早期胃癌SDF-1α表达与淋巴结转移的关系

目的:探讨早期胃癌(early gastric cancer,EGC)组织中基质细胞衍生因子-1α(stromal cellderived factor-1α,SDF-1α)的表达情况与EGC淋巴结转移危险性关系.方法:采用免疫组织化学方法检测168例EGC组织石蜡标本的SDF-1α的表达情况.结果:EGC组织中SDF-1α阳性组和SDF-1α阴性组分别为72例(42.9%)和96例(57.1%).SDF-1α阳性组和阴性组在年龄、性别、肿瘤大小(20 mm)、大体类型、浸润深度和组织分化程度之间差异无统计学意义.然而,SDF-1α阳性组与淋巴血管浸润和淋巴结转移之间存在显著相关性.单因素分析结果表明,淋巴血管侵袭、未分化组织和SDF-1α阳性表达是影响EGC患者淋巴结转移的危险因素.多变量分析显示,淋巴血管侵袭(HR=3.753,95%CI:1.674-8.415,P=0.001)、未分化组织(HR=2.038,95%CI:1.100-3.775,P=0.024)和SDF-1α阳性表达(HR=3.631,95%CI:1.101-11.977,P=0.034)是预测EGC淋巴结转移的独立危险因素.结论:SDF-1α高表达与EGC淋巴结转移危险性密切相关,肿瘤细胞表达SDF-1α是EGC淋巴结转移的一个预测指标.     

趋化因子CXCL12/CXCR4轴与lgr5基因在结直肠癌组织中的表达

目的 探讨人结直肠癌组织中趋化因子CXCL12/CXCR4轴、干细胞标志物lgr5基因的表达变化及与临床病理特征间的关系.方法 采用SYBR Green实时定量PCR检测27例结直肠癌组织、27例匹配的远端切缘正常组织中CXCL12、CXCR4及lgr5 mRNA表达.结果 结直肠癌组织中CXCR4、lgr5 mRNA表达明显高于匹配正常组织(P＜0.01),CXCL12 mRNA表达水平低于正常组织(P＜0.01).结直肠癌组织CXCL12、CX-CR4及lgr5mRNA在不同性别、年龄、肿瘤原发部位、大小、组织学类型组间表达差异均无统计学意义(均P＞0.05).但有淋巴结转移组CXCR4及lgr5 mRNA表达高于无淋巴结转移组,且有淋巴结转移组CXCL12 mRNA表达下降更显著(P＜0.05).结论 CXCL12基因表达下调、CXCR4、lgr5基因表达上调参与了结直肠癌组织生长及转移,CXCL12/CXCR4生物轴、lgr5有望成为抗肿瘤治疗的新靶点.     

非小细胞肺癌组织EGFR、CXCR4的表达及其与MVD的相关性

目的 探讨非小细胞肺癌(NSCLC)组织中表皮生长因子受体(EGFR)、趋化因子受体4(CXCR4)的表达与肺癌生物学行为以及血管形成之间的关系.方法 应用免疫组织化学方法(SP法)检测62例NSCLC癌组织、12例癌旁正常组织中EGFR、CXCR4的表达及微血管密度(MVD),并分析EGFR、CXCR4的表达及MVD与组织类型、肿瘤大小、TNM分期、分化程度、淋巴结转移的相关性.结果 CXCR4在肺癌组织中的阳性表达率为58.1%,在正常组织中的阳性表达率为16.7%,两者比较有显著性差异(P<0.05).NSCLC癌组织中,EGFR、CXCR4表达明显升高,MVD也明显高于正常组织,与肿瘤的分化程度、临床分期、淋巴结转移均有相关性(均P<0.05),与肿瘤的大小、病理分型无关(均P>0.05).EGFR、CXCR4在NSCLC中的表达与肿瘤MVD呈显著正相关.结论 同时检测NSCLC癌组织的EGFR、CXCR4的表达及MVD对判断肿瘤的恶性程度和估计预后有一定的意义.     

