Plasminogen kringle 5-engineered glioma cells block migration of tumor- associated macrophages and suppress tumor vascularization and progres- sion.

Angiostatin, a well-characterized angiostatic agent, is a proteolytic cleavage product of human plasminogen encompassing the first four kringle structures. The fifth kringle domain （K5） of human plasminogen is distinct from angiostatin and has been shown, on its own, to act as a potent endothelial cell inhibitor. We propose that tumor-targeted K5 cDNA expression may act as an effective therapeutic intervention as part of a cancer gene therapy strategy. In this study, we provide evidence that eukaryotically expressed His-tagged human K5 cDNA （hK5His） is exported extracellularly and maintains predicted disulfide bridging conformation in solution. Functionally, hK5His protein produced by retrovirally engineered human U87MG glioma cells suppresses in vitro migration of both human umbilical vein endothelial cells and human macrophages. Subcutaneous implantation of Matrigel-embedded hK5His-producing glioma cells in nonobese diabetic/severe combined immunodeficient mice reveals that hK5His indaces a marked reduction in blood vessel formation and signiticanfly suppresses the recruitment of tumor-infiltrating CD45（＋）Mac3（＋）Grl （-） macrophages. Therapeutically, we show ill a nude mouse orthotopic brain cancer model that tumor-targeted K5 expression is capable of effectively suppressing glioma growth and promotes significant long-term survival （〉120 days） of test animals. These data suggest that plasminogen K5 acts as a novel two-pronged anticancer agent, mediating its inhibitory effect via its action on host-derived endothelial cells and tumor-associated macrophages, resulting in a potent, clinically relevant antitumor effect.     

肿瘤相关巨噬细胞对肿瘤促进作用的研究进展

肿瘤相关巨噬细胞(tumor-associated macrophages,TAMs)广泛浸润于肿瘤组织中.越来越多的证据显示TAMs可促进肿瘤生长、侵袭和转移.本文就TAMs在肿瘤进展中的作用及相关机制做一综述.     

Role of tumor-associated macrophages in tumor progression and invasion

Tumor-Associated Macrophages (TAM) represent the major inflammatory component of the stroma of many tumors, able to affect different aspects of the neoplastic tissue. Many observations indicate that TAM express several M2-associated protumoral functions, including promotion of angiogenesis, matrix remodelling and suppression of adaptive immunity. The protumoral role of TAM in cancer is further supported by clinical studies that found a correlation between the high macrophage content of tumors and poor patient prognosis and by evidence showing that long-term use of non-steroidal anti-inflammatory drugs reduces the risk of several cancers. Here, we discuss evidence supporting the view that TAM represent a unique and distinct M2-skewed myeloid population and a potential target of anti-cancer therapy.     

不同表型肿瘤相关巨噬细胞在肿瘤进展中的作用

随着对肿瘤发生、侵袭和转移过程研究的不断深入,临床发现肿瘤相关巨噬细胞（tumor associated macrophage,TAM）在肿瘤微环境中扮演重要角色。由于经典活化的巨噬细胞（M1）/替代性活化的巨噬细胞（M2）理论过度简化了TAM在肿瘤微环境中的多种作用,目前临床大多根据表面蛋白表达的不同将TAM重新分为CD68+TAM、CD163+TAM、CD204+TAM、CD169+TAM、CCL18+TAM等。各型TAM表达的表面蛋白具有不同类型的配体并调控着不同的信号通路和细胞因子。因此,这些亚型的TAM具有促进或抑制肿瘤的类似作用,但其所牵涉的机制以及带来的临床表现均不相同。本文将就TAM各类表型对各类肿瘤的生长、转移、预后的影响及其临床关联进行综述。      

CD38 deficiency in the tumor microenvironment attenuates glioma progression and modulates features of tumor-associated microglia/macrophages

