肿瘤相关巨噬细胞极化的研究进展

肿瘤相关巨噬细胞是肿瘤组织局部浸润的巨噬细胞,在肿瘤组织微环境中,这些巨噬细胞发生M2型极化,从而发挥免疫抑制效应,促进肿瘤增殖。而M2型极化的肿瘤相关巨噬细胞也能够被再次诱导逆向极化形成具有抗肿瘤效应的M1型肿瘤相关巨噬细胞,激发机体产生特异性抗肿瘤免疫应答。促进肿瘤相关巨噬细胞M1型极化由此成为当前抗肿瘤免疫防治研究的热点。将对有关肿瘤相关巨噬细胞极化的新进展进行综述,为抗肿瘤免疫研究提供新的思路。     

MiRNA与肿瘤相关巨噬细胞CSCD

肿瘤相关巨噬细胞(TAM)是由血液循环中的单核细胞募集进入肿瘤微环境后分化而成的巨噬细胞,它与肿瘤的形成、发展、侵袭和转移密切相关。miRNA是一种内源性非编码小分子RNA,参与多种肿瘤的发生、发展进程。研究表明,特定miRNA在控制TAM的极化方向和功能表型中发挥重要作用,有可能成为抗肿瘤靶向治疗的潜在分子靶点。本文综述了本领域的研究新进展。     

EZH2作为抗肿瘤免疫治疗靶点研究进展

多梳蛋白复合体(PcG)的核心亚基zeste基因增强子同源物2(Enhancer of zeste homolog2,EZH2)是一种组蛋白甲基转移酶,参与维持细胞密度、干细胞多能性、细胞周期调节等重要的生理作用。研究发现,EZH2在多种肿瘤组织中高表达,是促进肿瘤发生和发展的致癌因子。由于EZH2在正常组织中低表达或者不表达,使其新近被鉴定为一种肿瘤相关抗原。已经在EZH2蛋白分子中鉴定出多条特异性抗原肽,这些抗原肽能激发机体免疫细胞对EZH2表达异常增高肿瘤细胞的杀伤活性。上述研究提示,EZH2可能是一种新的抗肿瘤治疗分子靶点,并在肿瘤免疫治疗中具有潜在的应用价值。就该领域的最新研究进展作一简要综述。     

巨噬细胞游走抑制因子在肿瘤中的作用研究进展

巨噬细胞游走抑制因子是一种具有多种生物学效应的糖蛋白,可以调节不同的下游信号如ERK/AKT、NF-κB等通路参与肿瘤细胞增殖、侵袭、转移、血管形成和自噬等生物学过程。临床相关研究表明巨噬细胞游走抑制因子与肿瘤发生发展关系密切,且在乳腺癌、肺癌、前列腺癌、甲状腺癌、结肠癌等多种肿瘤中高表达,因此以巨噬细胞游走抑制因子为靶点的相关肿瘤治疗逐渐受到重视。有关巨噬细胞游走抑制因子拓扑异构酶活性抑制剂及巨噬细胞游走抑制因子中和抗体在肿瘤治疗中的研究越来越多。本文对巨噬细胞游走抑制因子在肿瘤发生发展中的作用以及针对巨噬细胞游走抑制因子进行的肿瘤治疗研究作一综述。     

肿瘤干细胞与肿瘤相关巨噬细胞的相互作用

肿瘤微环境(tumor microenvironment,TME)不仅促进了肿瘤的早期形成和远处转移,而且随着肿瘤的进展,其自身也不断地发生变化。作为TME的重要组成部分,肿瘤相关巨噬细胞(tumor associated macrophages,TAMs)可通过分泌多种细胞因子激活IL-6/STAT3、TGF-β、Wnt/β-catenin等信号通路促进肿瘤干细胞(cancer stem cells,CSCs)的存活、自我更新和化疗耐药等。同时,CSCs也可通过分泌多种细胞因子和趋化因子等募集巨噬细胞,并将其诱导为TAMs重塑CSCs特定的生态位,维持CSCs表型并促进肿瘤进展。TAMs与CSCs的相互作用在促进肿瘤生长、转移及化疗耐药等方面发挥了重要作用。本文对TME中CSCs与TAMs相互作用的研究进行综述,并总结了以CSCs与TAMs相互作用为靶点在新型癌症治疗以及增强化疗效果等方面的重要潜力。     

