成纤维细胞激活蛋白α与肿瘤免疫抑制的研究进展

成纤维细胞激活蛋白α(Fibroblast activation proteinα,FAPα)是一种跨膜丝氨酸蛋白酶,高度表达在90%的上皮性肿瘤的间质--肿瘤相关成纤维细胞(Tumor association fibroblast,TAF)上。FAPα在促进上皮性肿瘤的恶性进展中起着十分重要的作用,近年来研究发现,FAPα在肿瘤微环境中发挥免疫抑制的作用。研究FAPα在肿瘤免疫抑制中的作用,已成为肿瘤研究的新的热点。为基于以FAPα为靶标的抗肿瘤免疫治疗提供参考,本文围绕引起肿瘤免疫抑制的因素、FAPα与肿瘤免疫抑制的研究进展以及FAPα在肿瘤的发展进程的作用作一综述。     

肿瘤相关成纤维细胞与成纤维细胞活化蛋白在肿瘤免疫治疗中的研究进展

除了依赖于肿瘤细胞自身的恶性增殖以外,肿瘤的发生和发展还依赖于肿瘤细胞与肿瘤间质微环境的相互作用。肿瘤间质中存在的肿瘤相关成纤维细胞（tumor-associatedfibroblasts,TAF）能够诱导免疫抑制,是肿瘤免疫治疗中的一大障碍。在TAF上存在一种成纤维细胞激活蛋白（fibroblast activationprotein,FAP）,它在细胞表面发挥作用,是一种膜丝氨酸肽酶,是Ⅱ型丝氨酸蛋白酶家族成员之一,具有二肽肽酶及胶原酶活性,在肿瘤微环境中表达FAP的肿瘤相关成纤维细胞是最早被鉴定的一种肿瘤间质细胞类型。它由肿瘤问质中的成纤维细胞与癌细胞相互作用而活化,是肿瘤微环境中最主要的宿主细胞,具有促进肿瘤细胞生长、侵袭及免疫抑制的作用,而且基因组稳定不易耐药,有望成为肿瘤免疫治疗的新靶标。就靶向TAF和FAP在肿瘤免疫治疗中的研究做一综述,为基于肿瘤间质微环境的免疫治疗提供参考。     

肿瘤相关成纤维细胞促进肿瘤侵袭转移的作用机制

肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是肿瘤微环境中最主要的成分之一,在肿瘤的发生发展中发挥着必不可少的作用。骨髓和脂肪的局部组织固有成纤维细胞及间充质干细胞是CAFs来源的主要前体细胞。大量研究表明,CAFs并不作为单独细胞在肿瘤周围存在,而是和肿瘤细胞相互作用,促进肿瘤的生长与存活并维持其恶性倾向。肿瘤细胞可以影响CAFs前体的招募,并诱导正常成纤维细胞活化为CAFs;同时,CAFs可以分泌多种细胞因子、生长因子和细胞外基质蛋白质,促进肿瘤细胞的增殖、耐药及侵袭转移,从而影响肿瘤的预后。CAFs还参与血管淋巴管的生成、细胞外基质重塑、免疫抑制以及肿瘤细胞上皮间质转化等有利于肿瘤发生发展的外源性途径,为肿瘤细胞提供了一个良好的微环境。大量研究显示,研发靶向CAFs的药物可以中断其与肿瘤细胞之间的联系,从而抑制肿瘤的生长和转移。因此,深入了解CAFs促肿瘤的作用机制将有利于肿瘤治疗新靶点的发现。本文将对CAFs促进肿瘤侵袭转移的作用机制加以综述。     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞（CAFs）是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

成纤维细胞激活蛋白α与肿瘤的靶向治疗

成纤维细胞激活蛋白α（FAPα）是肿瘤相关成纤维细胞特异性表达的一种表面抗原,具有二肽基肽酶和胶原酶活性,在肿瘤的生长、浸润、转移中发挥重要作用。故以FAPα作为肿瘤基质标志物的病理诊断、肿瘤基因治疗或免疫治疗将成为可能。本文就近年来对FAPα结构特点、活性作用及在肿瘤诊治中的研究进展进行综述。     