Gliomas are the most frequent primary tumors of the brain, and for highly malignant gliomas there is no successful treatment. The tumor microenvironment contains large numbers of infiltrating microglia and macrophages (MM). There is increasing evidence that the tumor-associated MM support glioma expansion. CD38 is a multifunctional ectoenzyme that uses nicotinamide adenine dinucleotide as a substrate to generate second messengers. Previously we showed that CD38 deficiency modulates microglial "activation" and impaired recovery from head trauma by a microglia-associated mechanism. In view of the supportive role of MM in glioma progression and the role of CD38 in microglia activation, we hypothesize that deficiency of CD38 in the tumor microenvironment would inhibit glioma progression. Using the syngeneic GL261 model of glioma progression in wild-type and CD38 null mice, we show here that CD38 deficiency significantly attenuates glioma expansion and prolongs the life span of the glioma-bearing mice. The CD38 deficiency effect was associated with increased cell death and decreased metalloproteinase-12 expression in the tumor mass, as well as modulation of the tumor-induced MM properties, as indicated by a reduction in the expression of the MM marker F4/80 and matrix metalloproteinases. Our results thus suggest that CD38 participates in the tumor-supporting action of MM and that targeting CD38 might be a potential therapeutic approach for glioma treatment.     

神经胶质瘤中肿瘤相关巨噬细胞研究进展

肿瘤相关巨噬细胞（TAM）是异质性细胞群体,是肿瘤微环境中炎性细胞的主要成分。这些细胞在神经胶质瘤中部分源自中枢神经系统小胶质细胞和循环单核细胞,并与神经胶质瘤的血管生成、免疫抑制、肿瘤进展和侵袭有关。文章综述了TAM通过各种途径促进神经胶质瘤发展的潜在机制,为神经胶质瘤的靶向治疗提供了新的可能性。     

肿瘤相关巨噬细胞对乳腺癌MCF-7细胞侵袭迁移能力的影响

目的观察肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)对乳腺癌MCF-7细胞侵袭迁移能力的影响,并初步探索其机制。方法选取人单核细胞系THP-1,体外经佛波酯(PMA)、人白细胞介素-4(IL-4)诱导获得TAMs细胞模型;通过流式细胞术(FCM)检测TAMs表面标记分子CD206表达水平;MCF-7细胞与TAMs共培养后,光学倒置显微镜观察细胞形态;利用Transwell小室分别检测MCF-7细胞的侵袭和迁移能力;蛋白印记法(Western blotting)检测E-钙黏蛋白(Ecadherin)、N-钙黏蛋白(N-cadherin)、闭合蛋白(Occludin)及波形纤维蛋白(Vimentin)的表达;采用酶联免疫吸附法(ELISA)测定细胞培养上清中转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)和血管内皮生长因子(VEGF)的浓度。结果与TAMs共培养后的MCF-7细胞伪足增多,细胞排列更松散。通过FCM检测到TAMs表面标记物CD206显著表达。Transwell实验结果显示,与TAMs共培养后的MCF-7细胞迁移能力增...     

胶质瘤干细胞、肿瘤相关巨噬细胞和B7-H1在脑胶质瘤组织中的表达及其意义

目的:探讨胶质瘤干细胞（glioma stem cells,GSCs）、肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）和负性共刺激分子B7-H1(B7 homolog 1)在不同病理级别脑胶质瘤组织中的表达及其相关性。方法:对30例低级别脑胶质瘤（WHOⅠ级、Ⅱ级）和30例高级别脑胶质瘤（WHOⅢ级、Ⅳ级）标本做连续石蜡包埋切片,用免疫组化SP法检测各组标本中GSCs、TAMs和B7-H1的表达情况,采用CD133作为GSCs的标志物,以CD68作为TAMs的标志物。用Image-Pro Plus 6.0软件分析每个视野阳性染色的积分光密度（IOD）,每个组织切片在400倍镜下分析20个视野。结果:CD133、CD68和B7-H1在高级别脑胶质瘤组织中的表达水平明显高于低级别脑胶质瘤组织（P＜0.01、P＜0.01、P＜0.01）;脑胶质瘤组织中B7-H1的空间表达位置在CD68+TAMs的分布区域较强;CD133与CD68的表达呈正相关（P＜0.001）,CD133与B7-H1的表达呈正相关（P＜0.001）。结论:随着病理级别的增高,脑胶质瘤组织中GSCs、TAMs和B7-H1的表达均增高,并且CD133与CD68和B7-H1的表达呈显著正相关。     