CXCR4及其配体SDF-1在甲状腺乳头状癌颈淋巴结转移中的作用

目的探讨趋化因子受体4（CXCR4）及其配体基质细胞衍生因子-1（SDF-1）在甲状腺乳头状癌颈部淋巴结转移中的作用。方法采用免疫组化SP法检测53例甲状腺乳头状癌患者癌组织中CXCR4蛋白和颈部转移淋巴结组织中SDF-1蛋白表达情况。结果癌组织中CXCR4蛋白呈高表达水平,与癌旁正常组织比较,P〈0．05;CXCR4蛋白表达与甲状腺乳头状癌临床分期及淋巴结转移有关;癌细胞转移者颈部淋巴结组织中SDF-1蛋白呈高表达,显著高于无转移者,SDF-1蛋白表达仅与淋巴结转移有关（P〈0．05）;癌组织中CXCR4蛋白表达与淋巴结组织中SDF-1蛋白表达水平呈负相关（r=-0．3207,P=-0．0171）。结论CXCRd及其配体SDF-1在甲状腺乳头状癌中相互协调,共同促进甲状腺乳头状癌细胞向颈部淋巴转移。     

miR-126表达水平与CXCR4及直肠癌患者临床病理特征之间的相关性

目的探究微小RNA(miR)-126的表达水平与CXCR4及直肠癌患者临床病理特征之间的相关性。方法 92例直肠癌手术病人切除标本及距切缘远端5 cm以外正常组织标本,所有组织采用手术分离并在术后立即置于液氮中保存。qRT-PCR法检测CXCR4 mRNA表达,Western印迹法检测miR-126、CXCR4蛋白表达,对待测标本进行免疫组化染色,使用多因素回归分析直肠癌患者预后的影响因素。结果直肠癌组织中miR-126蛋白表达明显低于癌旁组织(P0.05),CXCR4 mRNA表达明显高于癌旁组织(P0.05)。直肠癌组织中CXCR4蛋白表达明显高于癌旁组织,CXCR4在直肠癌组织细胞质中大量表达,而在正常的直肠组织中呈不表达或弱阳性表达状态。miR-126、CXCR4表达与直肠癌患者性别、年龄无关,与直肠癌患者肿瘤体积、病理分期、分化程度、淋巴结转移、远处转移情况有关,肿瘤体积较大、Ⅲ+Ⅳ期、分化程度较低、淋巴结转移、远处转移阳性的患者miR-126表达明显降低,CXCR4表达明显升高(P0.05)。肿瘤体积、miR-126、CXCR4表达、病理分期、分化程度、淋巴结转移及远处转移等为直肠癌患者预后的影响因素,其中miR-126、CXCR4表达为直肠癌患者预后的独立预测因素。结论 miR-126在直肠癌中呈异常低表达、CXCR4蛋白在直肠癌中呈异常高表达,且与直肠癌病理特征具有一定相关性,是直肠癌患者预后的独立预测因素。     

CD_(44)V_6在结直肠癌中的表连及其临床意义

目的:探讨CD_(44)V_6在结直肠癌中的表达及其临床意义。 方法:采用免疫组织化学方法SP法检测87例结直肠癌中的CD_(44)V_6表达。 结果:结直肠癌组织中CD_(44)V_6的阳性表达率为58.6％,结直肠癌中CD_(44)V_6的表达与肿瘤的分化程度、浸润深度、淋巴结转移和Dukes分期密切相关(P<0.05)。 结论:检测结直肠癌组织中CD_(44)V_6的表达可反映肿瘤的生物学行为。     

