CCL19/21-CCR7生物学轴与肿瘤转移

肿瘤转移有其选择性和特异性,不同组织来源的肿瘤易向某些特定的组织和器官如淋巴结、肺、肝、骨等转移,但人们对其机制知之甚少。近年来,发现不少趋化因子及其受体在肿瘤的转移中扮演重要角色。现就CCL19/21-CCR7生物学轴在肿瘤转移中的作用作一综述。     

CCL19/21-CCR7生物学轴与肿瘤转移

肿瘤转移有其选择性和特异性,不同组织来源的肿瘤易向某些特定的组织和器官如淋巴结、肺、肝、骨等转移,但人们对其机制知之甚少。近年来,发现不少趋化因子及其受体在肿瘤的转移中扮演重要角色。现就CCL19/21-CCR7生物学轴在肿瘤转移中的作用作一综述。     

CXCL12-CXCR4轴、CCL21-CCR7轴在非霍奇金淋巴瘤中的研究进展

非霍奇金淋巴瘤(non-Hodgkin's lymphoma,NHL)是由免疫系统中成熟和未成熟细胞的恶性转化所致,涉及B淋巴细胞(B细胞,约占所有NHL的86％)、较小比例的T细胞和自然杀伤(NK)细胞(在发展中地区约占14％).近年来相关研究表明,趋化因子受体4(CXCR4)、趋化因子受体7(CCR7)在淋巴细胞归...     

CCL20-CCR6-Th17轴与肝细胞癌血管浸润转移的关系

目的 探讨CCL20-CCR6-Th17轴在肝细胞癌血管浸润转移中的作用.方法 采用SYBR Green实时定量PCR测定人肝细胞系L-02、肝细胞癌细胞系Hep3B、Huh7和HepG2中CCL20mRNA的表达,采用酶联免疫吸附试验(ELISA)检测上清中CCL20蛋白的分泌,Transwell迁移实验检测肝细胞癌细胞系对人外周血单个核细胞的趋化作用.采用ELISA定量检测93例肝细胞癌患者(转移组51例,无转移组42例)术前外周血中白细胞介素1α(IL-1α)、IL-1β 、IL-6 、IL-8 、IL-10、IL-17、IL-23、γ-干扰素、肿瘤坏死因子α和CCL20的水平,采用SYBR Green RT-PCR检测41例肝细胞癌癌组织及其相应的癌旁组织中CCL20和CCR6的表达水平,免疫组织化学染色检测肝细胞癌及其对应的癌旁组织和正常人供肝组织中CCL20的表达水平.结果 人肝细胞癌细胞系中CCL20的表达水平高于正常肝细胞,对外周血表达CCR6的T细胞具有趋化作用.93例肝细胞癌患者血清中CCL20蛋白的表达水平为(38.2±28.4) pg/ml,高于肝血管瘤患者[(7.8±17.8) pg/ml,P＜0.01].肝细胞癌患者血清中CCL20蛋白的表达水平与肿瘤直径呈正相关(r=0.32,P=0.0018).41例肝细胞癌组织CCL20 mRNA的表达水平高于癌旁组织(P＜0.05),CCL20蛋白主要在肝细胞癌细胞质中表达,某些浸润的免疫细胞也有一定程度表达.多因素分析结果显示,血清中IL-17和CCL20水平是影响肝细胞癌患者发生血管浸润转移的独立影响因素(均P ＜0.05).41例肝细胞癌患者癌组织及对应的癌旁组织中CCL20 mRNA的表达水平与肝细胞癌发生血管浸润转移均无关(均P＞0.05).在发生血管浸润转移患者的癌组织及其对应的癌旁组织中CCR6 mRNA的表达水平分别为5.75 (1.79,19.13)和7.99(4.49,19.54),均高于未发生血管浸润转移的患者[分别为1.69 (0.76,2.87)和3.58(1.84,4.32)],差异均有统计学意义(均P＜0.05).结论 CCL20/CCR6/Th 17轴可能促进肝细胞癌的血管浸润转移.     