胶质瘤组织肿瘤相关巨噬细胞表型检测临床意义分析

目的:检测人脑胶质瘤组织中TAM的M1和M2型表达水平,探讨其与患者临床病理特征和预后的相关性。方法:采用免疫组化SP法检测48例人脑胶质瘤组织M1和M2型巨噬细胞的表达水平,分析表达强度与临床病理特征的关系,Kaplan-Meier生存曲线分别比较M1和M2型高表达组与低表达组患者的无进展生存期和总生存期。结果:M1和M2型肿瘤相关巨噬细胞表达在不同性别、年龄、肿瘤大小、肿瘤位置和有无囊变组织中差异均无统计学意义,P值均>0.05。M1型巨噬细胞表达在Ⅰ～Ⅳ级胶质瘤组织中随肿瘤恶性度增加而逐渐降低,表达与病理级别呈负相关,r=-0.705,P=0.000;高表达组和低表达组无进展生存期及总生存期差异均有统计学意义,P值均为0.000。M2型巨噬细胞表达在Ⅰ～Ⅳ级胶质瘤组织中随肿瘤恶性度增加而逐渐增高,表达与病理级别呈正相关,r=0.857,P=0.000;高表达组和低表达组无进展生存期及总生存期差异均有统计学意义,P值均为0.000。结论:M1和M2型肿瘤相关巨噬细胞表达与胶质瘤发生及恶性程度相关,检测两者表达情况可为脑胶质瘤的临床诊治及预后判断提供依据。     

肿瘤相关巨噬细胞对鼻咽癌进展和预后的影响

背景与目的:有研究表明,在肺癌、乳腺癌等肿瘤组织中,肿瘤相关巨噬细胞(tumor-associatedmacrophages,TAMs)与肿瘤的预后呈负相关。然而在胃癌和部分结直肠癌的研究中得出了TAMs与预后呈正相关的结论。本研究旨在探讨TAMs对鼻咽癌(nasopharyngealcarcinoma,NPC)进展和预后的影响。方法:应用免疫组化技术检测60例鼻咽癌组织中TAMs标记物CD68的表达;分别培养正常巨噬细胞、鼻咽癌细胞株CNE-1和CNE-2以及肺癌细胞株95D,将同浓度的3种癌细胞株的上清液加入同量的巨噬细胞中共培养1天,6天及加入LPS活化后继续培养1天,应用ELISA技术检测共培养后TAMs释放的细胞因子TNF-α和IL-10的表达。以与肺癌细胞株95D上清液共培养后的巨噬细胞作为阳性对照;正常巨噬细胞作为阴性对照。结果:鼻咽癌组织中TAMs高密度表达者的3年无瘤生存率(85.7%)明显高于低密度表达者(56.3%)(P=0.017)。与阳性对照组比较,接受鼻咽癌细胞株CNE-1和CNE-2上清液刺激后的TAMs分泌TNF-α较少(73pg/ml,64pg/mlvs.7794pg/ml,P=0.001),经LPS活化后明显增多(6905pg/ml,6788pg/mlvs.137pg/ml,P=0.001);分泌IL-10很少(1pg/ml,1pg/mlvs.94pg/ml,P=0.002),经LPS活化后升高不明显(87pg/ml,99pg/mlvs.416pg/ml,P=0.015),与阴性对照组比较差异无显著性。结论:鼻咽癌组织中TAMs的密度与患者的预后呈正相关;与鼻咽癌细胞上清液共培养后TAMs分泌的细胞因子倾向于杀伤肿瘤细胞,促进机体的抗瘤免疫作用。     