肿瘤相关成纤维细胞与肿瘤微环境

肿瘤的发展过程与肿瘤微环境密切相关,而肿瘤相关成纤维细胞(CAFs)是上述微环境中最主要的宿主细胞,CAFs是一类不同细胞源性的细胞群,可来源于多种细胞包括静止的成纤维细胞、上皮细胞、内皮细胞和间质干细胞的分化过程。体内和体外生物学实验均证实,成纤维细胞在肿瘤微环境中并不是被动的对肿瘤发展提供支持,而是发挥了至关重要的作用,所以靶向CAFs有望成为肿瘤治疗的新方向,对CAFs相关分子标记物和分子事件的进一步探索将为抗肿瘤的临床治疗提供新的思路。本文将对CAFs的来源以及CAFs对肿瘤发生发展、转移及VEGF耐受等方面的作用做一综述。     

人成纤维细胞生长因子受体2的研究进展

人成纤维细胞生长因子受体（FGFRs)家族在细胞的增殖、分化、血管生成、胚胎及骨骼发育和在与生长发育相关的进程中起着十分重要的作用。成纤维细胞生长因子受体2（FGFR2）是该家族4个成员中的一员,本文就其结构特点及与骨骼发育、肿瘤形成和其他疾病的关系加以综述。     

调节性B细胞在肿瘤免疫治疗中的作用

调节性B细胞(regulatory B cell, Breg)是一类具有免疫抑制功能的B细胞亚群,在维持机体免疫平衡中发挥重要作用,主要通过分泌抗炎性细胞因子发挥免疫抑制功能。Breg在炎症、自身免疫性疾病及肿瘤等疾病中发挥重要作用,并逐渐成为肿瘤免疫治疗研究的新焦点。本文介绍了肿瘤微环境中Breg的表型及其作用,综述了近年来以Breg为靶点的肿瘤免疫治疗研究进展,以期为利用Breg提高肿瘤免疫治疗效果提供新思路。     

成纤维细胞激活蛋白α与肿瘤发展进程的研究

肿瘤微环境对肿瘤的发生、发展具有重要的意义。选择性表达于肿瘤微环境重要组成部分——肿瘤相关成纤维细胞（carcinoma associated fibroblasts,CAFs）表面的成纤维细胞激活蛋白α（fibroblast activation protein-α,FAPα）广泛参与了肿瘤的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等过程,从而促进了肿瘤的发展进程。FAPα具有蛋白水解酶活性,并作用于细胞信号通路,但FAPα在肿瘤微环境中发挥功能的具体分子机制还有待进一步研究。由于FAPα的表达具有肿瘤组织特异性,因此,以FAPα作为肿瘤基质标志物,对肿瘤进行病理诊断和免疫治疗将成为新兴的研究靶点。对FAPα的主要生物学性状进行概述,并综述了其对肿瘤细胞的生长、侵袭、转移以及肿瘤细胞外基质重建、血管生成、免疫逃逸等方面的重要影响。     

β-catenin和E-cadherin在肿瘤发展中的研究

肿瘤细胞的侵袭和转移是恶性肿瘤的主要特征之一,其间涉及多种机制,研究表明某些蛋白在肿瘤的转移过程中起着重要的作用,其中上皮钙粘蛋白（E-cadherin）β-连环蛋白（β-catenin）与肿瘤发生、发展及转移有密切关系的蛋白之一。本文就β-catenin和E-cadherin与肿瘤发展,转移关系的研究进展作一综述。     

富亮氨酸alpha2 糖蛋白1（LRG1）在肿瘤中的研究进展

富亮氨酸琢2 糖蛋白1(Leucine-rich-alpha-2-glycoprotein1,LRG1）是富亮氨酸重复序列(leucine-rich repeat, LRR)家族蛋白成 员之一。LRG1 在人类多种肿瘤中表达异常,可以作为部分肿瘤早期诊断的潜在生物标记,而且这种异常表达可能提示患者预后 不良。LRG1 在肿瘤的发生、侵袭转移、上皮间质转化和血管生成中发挥重要作用。这些环节中,协同参与调控的辅助因子众多且 有差异,因而经历的信号途径有所不同。本文综合目前的研究进展,旨在阐述LRG1 与肿瘤的关系以及其调控肿瘤发生发展的分 子机制。LRG1 有望成为一种新的肿瘤分子标志物,将为恶性肿瘤的分子诊断及靶向治疗提供新的方向和手段。     