SDF-1、CXCR4在三阴性乳腺癌组织中的表达及其与患者预后的相关性

目的探讨基质细胞衍生因子-1（SDF-1）及基质细胞衍生因子受体-4（CXCR4）在三阴性乳腺癌（TNBC）组织中的表达和临床意义。方法用免疫组化法检测77例TNBC组织中SDF-1和CXCR4的表达,分析SDF-1和CXCR4与TNBC临床病理特征及患者预后的关系。结果 SDF-1和CXCR4在TNBC中高表达率分别为41.6%、64.9%,且二者表达呈显著正相关（P=0.041）;SDF-1和CXCR4高表达与患者年龄、肿瘤大小、临床分期及组织学分级不相关（P〉0.05）,与淋巴结转移及无瘤生存呈显著正相关;多因素分析结果表明：SDF-1是TNBC患者无瘤生存的独立预后因素（OR=2.318,95%CI=1.028～5.230）。生存分析显示SDF-1和CXCR4高表达者无瘤生存时间短于低表达者（P均〈0.05）。结论 TNBC中SDF-1/CXCR4表达可作为判断TNBC预后的重要生物学指标。     

环氧化酶-2/前列腺素E_2在结直肠癌中的表达及临床意义

目的探讨环氧化酶-2(COX-2)、前列腺素E_2(PGE2)在结直肠癌中的表达及其与结直肠癌临床特征的关系。方法选取2009年8月1日-2012年8月1日于河北北方学院附属医院经病理检查确诊为结直肠癌78例患者的组织标本。免疫组化染色检测COX-2和PGE2的表达,并分析其与患者临床病理学特征的关系。结果结直肠癌组织中COX-2阳性表达率显著增加,与肿瘤大小、分化程度、浸润深度、淋巴结转移和Dukes分期相关;结直肠癌组织中PGE2阳性表达率显著增加,与肿瘤的分化程度、浸润深度、淋巴结转移和Dukes分期相关。Pearson相关分析表明,COX-2与PGE2在结直肠癌组织中的阳性表达显著正相关。结论COX-2、PGE2与结直肠癌的浸润、侵袭和转移密切相关。     

癌基因C-erbB-2在结直肠癌中的表达及其与浸润转移的相关性

目的:探讨癌基因C-erbB-2在结直肠癌中的表达及其与局部浸润和淋巴结转移的相关性.方法:采用免疫组化SP法检测69例原发性结直肠癌患者根治性手术切除的癌组织及周围组织中C-erbB-2的表达.结果:C-erbB-2基因主要为细胞膜及胞质内表达.结直肠癌组织中C-erbB-2阳性表达率为65.2%(45/69),而在结直肠良性肿瘤中仅有2例表达(2/20),两者存在显著差异(P<0.01);其阳性表达率在结直肠癌组织(65.2%)及周围组织(系膜组织47.8%、癌旁组织30.4%、远端切缘组织13.0%)中有显著差异(P<0.05);其表达与肿瘤大体类型、肿瘤细胞分化程度、临床分期(Dukes分期)及淋巴结转移关系密切(P<0.05),而与结直肠癌患者年龄、性别、肿瘤部位及大小和远处转移无明显关系(P>0.05);C-erbB-2在系膜组织及癌旁组织中的表达证实免疫组织化学方法同常规病理检测比较有显著差异(P<0.05).结论:C-erbB-2在结直肠癌中阳性表达与肿瘤浸润转移密切相关,可作为预测预后的指标.     

大肠腺瘤及癌组织HIF-1α的表达与凋亡增生的关系

目的:研究缺氧诱导因子1-α(HIF-1α)在大肠肿瘤中的表达及其与凋亡、增生的关系,探讨HIF-1α在大肠癌发生发展中的作用. 方法:运用免疫组化的方法检测HIF-1α,Bcl-2,Bax, PCNA在正常大肠组织13例,大肠腺瘤26例,大肠癌50例中的表达. 结果:正常大肠组织HIF-1α均为阴性表达,腺瘤及癌组织中HIF-1α阳性表达率为30.8%和64%,大肠癌HIF-1α表达率显著高于腺瘤(x2=8.546,P<0.01).大肠癌HIF-1α表达与浸润,淋巴结转移,Dukes分期相关(x2=6.339, P<0.05;x2=9.091,P<0.01;x2=10.72,P<0.05).HIF- 1α表达与肿瘤大小、分化程度无关(P>0.05).Bcl-2在3 组中阳性表达率为15.4%,50.0%和76.0%,三者间表达率差别有显著意义(P<0.05).Bax在3组中阳性表达率为76.9%,65.4%和58.0%,三者间表达率无显著性差异(P>0.05).Bcl-2,Bax表达与肿瘤大小,分化,Dukes 分期无关(P>0.05).正常大肠组织PCNA表达均为低增生活性,腺瘤及癌中PCNA高增生活性者26.9%和56.0%, 癌组织PCNA高增生活性表达显著高于腺瘤(x2=5.073, P<0.05).大肠癌增生程度与浸润及Dukes分期相关(x2=6336, P<0.05;x2=11.219,P<0.01).腺瘤及大肠癌HIF-1α表达与Bcl-2,PCNA增生程度呈正相关(r=0.5,r=0.535, P<0.05;r=0.457,r=0.426,P<0.01),与Bax表达无关. 结论:HIF-1α抑制大肠肿瘤凋亡,促进增生,与肿瘤浸润转移密切相关,在大肠癌发生发展中发挥重要作用.     