肿瘤靶向治疗的心血管毒性研究进展肿瘤靶向治疗的心血管毒性研究进展

靶向治疗是选择性作用于肿瘤发生中关键分子的新型抗肿瘤治疗策略。由于最大限度减少了正常细胞的损伤,其与化疗相比具有高效低毒的优势。然而,近年来靶向治疗导致的心血管毒性严重影响患者的预后,因而得到越来越多的重视与关注。临床常见靶向药物的心血管毒性包括心力衰竭、高血压、心律失常、血栓形成等。绝大部分心血管毒性的发生机制仍不是很清楚。在治疗基线完善心血管检查并后续进行密切随访和管理,对常见心血管毒性进行早期预防监测并及早干预对于心脏毒性的防治具有重要意义。     

肿瘤血管靶向治疗研究进展

肿瘤血管是实体瘤发生、发展的基础条件，故破坏肿瘤血管，能够高度选择性地杀灭恶性肿瘤细胞。使用诸如DMXAA、CA4DP、ZD6126低分子制剂能使血管破坏，血流减少，大范围缺氧，诱导肿瘤细胞坏死。低分子药物辅助以传统放疗和化疗，能显著提高治疗效果。现就选择性诱导肿瘤血管网快速破裂的血管靶向制剂（VTA），以及应用VTA的临床试验进行综述。     

肿瘤坏死靶向治疗研究进展

肿瘤坏死靶向治疗（Tumor necrosis targeted therapy,TNT）是分子靶向治疗方法之一,但与其它分子靶向治疗有根本的不同,其针对的靶点是细胞核成分,这些分子本身是非特异组份,因此从理论上讲,TNT靶向分子可适用于包括实体瘤在内的各种肿瘤。靶向分子是TNT技术的关键所在,在此基础上,人们可以选择任一种杀瘤物质与靶向分子结合。在TNT的几种抗体中,以嵌合性肿瘤细胞核单克隆抗体-3（chTNT-3）的临床实验效果最佳,本文将介绍chTNT-3及衍生物与各种杀瘤物质复合后的TNT制剂研究在肿瘤中的研究及应用进展。     

靶向端粒酶治疗肿瘤研究进展

近年来，随着对端粒酶的研究深入，应用靶向端粒酶的方法治疗肿瘤成为热点，并有较多的新进展，如：应用端粒酶hTERT的免疫抗原性进行肿瘤的免疫治疗；端粒酶启动子驱动的肿瘤基因治疗等。本文简要介绍端粒酶与肿瘤的密切关系，并就针对端粒酶靶向治疗肿瘤的研究进展进行综述。     

肿瘤血管靶向治疗研究进展

肿瘤血管是实体瘤发生、发展的基础条件,故破坏肿瘤血管,能够高度选择性地杀灭恶性肿瘤细胞。使用诸如DMXAA、CA4DP、ZD6126低分子制剂能使血管破坏,血流减少,大范围缺氧,诱导肿瘤细胞坏死。低分子药物辅助以传统放疗和化疗,能显著提高治疗效果。现就选择性诱导肿瘤血管网快速破裂的血管靶向制剂(VTA),以及应用VTA的临床试验进行综述。     

靶向血管治疗肿瘤的研究进展

靶向血管治疗肿瘤已有三十年的历史,近十年来有突飞猛进的发展,现就几方面的进展简要论述.1 肿瘤区血管的发生发展及特点1.1 肿瘤细胞由休眠转为生长:没有血管,肿瘤停止在1～2mm直径以下,肿瘤细胞处于休眠状态称为无血管期(in situ),即Ⅰ期.血管长入后,肿瘤细胞分裂生长,称为有血管期,Ⅱ期.促使肿瘤由Ⅰ期向Ⅱ期转变的因素,已知的有:①微环境的改变:缺氧,缺营养,PH变酸性,NO升高等;②基因的改变:癌变时,突变型P53上调VEGF,FGF-B;野生型p53减少,内源性抑血管生长因子,凝血栓蛋白(thrombospontin,TSP-1)则下调.突变Ras基因也可上调VEGF.     