胃癌的肿瘤微环境研究进展

肿瘤微环境是决定肿瘤细胞行为的主要影响因素,有别于正常细胞与其周围组织所形成的微环境,组织缺氧和酸中毒、间质高压形成、大量生长因子和蛋白水解酶的产生及免疫炎性反应等构成了肿瘤组织代谢环境的生物学特征,这种特性在肿瘤的发生、进展、转移中扮演重要的角色。胃癌早期症状不典型、转移迅速、死亡率高,是消化系统最常见的恶性肿瘤,目前,关于肿瘤微环境的研究尚处于起步阶段,对胃癌肿瘤微环境的研究有助于我们进一步认识胃癌发生发展的机制,并为临床诊断、治疗胃癌提供依据。因此,本文就近年来在胃癌肿瘤微环境方面的研究进展作一综述。     

Effect of P2X purinergic receptors in tumor progression and as a potential target for anti-tumor therapy

The development of tumors is a complex pathological process involving multiple factors, multiple steps, and multiple genes. Their prevention and treatment have always been a difficult problem at present. A large number of studies have proved that the tumor microenvironment plays an important role in the progression of tumors. The tumor microenvironment is the place where tumor cells depend for survival, and it plays an important role in regulating the growth, proliferation, apoptosis, migration, and invasion of tumor cells. P2X purinergic receptors, which depend on the ATP ion channel, can be activated by ATP in the tumor microenvironment, and by mediating tumor cells and related cells (such as immune cells) in the tumor microenvironment. They play an important regulatory role on the effects of the skeleton, membrane fluidity, and intracellular molecular metabolism of tumor cells. Therefore, here, we outlined the biological characteristics of P2X purinergic receptors, described the effect of tumor microenvironment on tumor progression, and discussed the effect of ATP on tumor. Moreover, we explored the role of P2X purinergic receptors in the development of tumors and anti-tumor therapy. These data indicate that P2X purinergic receptors may be used as another potential pharmacological target for tumor prevention and treatment.

     

Interleukin 18: Friend or foe in cancer

In the last few years, the field of tumor immunology has significantly expanded and its boundaries, never particularly clear, have become less distinct. Although the immune system plays an important role in controlling tumor growth, it has also become clear that tumor growth can be promoted by inflammatory immune responses. A good example that exemplifies the ambiguous role of the immune system in cancer progression is represented by interleukin 18 (IL-18) that was first identified as an interferon-γ-inducing factor (IGIF) involved in T helper type-1 (Th1) immune response. The expression and secretion of IL-18 have been observed in various cell types from immune cells to circulating cancer cells. In this review we highlighted the multiple roles played by IL-18 in immune regulation, cancer progression and angiogenesis and the clinical potential that may result from such understanding.     

胰腺癌微环境及其免疫抑制作用的研究进展

：胰腺癌的微环境在胰腺癌细胞的发生以及增殖中起重要作用,其构成与其他恶性肿瘤的微环境类似,但又有其自身的特 点,如存在大量的细胞外基质以及胰腺星状细胞非正常的大量增生形成了胰腺癌致密结实乏血供纤维结构基础。同时,胰腺癌微 环境中存在大量的免疫细胞,其在肿瘤细胞的诱导下处于数量和功能的失衡状态,具有杀伤肿瘤的效应性免疫细胞数量减少、功 能丧失。大量免疫抑制细胞的存在使胰腺癌处在免疫抑制的微环境中,有利于胰腺癌细胞逃避免疫监视从而有利于胰腺癌细胞 的增殖、侵袭、转移。本文就胰腺癌微环境的相关研究进展进行了总结。     

The role of PML ubiquitination in human malignancies

Tumor suppressors are frequently downregulated in human cancers and understanding of the mechanisms through which tumor cells restrict the expression of tumor suppressors is important for the prognosis and intervention of diseases. The promyelocytic leukemia (PML) protein plays a critical role in multiple tumor suppressive functions, such as growth inhibition, apoptosis, replicative senescence, suppression of oncogenic transformation, and inhibition of migration and angiogenesis. These tumor suppression functions are recapitulated in several mouse models. The expression of PML protein is frequently downregulated in diverse types of human tumors and this downregulation often correlates with tumor progression. Recent evidence has emerged that PML is aberrantly degraded in various types of tumors through ubiquitination-dependent mechanisms. Here, we summarize our current understanding of the PML ubiquitination/degradation pathways in human cancers. We point out that multiple pathways lead to PML ubiquitination and degradation. Furthermore, the PML ubiquitination processes are often dependent on other types of posttranslational modifications, such as phosphorylation, prolylisomerization, and sumoylation. Such feature indicates a highly regulated nature of PML ubiquitination in different cellular conditions and cell contexts, thus providing many avenues of opportunity to intervene PML ubiquitination pathways. We discuss the potential of targeting PML ubiquitination pathways for anti-cancer therapeutic strategies.     

