肿瘤相关成纤维细胞在大肠癌发生发展中的研究进展

肿瘤相关成纤维细胞(Cancer-associated-fibroblasts,CAFs)是肿瘤外部微环境中最重要的细胞成分之一。CAFs可以与肿瘤细胞发生相互作用,分泌多种可溶性因子如生长因子、趋化因子等,并通过调控大肠癌进展过程中发挥关键作用的多条信号通路,参与大肠癌的增殖、侵袭、转移以及耐药等生物学过程。近年研究发现,CAFs相关标记物及基因可作为大肠癌患者预后判断的参考指标,因此,靶向CAFs有望成为大肠癌早期诊断、治疗以及预后判断的关键靶点。本文主要就CAFs的特征、募集与活化过程以及在大肠癌发生发展中的作用进行总结,以期为CAFs在大肠癌中作用机制研究及临床应用提供新的科研方向。     

癌相关成纤维细胞的异质性在靶向胰腺癌治疗中的角色

胰腺癌发病率逐年增高,但临床诊治进展有限,预后差。胰腺癌中肿瘤微环境(TME)与肿瘤侵袭转移和化疗耐药密切相关。癌相关成纤维细胞(CAF)是一种处于持续活化状态的成纤维细胞,是TME中最重要的细胞成分之一。CAF可通过多种分子介导的多种机制,促进胰腺癌的恶性生物学行为。而靶向CAF治疗胰腺癌疗效不佳,可能与胰腺癌中CA...     

癌相关成纤维细胞在非小细胞肺癌进展中的作用

癌相关成纤维细胞(Cancer-associated fibroblasts, CAFs)是基质和相关肿瘤微环境中的主要成分,在非小细胞肺癌(Non-small cell lung cancer, NSCLC)的发生发展过程中发挥重要的作用。研究表明,CAFs通过分泌多种类型的细胞因子、趋化因子、生长因子和细胞外基质蛋白,参与调控癌细胞的增殖、侵袭、转移和对化疗药物的耐药性。本文将从CAFs的来源、活化机制及其在NSCLC发生发展过程中的作用进行综述,以深入了解NSCLC进展机制并为其治疗提供新思路。     

肺癌相关成纤维细胞的研究进展

癌相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤组织中被癌细胞激活的成纤维细胞,具有成肌纤维细胞的特性。CAFs表型恶性转换与肿瘤演进密切相关,同时CAFs是肿瘤微环境的主要组织成分。本文主要从以下方面结合肺癌进行综述:①CAFs的来源及其形态学特征,CAFs异质性及其表型时、空转换的临床意义;②CAFs的研究现状及临床应用中的问题;③CAFs与肺癌侵袭与转移的关系;④CAFs对肺癌预后及其治疗的影响。     

癌相关成纤维细胞异质性的研究进展

癌相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境主要的间质成分,在肿瘤生长、进展和转移过程中起到关键性的作用.众多研究显示,不同来源的CAFs可表达不同的标志物并具有一定的异质性.对CAFs进行分类以及其所发挥的生物学效应进行研究,有利于深入了解CAFs对肿瘤进展和转...     

MicroRNAs在肿瘤相关成纤维细胞促进肿瘤发展进程中的作用

肿瘤相关成纤维细胞（CAFs）是肿瘤微环境（TME）中最主要的细胞组分之一,在肿瘤发生、进展中发挥重要作用。微小RNA（miRNAs）参与CAFs的转化与代谢重编程,并可调控CAFs 的干性及其介导的肿瘤细胞增殖、侵袭和化疗耐药等机制,在CAFs 的形成和CAFs 对肿瘤的促进作用中发挥重要功能;而CAFs 释放的miRNAs 可作为肿瘤的诊断、预后及用药选择的参考指标。因此探索miRNAs 在肿瘤细胞与CAFs 相互作用中的功能,揭示其作用机制,对于理解肿瘤的发生和发展具有重要意义;同时也可为新的肿瘤治疗策略提供研究方向。本文将对miRNAs在CAFs的形成及CAFs对肿瘤细胞调控中的作用加以介绍     

癌相关成纤维细胞的分化来源

癌相关成纤维细胞(CAF)是肿瘤微环境重要的组成部分,甚至有研究者提出CAF可能作为抗肿瘤治疗的新靶点.然而研究的难点在于CAF分化来源的多样性,包括宿主成纤维细胞、上皮细胞、内皮细胞、间质细胞和干细胞等,而不同的来源决定了CAF不同的表型和功能.全面了解CAF的分化来源,将为抗肿瘤治疗提供新思路.     

