ml、（312.60±28.62）pg/ml,差异均有统计学意义（P＜0.05）;三种不同病理类型肺癌患者血清及PBMC上清液中MCP-1浓度比较,差异无统计学意义（P＞0.05）;肺结核复治患者血清及PBMC上清液中MCP-1浓度分别为（173.65±13.22）pg/ml、（520.11±67.28）pg/ml,高于肺结核初治患者的（156.21±9.13）pg/ml、（498.34±50.03）pg/ml,差异有统计学意义（P＜0.05）。结论 血清MCP-1蛋白水平于肺癌及肺结核的发生、病情发展有密切的关系,且随病情的进展会升高,临床可将其作为诊治的重要指标。     

T淋巴细胞亚群检测在呼吸系统性疾病的诊断价值

目的：探讨T淋巴细胞亚群检测在呼吸系统性疾病的诊断价值。方法：采用流式细胞术对呼吸系统性疾病和正常健康人体内淋巴细胞亚群检测,并通过检测数据分析其淋巴细胞亚群功能变化。结果：①肺结核组、肺炎组和肺癌组的CD3^＋、CD3^＋CD4^＋及T4／T8比值水平均明显低于正常对照组,差异均有极显著变化（P〈0．01）,而CD3^＋CD8^＋水平明显高于正常对照组,差异有极显著变化（P〈0．01）;②肺结核组、肺炎组与肺癌组T淋巴细胞亚群比较：CD3^＋、CD3^＋CD4^＋及T4／T8比值水平均明显高于肺癌组,差异均有极显著变化（P〈0．01）,而CD3^＋CD8^＋水平明显低于肺癌组,差异有极显著变化（P〈0．01）;③肺结核组与肺炎组比较：CD3^＋、CD3^＋CD4^＋、CD3^＋CD8^＋及T4／T8比值水平无显著性差异（P〉0．05）。结论：T淋巴细胞亚群参与了呼吸系统性疾病（肺结核、肺炎和肺癌）的病理过程,在其呼吸系统性疾病的发生、发展中起着十分重要的作用。因此,监测呼吸系统性疾病患者外周血T淋巴细胞亚群,可对肺结核和肺炎患者的疗效作出评估和免疫增强提供理论依据,对肺癌患者的辅助免疫治疗支持参照。     

非小细胞肺癌中KLF6-SV1的表达及临床病理学意义

目的观察抑癌基因KLF6的剪切变异体KLF6-SV1在非小细胞肺癌(non-small cell lung cancer,NSCLC)中的表达特点,探讨其与临床病理学参数的关系。方法应用免疫组化检测42例NSCLC和40例良性肺疾病(肺的炎性肌纤维母细胞瘤、肺脓肿、肺结核、肺的硬化性血管瘤等)中KLF6-SV1蛋白的表达水平,原位杂交检测42例NSCLC和40例良性肺疾病中KLF6-SV1基因mRNA的表达。结果 KLF6-SV1在NSCLC中的蛋白阳性率为71.4%(30/42),表达水平均高于良性肺疾病(P<0.05)。KLF6-SV1基因mRNA的阳性率为69.0%(29/42),表达水平高于良性肺疾病(P<0.05)。KLF6-SV1的蛋白表达水平与其mRNA表达水平之间具有较好的一致性。KLF6-SV1的表达与有无淋巴结转移及肿瘤的分化程度有关,组间差异具有统计学意义(P<0.05),与病理分型、组织大小和临床分期无关,组间差异不具有统计学意义(P>0.05)。结论 KLF6-SV1的过表达可能与NSCLC的发生、发展及早期淋巴结转移密切相关,有望成为今后诊断的参考指标之一,并有可能成为肿瘤基因治疗的新靶点之一。