胰腺癌及胰腺星状细胞中基质细胞衍生因子SDF-1及其受体CXCR4的表达

目的 检测基质细胞衍生因子(SDF-1)及其受体CXCR4在胰腺癌组织、细胞株及星状细胞(PSC)中的表达.方法 采用免疫组织化学方法 检测37例胰腺癌及10例癌旁正常胰腺组织SDF-1、CXCR4、α-SMA蛋白表达以及细胞株AsPC-1、PSC的SDF-1、CXCR4蛋白表达.RT-PCR检测AsPC-1、BxPC3、SW1990及PSC的SDF-1、CXCR4 mRNA表达.结果 37例胰腺癌CXCR4表达(+)8例、(++)20例、(+++)9例;10例癌旁正常胰腺组织CXCR4表达(-)2例、(+)7例、(++)1例,两者差异显著(P<0.01).胰腺癌的间质组织SDF-1的表达高于癌旁间质组织(P<0.01),并随α-SMA表达的增加而增加.胰腺癌细胞株AsPC-1有CXCR4蛋白表达,而PSC有SDF-1蛋白表达.AsPC-1、BxPC3、SW1990细胞株均有CXCR4 mRNA的表达,而无SDF-1 mRNA的表达;PSC有SDF-1 mRNA表达,CXCR4 mRNA微弱表达.结论 胰腺癌组织及细胞系表达CXCR4,PSC表达SDF-1,PSC有可能通过SDF-1/CXCR4轴促进胰腺癌的侵袭转移.     

Chemokine receptor CXCR4-prognostic factor for gastrointestinal tumors

To review the implication of CXCR4 for gastrointestinal cancer, a ＂Pubmed＂ analysis was performed in order to evaluate the relevance of CXCR4 and its ligands for gastrointestinal cancers. Search terms applied were ＂cancer, malignoma, esophageal, gastric, colon, colorectal, hepatic, pancreatic, CXCR4, SDF- 1α, and SDF-1β＂. CXCR4 expression correlated with dissemination of diverse gastrointestinal malignomas. The CXCR4 ligand SDF-1α might act as ＂chemorepellent＂ while SDF-1β might act as ＂chemorepellent＂ for CTLs, inducing tumor rejection. The paracrine expression of SDF-1α was furthermore closely associated with neoangiogenesis. CXCR4 and its ligands influence the dissemination, immune rejection, and neoangiogenesis of human gastrointestinal cancers. Inhibition of CXCR4 might be an interesting therapeutic option.     

Role of stromal-derived factor-1 in the hematopoietic-supporting activity of human mesenchymal stem cells