Targeting of CCL2-CCR2-Glycosaminoglycan Axis Using a CCL2 Decoy Protein Attenuates Metastasis through Inhibition of Tumor Cell Seeding

The CCL2-CCR2 chemokine axis has an important role in cancer progression where it contributes to metastatic dissemination of several cancer types (e.g., colon, breast, prostate). Tumor cell–derived CCL2 was shown to promote the recruitment of CCR2⁺/Ly6C^hi monocytes and to induce vascular permeability of CCR2⁺ endothelial cells in the lungs. Here we describe a novel decoy protein consisting of a CCL2 mutant protein fused to human serum albumin (dnCCL2-HSA chimera) with enhanced binding affinity to glycosaminoglycans that was tested in vivo. The monocyte-mediated tumor cell transendothelial migration was strongly reduced upon unfused dnCCL2 mutant treatment in vitro. dnCCL2-HSA chimera had an extended serum half-life and thus a prolonged exposure in vivo compared with the dnCCL2 mutant. dnCCL2-HSA chimera bound to the lung vasculature but caused minimal alterations in the leukocyte recruitment to the lungs. However, dnCCL2-HSA chimera treatment strongly reduced both lung vascular permeability and tumor cell seeding. Metastasis of MC-38GFP, 3LL, and LLC1 cells was significantly attenuated upon dnCCL2-HSA chimera treatment. Tumor cell seeding to the lungs resulted in enhanced expression of a proteoglycan syndecan-4 by endothelial cells that correlated with accumulation of the dnCCL2-HSA chimera in the vicinity of tumor cells. These findings demonstrate that the CCL2-based decoy protein effectively binds to the activated endothelium in lungs and blocks tumor cell extravasation through inhibition of vascular permeability.     

The inflammatory chemokines CCL2 and CCL5 in breast cancer

A causal role was recently attributed to inflammation in many malignant diseases, including breast cancer. The different inflammatory mediators that are involved in this disease include cells, cytokines and chemokines. Of these, many studies have addressed the involvement and roles of the inflammatory chemokines CCL2 (MCP-1) and CCL5 (RANTES) in breast malignancy. While minimally expressed by normal breast epithelial duct cells, both chemokines are highly expressed by breast tumor cells at primary tumor sites, indicating that CCL2 and CCL5 expression is acquired in the course of malignant transformation, and suggesting that the two chemokines play a role in breast cancer development and/or progression. Supporting this possibility are findings showing significant associations between CCL2 and CCL5 and more advanced disease course and progression. Furthermore, studies in animal model systems have shown active and causative roles for the two chemokines in this disease. In line with the tumor-promoting roles of CCL2 and CCL5 in breast cancer, the two chemokines were shown to mediate many types of tumor-promoting cross-talks between the tumor cells and cells of the tumor microenvironment: (1) they shift the balance at the tumor site between different leukocyte cell types by increasing the presence of deleterious tumor-associated macrophages (TAM) and inhibiting potential anti-tumor T cell activities; (2) of the two chemokines, mainly CCL2 promotes angiogenesis; (3) CCL2 and CCL5 which are expressed by cells of the tumor microenvironment osteoblasts and mesenchymal stem cells play a role in breast metastatic processes. In addition, both chemokines act directly on the tumor cells to promote their pro-malignancy phenotype, by increasing their migratory and invasion-related properties. Together, the overall current information suggests that CCL2 and CCL5 are inflammatory mediators with pro-malignancy activities in breast cancer, and that they should be considered as potential therapeutic targets for the limitation of this disease.     

Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers

Ovarian cancer is associated with a leukocyte infiltrate and high levels of chemokines such as CCL2. We tested the hypothesis that CCL2 inhibition can enhance chemotherapy with carboplatin and paclitaxel. Elevated CCL2 expression was found in three non‐MDR paclitaxel resistant ovarian cancer lines ES‐2/TP, MES‐OV/TP and OVCAR‐3/TP, compared to parental cells. Mice xenografted with these cells were treated with the anti‐human CCL2 antibody CNTO 888 and the anti‐mouse MCP‐1 antibody C1142, with and without paclitaxel or carboplatin. Our results show an additive effect of CCL2 blockade on the efficacy of paclitaxel and carboplatin. This therapeutic effect was largely due to inhibition of mouse stromal CCL2. We show that inhibition of CCL2 can enhance paclitaxel and carboplatin therapy of ovarian cancer.     