查尔酮类化合物抗肿瘤作用靶点的研究进展

查尔酮是一种天然化合物,为多种药用植物的有效成分,国内外已经陆续报道了其抗肿瘤活性。查尔酮类化合物抗肿瘤作用靶点较为广泛,但缺乏系统性的文献综述。因此,该文将针对查尔酮类化合物作为潜在的抗肿瘤药物靶向抑制IκB激酶、硫氧还蛋白还原酶、微管蛋白、血管表皮生长因子、p53通路来发挥抗肿瘤作用的研究进行综述,以期为肿瘤的治疗提供更多的理论参考。     

靶向肿瘤相关巨噬细胞免疫治疗的研究进展

肿瘤相关巨噬细胞(TAMs)存在于肿瘤微环境中,分为经典活化的M1型和交替活化的M2型。M1型巨噬细胞通过释放促炎细胞因子来抑制肿瘤的生长,而M2型巨噬细胞通过促进肿瘤的增殖、血管生成和转移来促进肿瘤的进展。由于巨噬细胞对肿瘤的影响具有双重性,TAMs一直是肿瘤研究的热点。本文就TAMs的异质性和可塑性、TAMs与其他免疫细胞之间的串扰和TAMs对肿瘤的作用等问题进行了综述,并对TAMs的多种靶向治疗策略进行了总结和讨论。这些治疗策略包含抑制TAMs的招募、消耗TAMs以及调控TAMs的极化等方法和手段。这些研究有助于深入理解TAMs与肿瘤相互作用的机理,并为肿瘤的联合治疗提供借鉴和参考。     

肿瘤免疫治疗新兴靶点

近年来,肿瘤免疫治疗领域发展迅速,围绕肿瘤微环境中的免疫抑制、表观遗传修饰和能量代谢等多种机制涌现出诸多新靶点.这些新兴靶点为药物临床前研究及临床应用提供了更多参考,有望改善现有肿瘤免疫疗法的不足,具有潜在的应用前景及临床价值.该文对当前肿瘤免疫新兴靶点的特性及其药物开发情况进行综述.     

肿瘤相关巨噬细胞及其靶向治疗的研究进展

肿瘤是一种与机体免疫系统功能密切相关的疾病,是人类迄今为止仅次于心血管疾病的主要死亡原因。肿瘤相关巨噬细胞(tumor associated macrophage,TAM)作为肿瘤微环境(tumor microenvironment,TME)中主要的免疫细胞亚群发挥着重要的作用。M2样TAM的高浸润与实体肿瘤患者的低生存率密切相关。了解复杂的TME中TAM所经历的一系列代谢变化以及功能可塑性,有助于将TAM作为肿瘤免疫治疗的靶点,开发更有效的肿瘤治疗策略。该综述总结了TAM的来源、功能状态、代谢变化等最新研究,并着重讨论了TAM在实体肿瘤中的靶向治疗方法。     

炎症相关因子在血管性痴呆发病机制中的作用

血管性痴呆（vascular dementia,VD）是指由各种脑血管病,包括缺血性脑血管病、出血性脑血管病及急性与慢性缺氧性脑血管病引起的脑功能障碍,进而产生认知功能障碍的临床综合征。血管性痴呆是一种慢性进行性疾病,被认为是仅次于阿尔兹海默症,导致痴呆的第2位原因。目前,血管性痴呆的发病机制尚不明确,有可能与炎症、神经元损伤、胆碱能系统功能障碍、脑白质病变及氧化应激等有关。其中,炎症反应在急性与慢性脑缺血继发性脑损伤中起主要作用。抑制炎症能改善血管性痴呆动物模型的症状,显示炎症可能在血管性痴呆发病机制中发挥重要作用。参与炎症反应的相关因子,如细胞因子等可对中枢神经系统造成损伤。同时,炎症相关因子会触发炎症级联反应,加重脑损伤。本文总结了有关炎症相关因子参与导致血管性痴呆的各种病理损害和促进其发生发展的分子机制的最新研究进展,这些都有助于了解炎症相关因子在血管性痴呆发病机制中的作用。     

Tsp2 Facilitates Tumor-associated Fibroblasts Formation and Promotes Tumor Progression in Retroperitoneal Liposarcoma