Mesenchymal stem cells (MSC) have the ability to support and maintain hematopoiesis in vitro. However, mechanisms implicated in this support are not fully characterized. In the present study, the role of stromal-derived factor-1 (SDF-1)/CXCR4 axis in the interactions between MSC and hematopoietic stem/progenitor cells (HSPC) was studied. Human bone marrow MSC were plated as feeder layers in Dexter-type long-term cultures (LTC) with human cord blood CD34(+) HSPC. Cultures were supplemented weekly with neutralizing antibodies against CXCR4 or SDF-1 for 5 wk. LTC-initiating cell (IC) activity was strongly dependent on the SDF-1/CXCR4 axis, as both antibodies significantly decreased secondary colony-forming cell production. To assess the effect of SDF-1/CXCR4 axis on progenitor cell proliferation, LTC-IC killing assays were carried out: in LTC of CD34(+) cells in contact with MSC, treatment with anti-CXCR4 antibody significantly reduced the number of cycling progenitors. These results indicate that the SDF-1/CXCR4 axis promotes HSPC proliferation in contact with MSC. Interestingly, when HSPC were separated from MSC by a semipermeable membrane, LTC-IC activity became CXCR4 independent. Multiplex analysis of MSC-conditioned medium revealed that in addition to SDF-1, MSC produced stimulatory and inhibitory factors, such as interleukin (IL)-6, IL-11, granulocyte macrophage-colony stimulating factor as well as monocyte-chemoattractant protein-1. Altogether, human MSC support hematopoiesis in Dexter-type cultures through the activation of the SDF-1/CXCR4 axis. Our data further suggest that SDF-1 stimulates retention of HSPC in MSC niches which expose them to stimulatory and inhibitory factors in a paracrine manner.     

基质细胞衍生因子-1和受体CXCR4在急性白血病和恶性淋巴瘤中的表达

目的分析急性白血病(AL)和恶性淋巴瘤(ML)患者外周血血清基质细胞衍生因子1(SDF1)及其骨髓单个核细胞(MNC)表面特异性受体CXCR4的表达,并进行对照研究。方法ELISA法检测血清中SDF1表达,流式细胞术检测骨髓MNC表面CXCR4的表达。结果26例AL患者包含9例急性淋巴细胞白血病和17例急性非淋巴细胞白血病,其SDF1、CXCR4表达分别为(7115.8±946.5)ng/L、(77.2±9.7)%和(4642.2±1146.8)ng/L、(38.9±11.0)%;18例ML患者包含5例霍奇金淋巴瘤和13例非霍奇金淋巴瘤,其SDF1、CXCR4表达分别为(3728.9±690.9)ng/L、(9.2±2.7)%和(4442.1±1073.0)ng/L、(8.5±2.4)%,上述各组SDF1/CXCR4表达均高于对照组水平(2369.3±966.5)ng/L、(2.7±1.5)%(P<0.01)。有髓外浸润的AL患者其SDF1/CXCR4的表达水平高于同组其他患者,有广泛浸润的ML患者其SDF1的表达水平高于同组其他患者。结论CXCR4/SDF1的高表达与AL和ML的发病及其浸润特性存在一定联系,为上述肿瘤的治疗提供了新思路。     

荷叶碱通过上调SDF-1/CXCR4信号通路促进人主动脉内皮细胞增殖

目的 探讨荷叶碱是否通过调控基质细胞衍生因子1(SDF-1)/趋化因子受体4(CXCR4)信号通路影响动脉内皮细胞增殖。方法 分别使用不同质量浓度(0 mg/L、10 mg/L、20 mg/L、50 mg/L、100 mg/L)的荷叶碱培养人主动脉内皮细胞(HAEC)24 h,通过RT-QPCR和Western blot技术分别检测各组细胞中SDF-1和CXCR4 mRNA及其蛋白的表达情况。采用体外内皮细胞小管形成实验观察不同质量浓度荷叶碱对HAEC增殖能力的影响。结果 SDF-1、CXCR4蛋白和mRNA在荷叶碱组HAEC中表达升高,在50 mg/L荷叶碱组中表达最显著。荷叶碱组HAEC体外小管形成能力与荷叶碱呈浓度依赖性增强,在50 mg/L荷叶碱组中最明显。结论 荷叶碱可能通过上调SDF-1/CXCR4信号通路的表达促进血管内皮细胞增殖。     

The chemokine receptor CXCR4 enhances integrin-mediated in vitro adhesion and facilitates engraftment of leukemic precursor-B cells in the bone marrow