肿瘤相关成纤维细胞在胰腺癌发生发展中的研究进展

胰腺癌是致命的恶性肿瘤之一,由于缺乏早期、敏感及特异性的诊断标志物,大多数患者确诊时已处于晚期。胰腺癌又称硬癌,其肿瘤组织中含有大量的间质成分,广泛的纤维化是胰腺癌的重要特征。肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中重要的组成成分,研究表明CAFs参与胰腺癌细胞增殖、迁移、侵袭、耐药等生物学过程。全文主要介绍胰腺癌中CAFs的异质性及其在胰腺癌发生发展中的作用,并阐述了类器官培养技术在CAFs研究中的应用,以及靶向CAFs进行肿瘤治疗的进展。     

癌相关成纤维细胞活化机制的研究进展

摘 要：癌相关成纤维细胞（cancer associated fibroblasts,CAFs）是肿瘤微环境的重要组成部分,具有活性的CAFs已经被证实可促进肿瘤的发生、发展、转移和耐药,成为癌症治疗的重要目标。现已发现细胞因子、炎症、缺氧、活性氧、自噬及放射线等都可以引起CAFs的活化。深入了解CAFs活化的分子机制和病理机制,有利于为恶性肿瘤治疗提供新的思路和靶点。     

外泌体在肝癌发生发展中的研究进展

肝细胞癌（HCC）是最常见的恶性肿瘤之一,死亡率高,预后极差。HCC的发生涉及多种癌基因或抑癌基因的突变,但具体的分子机制尚不清楚。外泌体是细胞外囊泡的一种,可介导细胞间的物质交换和信息交流,近年来发现外泌体在肝癌的发生发展中具有关键作用,可应用于肝癌的诊断与治疗。本文就外泌体的组成与功能及其在肝癌的发生发展、诊断与治疗中的作用作一综述。     

The effect of hepatocellular carcinoma-associated fibroblasts on hepatoma vasculogenic mimicry

Vasculogenic Mimicry (VM) is the main source of blood supply in the early stage of tumor growth. Carcinoma-associated fibroblasts (CAFs) are one of the most important host cells in the tumor microenvironment. Some studies have found that CAFs can promote tumor angiogenesis, but there are few reports on the relationship between CAFs and VM. Tissue samples were collected from 60 cases of hepatocellular carcinoma (HCC) and 10 persons with normal liver function. The relationship between VM expression and clinicopathologic features was analyzed. Furthermore, the relationship between VM expression and vimentin or α-SMA expression was analyzed. Primary culture of hepatocellular CAFs and the collection of conditioned media were carried out. The effects of hepatocellular CAF conditioned medium on the formation of VM and the levels of VM-related proteins and genes in MHCC-97H cells were studied. The positive rate of VM was 35.0% in HCC tissues. There was no VM expression in normal liver tissues. VM expression was related to tumor diameter, Edmondson grade, clinical stage, and liver cirrhosis. The expression of vimentin and α-SMA in VM-positive patients was higher than in VM-negative patients. Different concentrations of hepatocellular CAF conditioned medium could promote the formation of VM and increase the expression of VM-related genes and proteins (MMP2 and EphA2) in MHCC-97H cells. The results show that there was a significant correlation between VM formation and the expression of vimentin or α-SMA in HCC tissues. The conditioned medium of hepatocellular CAFs may promote VM formation and the expression of VM-related genes and proteins (MMP2 and EphA2) in hepatoma cell line MHCC-97H.     

Role of the microenvironment in hepatocellular carcinoma development and progression

Hepatocellular carcinoma (HCC) is the most common form of liver cancer throughout the world. The microenvironment of the HCC is composed of non-tumor cells and their stroma, with the stroma having been implicated in the regulation of tumor growth, metastatic potential and outcome following therapy. Thus, the tumor microenvironment has become an important target for HCC treatment. In this review article, we will discuss the cellular and molecular components of the hepatoma microenvironment, effects on tumor development and progression, the relationship to prognosis, and the implications for targeting of this microenvironment in the control of HCC.     

Angiogenesis and anti-angiogenesis in hepatocellular carcinoma

Experimental and clinical data indicate that in human hepatocellular carcinoma (HCC) tumor progression is associated with angiogenesis and that an increase in microvascular density is associated with a poor prognosis. This review summarizes the literature concerning the relationship between angiogenesis and progression in HCC. It is becoming increasingly evident that agents which interfere with blood vessel formation also block tumor progression. Accordingly, anti-angiogenic tumor therapy has gained much interest in preclinical and clinical assessments. The recent applications of anti-angiogenic agents which interfere or block HCC progression are reviewed.     