Role of Rho-ROCK signaling in MOLT4 cells metastasis induced by CCL25

Our previous research has revealed that binding of the chemokine CCL25 to the CCR9 provides chemotactic cues guiding leukemic cells to specific tissues and organs. The RhoA-ROCK pathway might be involved in cancer migration. The purpose of this study was to explore the role of the RhoA-ROCK-MLC axis in leukemic cell migration following exposure to CCL25. The results showed that CCL25 could increase the amount of the GTPase RhoA and activate MLC in MOLT4 cells in a time-dependent manner. C3 exoenzyme and Y-27632 could block MOLT4 cell migration and chemotaxis. Thus, the RhoA-ROCK-MLC axis might play an important role in MOLT4 cell metastasis induced by CCL25.     

重视肿瘤生酮治疗的研究

肿瘤细胞Warburg效应为肿瘤生酮治疗奠定了坚实的理论基础,大量研究发现生酮疗法是肿瘤治疗的一个有效手段,生酮治疗可以直接抑制肿瘤生长、增强放化疗效果、提高生活质量、延长生存时间;既可以独立使用,也可以与肿瘤治疗其他方法联合。但是不同肿瘤对生酮治疗反应差异显著,机制不明。肿瘤生酮治疗目前以细胞株及其荷瘤动物研究较多,临床上以病例报告为主,缺乏设计严谨的对照研究。为了更好地推动肿瘤治疗的进步与发展,改善我国肿瘤治疗现状,笔者呼吁高度重视生酮疗法等代谢调节治疗,加快转化医学研究,加强临床随机对照研究,探讨生酮治疗疗效差异的原因及其机制,寻找新的、能够指导生酮饮食（ketogenic diet, KD）治疗的分子标志物,为精准筛选生酮治疗对象提供分子标志、建立预测肿瘤生酮治疗敏感度的分子诊断方法,发掘提高肿瘤生酮治疗疗效的干预靶点,从而进一步提高肿瘤治疗效果。     

CCL21在人结肠癌SW480细胞侵袭过程中的作用

背景与目的：既往研究显示趋化冈子受体CCR7在胃肠道肿瘤中表达上调,并与淋巴管浸润和淋巴结转移相关。本研究旨在探讨趋化因子CCL21及其受体CCR7在人结肠癌SW480细胞体外侵袭中的作用。方法：在趋化因子CCL21作用的条件下,用划痕实验和Transwel!小室检测SW480细胞侵袭能力．免疫印迹检测SW480细胞中金属基质蛋白酶-9（matrix metalloproteinase-9．MMP-9）表达;CCL21预处理的SW480细胞在含足叶乙甙（VP—16）的体系中培养,MTr法检测细胞增殖活力,流式细胞术和Hoechst33258染色检测细胞凋亡。结果：CCL21（100ng／mL）组中SW480细胞向划痕处爬行的速度明显快于阴性对照组：阴性对照组与CCL21（100ng／mL）组中穿膜细胞数分别为（48±4）个和（113±7）个,差异有统计学意义（P〈0．05）;CCL21（100ng／mL）组中MMP-9的相对表达水平为0．83±0．02,高于阴性对照组的0．38±0．0l（P〈0．05）。CCL21单独作用不能促进SW480细胞增殖;VP-16组中SW480细胞的增殖抑制率为68．3％,CCL21预处理增强SW480细胞活力,CCL21（100ng／mL）中抑制率降至47．4％：VP-16组与CCL21（100ng／mL）组中凋亡率分别为（65．2±5．2）％和（48．7±3．1）％,差异有统计学意义（P〈0．05）。结论：CCL21／CCR7可以促进结肠癌SW480细胞的体外侵袭力,并增强其在微环境中的生存能力。     