肿瘤相关巨噬细胞的极化与肿瘤的发展

肿瘤相关巨噬细胞（TAM）在肿瘤微环境中扮演重要角色,它包含了两种可以相互极化的亚型:M1型(经典活化巨噬细胞)和M2型（替代活化巨噬细胞）。M1型TAM发挥着抑制肿瘤生长的作用,而M2型TAM对肿瘤的发生发展起促进支持作用。在特定的肿瘤微环境中,M2型TAM占据主导地位,促进肿瘤的发展。基于肿瘤相关巨噬细胞两种亚型的功能特点,如何诱导M2型向M1型极化是目前的研究热点,也将是肿瘤治疗的一个重要靶点。     

Plasminogen receptor S100A10 is essential for the migration of tumor-promoting macrophages into tumor sites

Macrophages are critical drivers of tumor growth, invasion, and metastasis. Movement of macrophages into tumors requires the activity of cell surface proteases such as plasmin. In this study, we offer genetic evidence that plasminogen receptor S100A10 is essential for recruitment of macrophages to the tumor site. Growth of murine Lewis lung carcinomas or T241 fibrosarcomas was dramatically reduced in S100A10-deficient mice compared with wild-type mice. The tumor growth deficit corresponded with a decrease in macrophage density that could be rescued by intraperitoneal injection of wild-type but not S100A10-deficient macrophages. Notably, macrophages of either genotype could rescue tumor growth if they were injected into the tumor itself, establishing that S100A10 was required specifically for the migratory capability needed for tumor homing. Conversely, selective depletion of macrophages from wild-type mice phenocopied the tumor growth deficit seen in S100A10-deficient mice. Together, our findings show that S100A10 is essential and sufficient for macrophage migration to tumor sites, and they define a novel rate-limiting step in tumor progression.     

肿瘤相关巨噬细胞的极化方式及其对乳腺癌进展的影响

乳腺癌是严重威胁女性健康的恶性肿瘤之一,在全球范围内,其发病率呈逐年升高以及年轻化的趋势。肿瘤相关巨噬细胞（tumor-associated macrophages,TAMs）是乳腺癌肿瘤微环境中重要的免疫细胞,功能多样,具有高度的可塑性。当前的研究认为,TAMs在乳腺癌形成早期常表现为M1样表型,而在乳腺癌进展的过程中则极化为M2样表型,M2型TAMs能够促进乳腺癌的细胞增殖、血管生成、免疫抑制以及耐药性,与乳腺癌的预后呈负相关。因此,对TAMs极化方向的干预可作为乳腺癌抗癌治疗的一个新的研究方向。本文主要对乳腺癌中TAMs极化的分子机制以及对乳腺癌进展的影响进行综述。     

肿瘤相关巨噬细胞与肿瘤关系的研究进展

肿瘤相关巨噬细胞（ Tumor associate macrophages ,TAMs）是肿瘤的炎症微环境与肿瘤细胞间的重要信使。它是从血液中的单核细胞演变而来,主要通过集落刺激因子（ Colony -stimulating factor , CSF）趋化至肿瘤组织中。本文简述了TAMs通过影响血管生成和淋巴管生成,抑制免疫,调节基质,与干细胞相互作用等方面促进肿瘤的进展。分析表明靶向于TAMs的治疗策略是未来治疗肿瘤的一个新方向。     

Interaction of coagulation factors and tumor-associated macrophages mediates migration and invasion of gastric cancer

Abundant macrophage infiltration and increased expression of coagulation factors have been observed in cancer patients. The aim of the present study was to determine how the interaction between activated coagulation factors and monocytes/macrophages contributes to gastric cancer (GC) cell migration and invasion. We assessed cytokine/chemokine production of coagulation-factor-treated macrophages by ELISA. The effects of the interaction between coagulation factors and tumor-associated macrophages (TAM) on GC cell migration and invasion were determined by in vitro migration and invasion assay. In addition, we used an in vitro co-culture system of GC cells/TAM treated by coagulation factors to evaluate the effect of coagulation factor/TAM interaction on the human umbilical vein endothelial cell line (HUVEC). We found that the M2-like phenotype of interleukin (IL)-4(high), IL-10(high), transforming growth factor (TGF)-β(high), tumor necrosis factor (TNF)-α(high) was exhibited when the human monocytic cell line THP-1 was stimulated by coagulation factors III (TF), VIIa (FVIIa) and XIIa (FXIIa). For the migration assay, the GC cells (BGC-823 or SGC-7901) that were co-cultured with activated coagulation factor/TAM both showed increased migration. For the invasion assay, both BGC-823 and SGC-7901 cells co-cultured with TF/TAM showed increased invasion. We also found that TAM activated by coagulation factors could induce vascular endothelial growth factor/MMP-9 expression, which could promote invasion of GC cells. The HUVEC co-cultured with TAM (PMA-treated THP-1 macrophages co-cultured with GC cells) expressed high levels of FXIIa. In conclusion, coagulation factors might facilitate GC cell migration and invasion by transforming macrophages toward TAM-like cells. Interaction of coagulation factors and TAM mediates migration and invasion of GC.     