血清促血管生成素在肝癌中的表达及影响

目的探讨促血管生成素-2（angiogehin-2,Ang-2）对肝细胞肝癌（Hepatocellularcarcinoma,HCC）诊断的临床意义,以期为临床提供有意义的诊断依据。方法采用酶联免疫吸附试验测定30例HCC患者、10例肝硬化患者和10例健康者血清Ang-2水平,同时监测AFP、CEA、CAl99、FERR等肝癌相关指标进行对比。结果HCC组血清Ang-2水平（1892．54±482．82）μg／L和肝硬化组Ang-2水平（1244．21±14．65）μg／L均显著高于健康对照组（943．01±12．52）pg／L（P〈0．01,P〈0．05）,此外HCC组血清Ang-2水平亦显著高于肝硬化组（P〈0．01）。HCC患者血清AFP（4397．61±613．82）μg／L、CA199（64．88±10．71）U／mL、FERR（401．53±51．32）μg／L、CEA（4．69±1．00）μg／L水平显著高于健康对照组（P〈0．01）;其中合并肝硬化组血清Ang-2（2045．41±155．31）μg／L、AFP（5097．17±2830．22）μg／L、CAl99（67．53±9．35）U／mL、FERR（462．87±56．79）μg／L、CEA（5．41±2．25）μg／L水平均高于未发生肝硬化组,差别有统计学意义（P〈0．05,P〈0．01）。结论肝癌患者血清Ang-2增高与HCC的发生、发展有关,血清中Ang-2水平检测可能为HCC临床诊断提供依据。     

Cuproptosis-related long non-coding RNAs model that effectively predicts prognosis in hepatocellular carcinoma

BACKGROUNDCuproptosis has recently been considered a novel form of programmed cell death. To date, long-chain non-coding RNAs (lncRNAs) crucial to the regulation of this process remain unelucidated.AIMTo identify lncRNAs linked to cuproptosis in order to estimate patients'' prognoses for hepatocellular carcinoma (HCC).METHODSUsing RNA sequence data from The Cancer Genome Atlas Live Hepatocellular Carcinoma (TCGA-LIHC), a co-expression network of cuproptosis-related genes and lncRNAs was constructed. For HCC prognosis, we developed a cuproptosis-related lncRNA signature (CupRLSig) using univariate Cox, lasso, and multivariate Cox regression analyses. Kaplan-Meier analysis was used to compare overall survival among high- and low-risk groups stratified by median CupRLSig risk score. Furthermore, comparisons of functional annotation, immune infiltration, somatic mutation, tumor mutation burden (TMB), and pharmacologic options were made between high- and low-risk groups.RESULTSThree hundred and forty-three patients with complete follow-up data were recruited in the analysis. Pearson correlation analysis identified 157 cuproptosis-related lncRNAs related to 14 cuproptosis genes. Next, we divided the TCGA-LIHC sample into a training set and a validation set. In univariate Cox regression analysis, 27 LncRNAs with prognostic value were identified in the training set. After lasso regression, the multivariate Cox regression model determined the identified risk equation as follows: Risk score = (0.2659 × PICSAR expression) + (0.4374 × FOXD2-AS1 expression) + (-0.3467 × {type:entrez-nucleotide,attrs:{text:AP001065.1,term_id:6693620,term_text:AP001065.1}}AP001065.1 expression). The CupRLSig high-risk group was associated with poor overall survival (hazard ratio = 1.162, 95%CI = 1.063-1.270; P < 0.001) after the patients were divided into two groups depending upon their median risk score. Model accuracy was further supported by receiver operating characteristic and principal component analysis as well as the validation set. The area under the curve of 0.741 was found to be a better predictor of HCC prognosis as compared to other clinicopathological variables. Mutation analysis revealed that high-risk combinations with high TMB carried worse prognoses (median survival of 30 mo vs 102 mo of low-risk combinations with low TMB group). The low-risk group had more activated natural killer cells (NK cells, P = 0.032 by Wilcoxon rank sum test) and fewer regulatory T cells (Tregs, P = 0.021) infiltration than the high-risk group. This finding could explain why the low-risk group has a better prognosis. Interestingly, when checkpoint gene expression (CD276, CTLA-4, and PDCD-1) and tumor immune dysfunction and rejection (TIDE) scores are considered, high-risk patients may respond better to immunotherapy. Finally, most drugs commonly used in preclinical and clinical systemic therapy for HCC, such as 5-fluorouracil, gemcitabine, paclitaxel, imatinib, sunitinib, rapamycin, and XL-184 (cabozantinib), were found to be more efficacious in the low-risk group; erlotinib, an exception, was more efficacious in the high-risk group.CONCLUSIONThe lncRNA signature, CupRLSig, constructed in this study is valuable in prognostic estimation of HCC. Importantly, CupRLSig also predicts the level of immune infiltration and potential efficacy of tumor immunotherapy.     

