肿瘤微环境对肿瘤免疫的影响

恶性实体肿瘤组织内微环境不同程度的存在着低pH﹑低O2、营养贫乏状态,这种状态影响了恶性肿瘤细胞对化疗药物的敏感性,不利于细胞因子﹑免疫细胞抑制杀伤恶性肿瘤细胞.该文简要叙述恶性肿瘤组织的微环境形成﹑细胞内外液特点、肿瘤免疫以及肿瘤微环境对细胞因子﹑免疫细胞和单克隆抗体抗恶性肿瘤作用影响,探讨如何改善这种微环境状态以提高恶性肿瘤的治疗效果.     

髓源性抑制细胞在肿瘤微环境中作用的研究进展

肿瘤微环境在肿瘤进展过程中发挥至关重要的作用,髓源性抑制细胞(MDSC)是介导微环境免疫抑制效应的关键组分。MDSC在骨髓中产生,并通过多种趋化因子募集至外周淋巴器官和肿瘤组织中来促进肿瘤微环境的形成。除免疫抑制作用外,MDSC在肿瘤微环境中还可以通过促进肿瘤内血管生成、肿瘤细胞侵袭转移能力等机制发挥促肿瘤效应。本文从MDSC的起源、分类、扩增活化机制、趋化因子、在肿瘤微环境中的功能以及以MDSC为靶点的免疫治疗等方面入手,就近几年的相关研究进行综述。     

槲皮素对缺氧诱导的乳腺癌细胞增殖及干性的影响

目的考察槲皮素对缺氧诱导的乳腺癌细胞增殖及干性的影响。方法缺氧诱导剂CoCl2体外培养BT549和MDA-MB-231细胞模拟缺氧微环境体系,CCK-8、平板克隆、肿瘤球形成及Western Blot实验考察槲皮素对缺氧微环境细胞的增殖及肿瘤细胞干性的影响。结果缺氧微环境能促进细胞增殖,槲皮素能一定程度抑制细胞增殖(P <0.05);相较于常氧的克隆形成率(31.93±6.25)%,缺氧微环境的克隆形成率(71.93±12.96)%显著升高,而槲皮素(10、20μmol·L~(-1))能够抑制克隆的形成(P<0.01);缺氧微环境肿瘤球形成数目比常氧条件显著升高(P <0.01),槲皮素能够显著抑制肿瘤球的形成;与常氧对照组相比,缺氧微环境显著升高肿瘤干性相关蛋白(CD44、CD133、Nanog、Sox-2)的表达(P <0.05),槲皮素能够显著降低肿瘤干性相关蛋白的表达。结论槲皮素能够抑制缺氧微环境中细胞的增殖,降低肿瘤细胞的干性。     

治疗癌症的新途径：靶向肿瘤微环境

传统的癌症治疗方法是以直接杀死肿瘤细胞为基础,近年来靶向肿瘤微环境成为治疗肿瘤的新途径。肿瘤微环境主要通过诱导新生血管形成、抑制免疫监视和免疫反应、孕育肿瘤干细胞等促进肿瘤发生及转移。理论上靶向肿瘤微环境的肿瘤治疗应有高效、低毒、广谱的特点。限于对肿瘤微环境的了解,目前以肿瘤微环境为靶成功治疗肿瘤的例子并不多。本文就肿瘤微环境对肿瘤的调控、靶向肿瘤微环境治疗肿瘤的现状、存在的问题及发展趋势进行综述。     

miRNAs 以非细胞自主机制参与肿瘤微环境调节的研究进展

肿瘤微环境是肿瘤发生发展过程中所处的内环境 , 由多种细胞及细胞外基质组成, 是肿瘤形成、 转移以及耐药的关键因素。对肿瘤微环境的调控将成为治疗肿瘤的靶点之一。MicroRNAs（miRNAs） 是一类 21~25 个核苷酸的非编码单链 RNA, 主要参与基因的表达调控。近年来, 随着非细胞自主抑癌机制的提出, 使 miRNAs 对肿瘤微环境的调控受到了极大关注。本文主要阐述 miRNAs 通过非细胞自主机制对肿瘤微环境的影响, 为对肿瘤微环境的深入研究以及肿瘤治疗提供参考。     

常见恶性肿瘤中CAF来源外泌体的研究进展

癌相关成纤维细胞(CAF)是纤维细胞、骨髓间充质细胞和内皮细胞在一定细胞因子的作用下转化而成,分泌多种生物活性物质和吸引炎性细胞参与肿瘤微环境调控的肿瘤相关细胞.CAF分泌胶原蛋白、细胞因子和外泌体等调节细胞周围微环境,外泌体可以介导CAF向肿瘤细胞进行物质和信号传递,发挥调节肿瘤免疫抑制、改善肿瘤细胞生长微环境,提高...     