Correlation between glioblastoma stem-like cells and tumor vascularization

Glioblastoma multiforme (GBM) is the most lethal type of brain tumor. The formation of abnormal, dysfunctional tumor vasculature and glioblastoma stem-like cells (GSCs) are believed to be the major components of the inability to treat these tumors effectively. We analyzed 70 glioblastoma samples by immunohistochemistry and double immunofluorescence staining. The immunohistochemical expression of the putative brain tumor stem cell markers CD133 and Nestin in paraffin sections was analyzed using morphometry. In all GBM samples, CD133 or Nestin was expressed in tumor and endothelial cells. Double immunofluorescence stainings showed that the two different marked GSCs were found accumulated around the CD31+ blood vessels and CD133/CD31 or Nestin/CD31 co-expression was found in the endothelial cells and GSCs. Furthermore, the vascular endothelial growth factor (VEGF) and the endothelial marker CD31 were co-expressed in GSCs. Therefore, GSCs not only showed distinct perivascular distribution but were capable of differentiating into endothelial cells. We demonstrate that GSCs contribute directly to the tumor vasculature by endothelial cell differentiation. GSCs and tumor vascularization are closely related to each other, not only in the regional distribution but also in biological function. These findings describe a new mechanism for tumor vasculo-genesis and may provide new insights for targeted therapy against brain tumors.     

肿瘤相关巨噬细胞与长链非编码RNA在肿瘤发展中的研究进展

肿瘤相关巨噬细胞是肿瘤微环境重要组成部分,极化亚型影响肿瘤进展过程。长链非编码RNA(long non-coding RNA,lncRNA)不编码蛋白质,但是同样参与生物学过程,异常表达的lncRNA影响生理和病理进程,尤其对肿瘤发展有重要调控作用。癌症中一些异常表达的lncRNA直接或者间接影响巨噬细胞极化亚型调控肿瘤发展进程,lncRNA和巨噬细胞之间调节机制尚未清楚。lncRNA同肿瘤相关巨噬细胞可作为肿瘤潜在靶点和治疗中间物。本文将对在肿瘤中相互作用的肿瘤相关巨噬细胞与长链非编码RNA调控肿瘤进展过程进行综述。     

肿瘤相关成纤维细胞与肿瘤发生及演进关系的研究进展

作为肿瘤间质的主要细胞成分,肿瘤相关成纤维细胞(tumor-associated fibroblasts,TAFs)与正常组织间质成纤维细胞(fibroblasts)的生物学特性差异明显。TAFs在肿瘤的发生及演进过程中起着重要的作用,关于这方面的研究日益成为热点。本文就TAFs与肿瘤发生及演进关系的研究进展做一综述。     

肿瘤相关成纤维细胞与肿瘤发生及演进关系的研究进展

作为肿瘤间质的主要细胞成分,肿瘤相关成纤维细胞（tumor-associated fibroblasts,TAFs）与正常组织间质成纤维细胞（fibroblasts）的生物学特性差异明显。TAFs在肿瘤的发生及演进过程中起着重要的作用,关于这方面的研究日益成为热点。本文就TAFs与肿瘤发生及演进关系的研究进展做一综述。     

Role of tumor-associated macrophages at the invasive front in human colorectal cancer progression

Macrophages are an essential component of antitumor activity; however, the role of tumor-associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM-CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM-CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM-CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan-, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.