Retroperitoneal liposarcoma (RLPS) is the most common subtype of retroperitoneal soft tissue sarcoma, characterized by a high recurrence rate and insensitivity to radiotherapy and chemotherapy. The function of tumor microenvironmental components, especially tumor-associated fibroblasts (TAFs), remains unclear in RLPS. The crosstalk between tumor cells and stromal cells should be clarified for therapy target discovery in RLPS. In this study, we demonstrated that TAFs from dedifferentiated liposarcoma (DDLPS) could attract LPS cells and promote their proliferation and migration. However, although α-SMA is positively expressed in RLPS, its expression does not indicate prognosis. By screening differentially expressed genes, performing Oncomine visualization, TCGA gene expression correlation analysis and qPCR verification, we determined that thrombospondin-2 (THBS2) gene expression was related to TAFs. The expression of Tsp2 protein, which was encoded by THBS2, was correlated with α-SMA expression, and it was an independent predictive factor for disease-free survival and recurrence-free survival in patients with RLPS. In vitro, Tsp2 facilitated the transformation of bone marrow-derived fibroblasts (BMFs) to TAFs and promoted the malignant biological behaviors of LPS cells by activating the MAPK/MEK/ERK pathway. Therefore, suppression of Tsp2 is expected to be a promising treatment method for RLPS patients.     

半乳凝集素-3与肿瘤形成和转移的关系研究进展

半乳凝集素-3是β-半乳糖苷凝集素家族的蛋白,广泛分布于各种正常组织和肿瘤组织,在不同的生理及病理条件下发挥着多种生物功能。目前有关半乳凝集素-3与肿瘤细胞的黏附、增殖、血管生成、肿瘤组织的发展及转移的研究取得了较大的进展,并成为疾病诊治特别是癌症治疗的很有前景的靶标。简要综述了半乳凝集素-3与癌症相关性的研究进展。     

Tumor-associated macrophages in direct contact with prostate cancer cells promote malignant proliferation and metastasis through NOTCH1 pathway

Background: M2 macrophages are well accepted to promote cancer progression in the prostate cancer (PCa). Paracrine is the principally studied mode of communication between M2 macrophages and tumor cells. In addition to this, we present here a novel model to demonstrate these cellular communications.Methods: PCa cells were co-cultured with THP-1/ human peripheral blood mononuclear cells derived M2 macrophages in direct contact manner. Cancer cell proliferation and invasion were examined to explain how direct contact communicates. Cell-based findings were validated in two xenograft models and patients samples.Results: M2 macrophage direct contact induced a higher proliferation and invasion in PCa cells when compared with noncontact coculture manner. In direct contact manner, NOTCH1 pathway was greatly activated in PCa cells, induced by elevated γ-secretase activity and higher coactivator MAML2 expression. Additionally, blocking γ-secretase activity and depletion of MAML2 completely abolished M2 macrophage direct contact-mediated PCa cell proliferation and invasion. In vivo, inhibiting NOTCH1 signalling impaired M2 macrophage-mediated PCa tumor growth and lung metastasis. Notably, M2 macrophage infiltration as well as high NOTCH1 signaling in cancer cells indicated more aggressive features and worse survival in PCa patients.Conclusion: Our results demonstrated the cell-cell direct contact pattern is an important way in PCa microenvironment cell communication. In this manner, elevated γ-secretase activity and MAML2 expression induced higher NOTCH1 signalling in PCa cells, which increased tumor cells proliferation and invasion. This potentially provided a therapeutic target for PCa.     

Origin,production and molecular determinants of macrophages for their therapeutic targeting

Macrophages, the most heterogeneous cells of the hematopoietic system and the giant eaters of the immune system that present either as tissue-resident cells or infiltrated immune cells, eliminate foreign pathogens and microbes and also play different physiological roles to maintain the body's immune response. In this review, we basically provide a broad overview of macrophages from their origin, functional diversity to M1-M2 polarization, specialized markers, and their role as important therapeutic targets in different diseases based on the current research and evidence. Apart from this, we have precisely discussed about tumor-associated macrophages (TAMs) and their role in tumor progression and newly discovered lesser-known markers of TAMs that could be used as potential therapeutic targets to treat life-threatening diseases. It is really very important to understand the diversity of macrophages to develop TAM-modulating strategies to activate our own immune system against diseases and to overcome immune resistance.     