异常代谢物与肿瘤免疫微环境的改造

代谢重编程是肿瘤常见的特征之一,受到细胞内在因素和肿瘤免疫微环境（TIME）中代谢物的调节。微环境中的肿瘤细胞与免疫细胞对营养物质的利用存在竞争关系,肿瘤细胞代谢活性增强会导致免疫细胞所需关键营养物质被过度消耗,并减少抑制肿瘤免疫的代谢副产物的产生和蓄积,进而导致免疫细胞功能障碍。TIME中的肿瘤细胞、免疫细胞和基质细胞均可通过代谢中间物或产物的消耗和分泌来改变TIME,而改造后的TIME亦可反过来影响这些细胞的功能。本文就TIME中的异常代谢物对其的改造进行简要综述,深入了解并揭示异常代谢物与TIME的关系,以期为肿瘤免疫治疗提供理论基础及新的思路。     

宿主微环境与肿瘤多药耐药和血管新生的关系

特殊的宿主微环境作为肿瘤细胞生存、增殖的土壤通过多种途径影响细胞的生物学特性,宿主微环境对肿瘤细胞的耐药及血管新生的影响是其中最为重要的途径,以此为基础将为攻克恶性肿瘤特别是耐药的难治性肿瘤提供新的诊断治疗手段。     

鞘氨醇激酶和1-磷酸鞘氨醇及其受体信号在肿瘤微环境中的研究进展

鞘氨醇激酶(SphK)、1-磷酸鞘氨醇(S1P)及其受体(S1PR)参与肿瘤细胞增殖、迁移等生物学过程,在癌症的发生发展中起重要作用。近年来,研究者日益关注癌细胞与肿瘤微环境之间的相互作用,肿瘤微环境具有遗传稳定性并且能够被诱导为抗肿瘤表型,具有显著的治疗优势。研究显示, SphK/S1P/S1PR能够调节肿瘤微环境的多个方面。本文从肿瘤免疫微环境、癌症相关成纤维细胞、肿瘤血管生成、肿瘤缺氧微环境4个角度对SphK和S1P/S1PR信号对肿瘤微环境的影响进行综述,并简要概述相关药物研究情况,旨在阐明SphK/S1P/S1PR在癌症中的作用及为抗肿瘤药物的研究提供新思路。     

肿瘤坏死因子-α在恶性肿瘤发生发展中的作用及研究进展

慢性炎症,无论是否由病原菌感染引起,在很多癌的发生中起着重要作用。研究发现,炎微环境在肿瘤细胞的恶性转化、增殖、侵袭、转移以及凋亡等肿瘤发展的各个阶段,通过各种机制发挥了重要的影响[1]。肿瘤的炎性微环境主要由新生血管、淋巴细胞、成纤维细胞以及由它们分泌产生的各种炎症因子及细胞基质等组成。肿瘤坏死因子     

间充质干细胞介导线粒体转移机制及其在癌症治疗中的应用进展

含有间充质干细胞的肿瘤微环境在癌细胞增殖、耐药和转移过程中起到了关键作用。间充质干细胞介导线粒体转移至癌细胞,增强线粒体的氧化磷酸化,促进癌症进展。干扰线粒体转移的相关因素对癌症治疗产生积极影响。该文就间充质干细胞介导线粒体转移及其在癌症治疗中的相关应用进行阐述,旨在为癌症治疗提供新的策略和思路。     