靶向uPA-uPAR系统在肿瘤治疗中的研究进展

uPA-uPAR系统在多种肿瘤组织中表达增高,该系统不但可促进细胞外基质蛋白降解,而且可以与玻连蛋白、整合素等结合参与细胞内信号转导,从而介导肿瘤的发生与发展。近年来,一系列靶向uPA-uPAR系统的方案在肿瘤治疗中取得了显著效果,并且其中部分药物已经进入临床试验阶段,为肿瘤的靶向治疗提供了新思路。本文拟从靶向uPA-uPAR系统的基因治疗、药物治疗和免疫治疗等方面的研究进展进行综述。     

恶性肿瘤患者血清sIL－2R临床意义的评估

用ＥＬＩＳＡ法测定３６５例肿瘤患者（包括胃癌、肝癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、肺癌、恶性淋巴瘤、白血病）和２３０例相关脏器的良性疾病患者以及５１名健康人的血清ｓＩＬ－２Ｒ浓度，发现恶性肿瘤患者血清ｓＩＬ－２Ｒ水平明显高于良性疾病患者和健康人对照组（Ｐ＜０．００１），伴转移患者的ｓＩＬ－２Ｒ升高更明显，与不伴转移者相比，差异显著（Ｐ＜０．００１）。作为免疫活性标志，血清ｓＩＬ－２Ｒ可以作为评估肿瘤发生和检测复发的辅助手段。     

乌司他丁抑制CCL17/CCL22-CCR4介导的小鼠乳腺癌肝转移

背景与目的：越来越多的研究表明趋化因子及其受体在癌症的发生、发展和转移中起关键作用。本文研究了乌司他丁（ulinastatin）对胸腺和活化调节趋化因子（thymus and activation-regulated chemokine,TARC）即CCL17/巨噬细胞来源的趋化因子（macrophage-derived chemokine,MDC）即CCL22-CC族趋化因子受体4（CC chemokine receptor 4,CCR4）信号通路介导的乳腺癌肝转移的影响及其作用机制。方法：通过小鼠乳腺脂肪垫（mfp）接种4T1乳腺癌细胞的方式构建小鼠乳腺癌模型,15 d后取小鼠乳腺肿瘤,并记录乳腺肿瘤的质量;采用免疫组织化学法检测乳腺肿瘤组织中CCR4及肝脏转移瘤中CCL22、CCL17蛋白的表达;采用慢病毒转染的方式抑制4T1乳腺癌细胞CCR4基因,采用蛋白质印迹法（Western blot）检测抑制效果,并以同样方式进行小鼠乳腺成瘤并观察肿瘤生长情况;用三种不同浓度乌司他丁处理4T1细胞荷瘤小鼠,15 d后采用免疫组织化学法检测乳腺癌组织中CCR4及肝脏组织中CCL22及CCL17的表达,采用Westernblot和实时荧光定量聚合酶链反应（real-time fluorescent quantitative polymerase chain reaction,RTFQ-PCR）分别检测肝脏组织中TGF-β的表达以及microRNA-34a和microRNA-31的含量,并进行TGF-β和microRNA-34a、microRNA-31、CCL22以及CCL17的相关性分析。结果：小鼠乳腺癌组织高表达CCR4,肝脏转移瘤高表达CCL22和CCL17;沉默4T1乳腺癌细胞CCR4的表达,可抑制乳腺癌成瘤性;乌司他丁抑制CCR4、TGF-β、CCL22、microRNA-31和CCL17的表达,促进microRNA-34a的表达。结论：乌司他丁具有抑制乳腺癌肝转移的作用,其具体机制可能与乌司他丁通过TGF-β-microRNA-34a-CCL22轴及microRNA-31-TGF-β-CCL17轴抑制肝乳腺癌;肝转移;乌司他丁;CCR4;CCL22;CCL17脏组织中与乳腺癌肝转移密切相关的CCL17/CCL22-CCR4信号通路有关。