Differentiation Antigens: Dependence on Carcinogenesis Mechanisms and Tumor Progression (A Hypothesis)

The data considered in the paper indicate that a tumor clone resulting from cell transformation, in order to develop into an overt neoplasm, should overcome a microenvironmental constraint. This destroys intercellular contacts and cell interactions with extracellular matrix required for induction and maintenance of epithelium differentiation. The possible reasons for this lie in mutations of genes that control cell adhesion molecules and integrins, as well as proteases secreted by a tumor. These events lead to partial loss of differentiation antigens by a cell or to their incorrect localization in a cell. Simultaneously, the expression of embryo-specific genes is unblocked, leading to overexpression of embryonic antigens and their abnormal secretion into blood, which results in appearance of oncofetal serum markers. Discussed from this point of view are alpha-fetoprotein, the carcinoembryonic antigen, and the prostate-specific antigen, which are used as tumor markers.     

Comparative Characteristics of Immunological,Clinical and Morphological Features of Human Lymphoid Tumors in Respect with Tumor Genesis and Progression

We describe three lymphoid tumors with the same immunophenotype characteristic for chronic lymphoid leukemia (CD19⁺/CD5⁺, clonality of the light immunoglobulin chains, CD23⁺ and CD10^–). However, clinical picture and morphology of neoplastic cells dictate different clinical forms of these cases: chronic lymphoid leukemia, large cell transformation of chronic lymphoid leukemia and diffuse large B-cell lymphoma. Taking into account that immunophenotype reflects the origin of tumor, while clinical outcome and morphological features of cells reflect the stage of tumor progression and/or pathway of tumor formation, we discuss the approach to natural classification of lymphoid tumors based on the process of their evolution.     

翻译调控肿瘤蛋白的结构、功能以及在肿瘤发展中的作用

翻译调控肿瘤蛋白(translational controlled tumor protein,TCTP),又称p23、组胺释放因子(histamine releasing factor,HRF)等,是一类在动植物中具有高度保守性和同源性的蛋白,主要介导细胞凋亡、细胞增殖与分化、细胞骨架重排、炎症反应等重要事件,与肿瘤的发生发展进程密切相关.针对TCTP的相关研究不仅有助于进一步了解各种肿瘤的生理病理周期,同时也提示其在寻找治愈肿瘤的方法中有望成为新的靶点.本文将对TCTP的结构、生物学功能以及在各种肿瘤中的作用进行综述.     

脂质运载蛋白-2在肿瘤进展中的作用

铁元素通过参与氧化损伤、分泌炎性因子、改变信号通路、影响免疫系统等过程,在肿瘤的发生发展中发挥重要的促进作用。靶向铁的治疗是肿瘤治疗的重要策略之一。转铁蛋白参与肿瘤细胞铁的运输,是肿瘤治疗的重要靶标。脂质运载蛋白-2(lipocalin-2,LCN2)是由肿瘤微环境中的肿瘤相关巨噬细胞分泌的胞内可运输铁离子的蛋白质。LCN2在多种类型的肿瘤中表达均明显升高,有望成为相关癌症不良预后的标志物,是近年来研究的热点。LCN2主要通过结合不同的配体与受体参与铁的运输,保护基质金属蛋白酶-9活性,分泌细胞因子等机制,参与肿瘤细胞的增殖与凋亡、肿瘤细胞的侵袭与转移,以及肿瘤血管生成过程而影响肿瘤的治疗与预后。其中,LCN2的存在形式不同,对铁的运输方式不同,决定其对肿瘤细胞增殖与凋亡的调控作用不同,以及LCN2对信号通路影响的差异,造成LCN2在不同肿瘤,甚至相同肿瘤的研究中获得不一致结果,具体机制尚待进一步研究。本文就LCN2蛋白的结构特征、LCN2蛋白与肿瘤进展的关系,及其在肿瘤进展中可能的作用机制进行综述,为进一步的药物开发与临床研究提供理论参考。     

Tumor microenvironment: Interactions and therapy

Tumor microenvironment (TME) is a host for a complex network of heterogeneous stromal cells with overlapping or opposing functions depending on the dominant signals within this milieu. Reciprocal paracrine interactions between cancer cells with cells within the tumor stroma often reshape the TME in favor of the promotion of tumor. These complex interactions require more sophisticated approaches for cancer therapy, and, therefore, advancing knowledge about dominant drivers of cancer within the TME is critical for designing therapeutic schemes. This review will provide knowledge about TME architecture, multiple signaling, and cross communications between cells within this milieu, and its targeting for immunotherapy of cancer.