基因修饰间充质干细胞治疗肿瘤研究进展

间充质干细胞（MSCs）是来源于中胚层的成体干细胞,体内分布广泛,可从骨髓、脂肪、牙髓、脐带/胎盘等组织中分离获取,具有高度的可增殖和分化潜能,较低的免疫原性,同时具有向炎症损伤部位微环境的趋向性,在疾病治疗方面可作为基因药物的载体实现精准治疗。癌症被认为是永远无法愈合的伤口,其组织微环境在损伤与修复中呈无休止的动态变化,MSCs在其中扮演了重要角色。利用MSCs具有的向肿瘤组织中归巢及定位的特点,对其进行抗肿瘤药物的基因工程改造可能在癌症的治疗上是一种新的策略。概述MSCs在癌症发生发展中的作用以及基因修饰MSCs治疗癌症的研究进展,旨在为临床使用基因修饰MSCs治疗癌症提供策略和见解。     

Fucoidan-functionalized activated platelet-hitchhiking micelles simultaneously track tumor cells and remodel the immunosuppressive microenvironment for efficient metastatic cancer treatment

Tumor metastasis is responsible for most mortality in cancer patients, and remains a challenge in clinical cancer treatment. Platelets can be recruited and activated by tumor cells, then adhere to circulating tumor cells (CTCs) and assist tumor cells extravasate in distant organs. Therefore, nanoparticles specially hitchhiking on activated platelets are considered to have excellent targeting ability for primary tumor, CTCs and metastasis in distant organs. However, the activated tumor-homing platelets will release transforming growth factor-β (TGF-β), which promotes tumor metastasis and forms immunosuppressive microenvironment. Therefore, a multitalent strategy is needed to balance the accurate tumor tracking and alleviate the immunosuppressive signals. In this study, a fucoidan-functionalized micelle (FD/DOX) was constructed, which could efficiently adhere to activated platelets through P-selectin. Compared with the micelle without P-selectin targeting effect, FD/DOX had increased distribution in both tumor tissue and metastasis niche, and exhibited excellent anti-tumor and anti-metastasis efficacy on 4T1 spontaneous metastasis model. In addition, due to the contribution of fucoidan, FD/DOX treatment was confirmed to inhibit the expression of TGF-β, thereby stimulating anti-tumor immune response and reversing the immunosuppressive microenvironment. The fucoidan-functionalized activated platelets-hitchhiking micelle was promising for the metastatic cancer treatment.     

Immunotherapeutic modulation of the suppressive liver and tumor microenvironments

The liver is an immunologically unique organ, consisting of resident hematopoietic and parenchymal cells which often contribute to a relatively tolerant microenvironment. It is also becoming increasingly clear that tumor-induced immunosuppression occurs via many of the same cellular mechanisms which contribute to the tolerogenic liver microenvironment. Myeloid cells, consisting of dendritic cells (DC), macrophages and myeloid derived suppressor cells (MDSC), have been implicated in providing a tolerogenic liver environment and immune dysfunction within the tumor microenvironment which can favor tumor progression. As we increase our understanding of the biological mechanisms involved for each phenotypic and/or functionally distinct leukocyte subset, immunotherapeutic strategies can be developed to overcome the inherent barriers to the development of improved strategies for the treatment of liver disease and tumors. In this review, we discuss the principal myeloid cell-based contributions to immunosuppression that are shared between the liver and tumor microenvironments. We further highlight immune-based strategies shown to modulate immunoregulatory cells within each microenvironment and enhance anti-tumor responses.     

靶向肿瘤相关成纤维细胞的肿瘤治疗研究进展

肿瘤是威胁人类生命健康的主要疾病之一。肿瘤细胞和肿瘤微环境(tumor microenvironment,TME)的相互作用在肿瘤发生、发展、转移和治疗过程中发挥关键作用。肿瘤相关成纤维细胞(cancer-associated fibroblasts,CAFs)是TME的重要组成部分,是一类具极强增殖、迁移、分泌与合成能力的激活态成纤维细胞。研究发现,CAFs可直接与肿瘤细胞相互作用,提高肿瘤细胞干性,促进肿瘤的侵袭和转移;还可分泌多种细胞因子、趋化因子和生长因子等介导与肿瘤细胞存活、免疫调节相关的信号通路,间接发挥促肿瘤作用。因此,靶向CAFs成为开发新的肿瘤治疗药物和策略的研究热点。该文概述了CAFs的来源、CAFs与TME中肿瘤细胞和基质细胞之间的相互作用、靶向CAFs的肿瘤治疗策略、CAFs作为肿瘤预后生物标志物的可能性及其存在的问题和挑战,为以CAFs为靶点的新型肿瘤治疗策略的应用提供依据。     