Das Miteinander im Tumor

Interactions in the tumor Cancer has long been regarded as a mass of cells growing aberrantly due to mutations leading to constant cell proliferation and inhibition of cell death. Meanwhile, it has been acknowledged that not only tumor cells but also stroma plays an important role in tumorigenesis and progression. Although infiltrating immune cells are found in many tumors, an effective response to the tumor often seems to fail. One of the reasons discussed in this context is the modulation and suppression of immune cells by the tumor environment. Tumor cells show an altered metabolism leading to the secretion of metabolites that have been shown to act on stromal cells such as immune cells. Therefore, tumor metabolism is a promising therapeutic target to inhibit tumor growth and reactivate an effective anti‐tumor immune response.     

增殖诱导配体(APRIL)研究进展

增殖诱导配体 (aproliferation inducingligand ,APRIL)是肿瘤坏死因子 (TNF)家族的新成员 ,在多种肿瘤组织中有高表达 ,能促进肿瘤细胞增殖 ,防止肿瘤细胞受CD95L、FasL等诱导的凋亡 ;调节体液免疫 ;并在T、B淋巴细胞的成熟和活化中起一定作用。因此 ,APRIL与肿瘤的发生、发展以及免疫系统的调节有密切关系。     

Glioma-derived T cell immunoglobulin- and mucin domain-containing molecule-4 (TIM4) contributes to tumor tolerance

Tumor tolerance plays a critical role in tumor growth and escape from immune surveillance. The mechanism of tumor tolerance development is not fully understood. Regulatory T cells (Tregs) play a critical role in tumor tolerance. TIM4 (T cell immunoglobulin- and mucin domain-containing molecule-4) is involved in immune regulation. We investigated the role of TIM4 in the induction of Tregs in tumors. Surgically removed glioma tissue and peripheral blood samples were obtained from 25 glioma patients. Immune cells were isolated from the tissue and blood samples. Confocal microscopy was employed to detect macrophages phagocytosing apoptotic T cells. The generation of tumor-specific Tregs and the immune suppression function of Tregs were observed in cell culture models. High levels of TIM4 were detected in glioma-derived macrophages. Phosphatidylserine (PS) was detected in glioma-derived T cells; naïve T cells expressed low levels of PS that could be up-regulated by hypoxia. Glioma-derived macrophages phagocytosed PS-expressing T cells, gaining the tolerogenic properties, which could induce tumor-specific Tregs; the latter could suppress tumor-specific CD8⁺ T cells. We conclude that macrophage-derived TIM4 plays an important role in the induction of Tregs in gliomas, which may play an important role in tumor tolerance.     

The Role of Respiratory Microbiota in Lung Cancer

Recently, the impact of microorganisms on tumor growth and metastasis has attracted great attention. The pathogenesis and progression of lung cancer are related to an increase in respiratory bacterial load as well as changes in the bacterial community because the microbiota affects tumors in many ways, including canceration, metastasis, angiogenesis, and treatment. The microbiota may increase tumor susceptibility by altering metabolism and immune responses, promoting inflammation, and increasing toxic effects. The microbiota can regulate tumor metastasis by altering multiple cell signaling pathways and participate in tumor angiogenesis through vascular endothelial growth factors (VEGF), endothelial cells (ECs), inflammatory factors and inflammatory cells. Tumor angiogenesis not only maintains tumor growth at the primary site but also promotes tumor metastasis and invasion. Therefore, angiogenesis is an important mediator of the interaction between microorganisms and tumors. The microbiota also plays a part in antitumor therapy. Alteration of the microbiota caused by antibiotics can regulate tumor growth and metastasis. Moreover, the microbiota also influences the efficacy and toxicity of tumor immunotherapy and chemotherapy. Finally, the effects of air pollution, a risk factor for lung cancer, on microorganisms and the possible role of respiratory microorganisms in the effects of air pollution on lung cancer are discussed.