基于肿瘤免疫微环境的肝癌分子分型研究进展

免疫治疗改善了肝癌整体治疗策略,其特有的免疫异质特征和对免疫微环境的高度耐受使免疫治疗进入瓶颈阶段,因此对于可能受益于免疫检查点治疗的患者来说,划分肝癌分子分型是必要的。随着二代测序技术的进步,科学家根据浸润性免疫细胞丰度、免疫检查点表达水平、多组学数据、免疫抑制互斥机制及肿瘤微环境异质性等各个层面进行分子分型探索,不仅将肝癌特定生物学、分子和临床病理特征与肿瘤微环境关联,而且显示出与转录组分子分型的重叠之处,有利于未来肝癌的诊断、治疗方式选择和预测临床结局,推动精确的肝癌个体化免疫治疗。     

Molecular targeted therapy for advanced hepatocellular carcinoma

Systemic anticancer therapy for hepatocellular carcinoma (HCC) is limited by intrinsic drug resistance and accompanying liver dysfunction. However, recent advances in molecular targeted therapy (MTT) have shed light on the treatment of advanced HCC. A recent randomized, placebo-controlled trial demonstrated that sorafenib, a multi-target tyrosine kinase inhibitor, prolonged overall survival and time-to-progression in patients with advanced HCC. This breakthrough highlights the potential of MTT targeting hepatocarcinogenic pathways, such as the Raf/MAPK/ERK pathway, angiogenic pathways and the EGFR signaling pathway. This review discusses the current status and the potential of developing novel MTTs for advanced HCC.     

The role of tumor-infiltrating B cells in the tumor microenvironment of hepatocellular carcinoma and its prognostic value: a bioinformatics analysis

BackgroundAccumulating evidence indicates that tumor heterogeneity is characterized by distinct immunosubtypes. However, prior studies have mainly focused on the functions of T cells. The role of tumor-infiltrating B cells in the microenvironment of hepatocellular carcinoma (HCC) requires further investigation.MethodsWe conducted an integrative analysis of single cell RNA sequencing (scRNA-seq) datasets in HCC tumor samples from Gene Expression Omnibus database. We analyzed the features of B cells in normal liver tissue and HCC. Additionally, we conducted a deconvolution analysis using the matrix of scRNA-seq datasets and the RNA-seq datasets in The Cancer Genome Atlas-Liver Hepatocellular Carcinoma (TCGA-LIHC) database. The survival analyses of the TCGA-LIHC cohort with different B cell infiltration rates and was further validated. Finally, we performed immunohistochemistry analysis of primary tumor tissue of HCC patients using antibodies against CD79A and validated the impact of tumor-infiltrating B cells in the prognosis of LIHC.ResultsWe identified several subtypes of B cells in the microenvironment of HCC, including the plasma cells and naïve B cells. The relative ratio of B cells, but not the plasma cells, was significantly decreased in HCC as compared to the normal liver tissue (P<0.05). In addition, genes related to antigen presentation and cell proliferation were decreased in tumor-infiltrating B cells (P<0.05). The observation of B cell infiltration was further validated with the TCGA-LIHC cohort. The overall survival and disease-free survival in HCC patients with higher B-cell infiltration rate were significantly longer than those in the lower infiltration group (P<0.05) in the TCGA-LIHC cohort. Moreover, we demonstrated higher infiltration rates of B cells were significantly associated with a better prognosis of HCC in our cohort.ConclusionsTumor-infiltrating B cells potentially exert a tumor-suppressive function in the microenvironment of HCC and the higher levels of B cell infiltration are associated with a favorable outcome of HCC. Targeted activation of B cells may improve the tumor immune-targeted therapy.     

癌相关纤维母细胞对胃癌细胞增殖、凋亡、迁移和侵袭活性的影响

目的 探讨癌相关纤维母细胞(CAFs)对胃癌细胞增殖、凋亡、迁移和侵袭活性的影响,为胃癌的合理有效治疗提供新的思路和作用靶点。方法 (1)原代培养正常纤维母细胞(NFs)和CAFs,用CCK8实验和流式细胞仪检测间接共培养后,NFs和CAFs对MGC-803细胞增殖和凋亡能力的影响;(2)通过transwell共培养小室建立MGC-803与CAFs相互作用的体外模型,分析CAFs对MGC-803迁移和侵袭能力的影响。结果 (1)与NFs相比,CAFs在体外传代培养过程中,仍高表达波形蛋白(Vimentin)、纤维母细胞活化蛋白(FAP);(2)与NFs组相比,CAFs促进MGC-803细胞增殖、迁移和侵袭,但是抑制其凋亡。结论 CAFs在胃癌的生长、迁移和侵袭等过程中起着重要的作用,并且可能成为胃癌治疗的新靶点。