Brain tumor-targeted drug delivery strategies

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.Key words: Barriers targeting, Tumor microenvironment, Tumor cells, Systematic targeted drug delivery     

Apoptosis and cancer stem cells: Implications for apoptosis targeted therapy

Evidence is accumulating showing that cancer stem cells or tumor-initiating cells are key drivers of tumor formation and progression. Successful therapy must therefore eliminate these cells, which is hampered by their high resistance to commonly used treatment modalities. Thus far, only a limited number of studies have addressed the cancer stem cell killing potential of apoptosis targeted therapies and mechanisms of apoptosis resistance in these cells. Apoptosis resistance may involve inherent cellular mechanisms that may change depending on the differentiations status of stem cells and, on the other hand, extrinsic factors provided by the microenvironment such as secreted survival factors, adhesion-mediated apoptosis resistance and hypoxic conditions. In order to metastasize, cancer stem cells from solid tumors have to break free from their primary epithelial sites and resist cell death activation after detachment (anoikis). The induction of an embryonic genetic program causing the transition from an epithelial to a mesenchymal state (EMT) has been implicated in enhanced migration and metastatic spread of tumor cells and may contribute to apoptosis and anoikis resistance. Considering the plasticity of cancer stem cells the question arises whether a particular apoptosis-inducing strategy will be sufficient for eliminating all the cellular appearances of these cells, also taking into account a varying microenvironment. Here, the different mechanisms of apoptosis resistance that may be encountered in the context of cancer stem cell plasticity described thus far are discussed in relation to the efficacy of apoptosis therapies, such as TRAIL, BCL-2 family and XIAP targeted therapies.     

Chemoattractant receptors as pharmacological targets for elimination of glioma stem-like cells

Malignant tumors are thought to be initiated by a small population of cells that display stem cell properties, including the capacity of self-renewal, multipotent differentiation, initiation of tumor tissues and resistance to therapy. Cancer stem cells (CSCs) have also been identified in gliomas in which they are named as glioma stem-like cells (GSLCs), or glioma stem cells. In xenograft transplantation models, GSLCs propagate tumor and promote tumor progression. The tumorigenesis of GSLCs depends not only on their autonomous proliferation but also on interaction with microenvironment components. Among these components, G protein coupled chemoattractant receptors (GPCRs) and their agonists have attracted much attention for their capacity to mediate leukocyte infiltration, angiogenesis, tumor invasion and metastasis. Chemoattractant GPCRs are widely expressed by tumor cells and stromal cells and recognize agonists present in the tumor microenvironment. Such GPCRs have been found to be expressed also by CSCs including GSLCs. In this brief review, we will summarize the recent development in the studies of the function, regulation and signal transduction of chemoattractant GPCRs in GSLCs in hope to promote a better understanding of the mechanistic basis of the progression of gliomas and the identification of molecular targets for the novel anti-glioma therapy.     

Breast tumor stroma: A driving force in the development of resistance to therapies

Breast cancer is the most common cancer and the second leading cause of cancer‐related death in women worldwide. In spite of huge advancements in early detection and ever‐increasing knowledge of breast cancer biology, approximately 30% of patients with early‐stage breast cancer experience disease recurrence. Most patients are chemosensitive and cancer free immediately after the treatment. About 50% to 70% of breast cancer patients, however, will relapse within 1 year. Such a relapse is usually concomitant with adenocarcinoma cells acquiring a chemoresistant phenotype. Both de novo and acquired chemoresistance are poorly understood and present a major burden in the treatment of breast cancer. Although, previously, chemoresistance was largely linked to genetic alterations within the cancer cells, recent investigations are indicating that chemoresistance can also be associated with the tumor microenvironment. Nowadays, it is widely believed that tumor microenvironment is a key player in tumor progression and response to treatment. In this study, we will review the interactions of breast tumor cells with their microenvironment, present the latest research on the resistance mediated by the stromal component in breast cancer, and discuss the potential therapeutic strategies that can be exploited to treat breast cancers by targeting tumor microenvironment.