OBJECTIVE: It has been demonstrated that acute lymphoblastic leukemia (ALL) blasts migrate into layers of bone marrow fibroblasts (BMF) in vitro using the beta1 integrins VLA-4 and VLA-5, and that the chemokine SDF-1 and its receptor CXCR4 influences ALL migration. We investigated whether this effect was due to SDF-1-mediated induction of adhesion through beta1 integrins. METHODS: Adhesion of pre-B ALL cells or the cell line NALM6 to extracellular matrix proteins was examined using short-term in vitro binding assays. The effects of exposure of cells to SDF-1, antibodies to CXCR4, and the G protein inhibitor pertussis toxin (PTX) were assessed. The consequences of down regulation of CXCR4 on the in vivo behavior of pre-B ALL cells after injection into sublethally irradiated NOD/SCID mice was studied. RESULTS: Treatment with SDF-1 of NALM6 cells or cells from cases of precursor-B ALL resulted in a doubling of adhesion to fibronectin, laminin, and VCAM-1, but had no effect on binding to collagens I or IV. Antibodies to CXCR4 and PTX inhibited SDF-1-induced adhesion on these substrates. NALM6 cells with CXCR4 expression downregulated by SDF-1 exposure demonstrated a reduced capacity to engraft into the bone marrow of NOD/SCID mice, with only 22 +/- 11% of marrow cells being of human origin in mice receiving SDF-1-treated cells compared to 48 +/- 5% in mice receiving untreated cells (p < 0.001). The homing of SDF-1-treated cells to the bone marrow after 24 hours was also reduced by 72 +/- 16% compared to control cells. CONCLUSIONS: These data show that SDF-1 and CXCR4 are involved in regulation of beta1 integrin function, and are important for the localization of pre-B cells to the bone marrow in vivo.     

CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma

AIM:To investigate the role of CXC chemokine receptor-4 (CXCR4) and stromal cell-derived factor-1 (SDF-1) in lymph node metastasis of gastric carcinoma.METHODS:In 40 cases of gastric cancer,expression of CXCR4 mRNA in cancer and normal mucous membrane and SDF-1 mRNA in lymph nodes around the stomach was detected using quantitative polymerase chain reaction (PCR) (TaqMan) and immunohistochemistric assay.SGC-7901 and MGC80-3 cancer cells were used to investigate the effect of SDF-1 on cell proliferation and m...     

基质细胞衍生因子-1及其受体对大鼠主动脉血管平滑肌细胞增殖与凋亡的影响

目的研究基质细胞衍生因子-1(SDF-1)对氧化低密度脂蛋白(ox-LDL)诱导的血管平滑肌细胞(VSMC)增殖与凋亡的影响。方法选用体外培养的大鼠主动脉VSMC,并分为正常对照组、ox-LDL组[动脉粥样硬化(AS)模型]、SDF-1组(AS模型+SDF-1)、SDF-1+12G5组(AS模型+SDF-1+CXCR4单克隆抗体)和12G5组(AS模型+CXCR4单克隆抗体),应用MTT法测VSMC细胞增殖,TUNEL法测细胞凋亡率,RT-PCR法测凋亡基因bax、bcl-2mRNA的表达。结果ox-LDL组的增殖率0.38±0.01,明显高于正常对照组0.28±0.02(P<0.01),明显低于SDF-1组0.44±0.02(P<0.01),与SDF-1+12G5组和12G5组比较差异无显著性(P>0.05);ox-LDL组的凋亡率24.2±2.4,高于正常对照组19.8±2.7和SDF-1组20.7±2.8(P<0.05),而与SDF-1+12G5组和12G5组比较差异无显著性(P>0.05);ox-LDL组bcl-2和bax的比值明显低于正常对照组和SDF-1组(P<0.01),而与SDF-1+12G5组和12G5组差异无显著性(P>0.05)。结论SDF-1可明显促进ox-LDL诱导的VSMC增殖,并抑制细胞凋亡;SDF-1及其受体CXCR4构成的生物学轴可能通过bcl-2/bax途径影响VSMC凋亡。