SDF-1/CXCR4及VEGF在结直肠腺癌中的表达及其意义

目的:研究VEGF、SDF-1及CXCR4在结直肠腺癌中的表达及其与临床病理学参数之间的相关性;探讨SDF-1/CXCR4轴与VEGF在结直肠腺癌发生发展浸润转移中的作用。方法:利用实时荧光定量PCR(RT-q PCR)法及免疫组织化学SP法检测80例结直肠腺癌及其对应癌旁组织中SDF-1、CXCR4和VEGF mRNA及蛋白的表达。结果:在mRNA水平上,结直肠癌组中SDF-1、CXCR4、VEGF的表达显著高于对应的癌旁组织。免疫组化结果显示,肿瘤中c蛋白表达阳性率分别为78.7%、60%和66.3%高于对应癌旁组织的37.5%、42.5%和28.8%,差异显著(P0.05);结直肠癌中SDF-1表达水平与肿瘤细胞淋巴结转移、远处转移及TNM分期密切相关(P0.05),与患者的年龄、性别、肿瘤的大小、浸润深度等无关;CXCR4的表达与患者的淋巴结转移及TNM分期密切相关;SDF-1的表达与CXCR4及VEGF的表达成显著正相关。结论:SDF-1/CXCR4及VEGF在结直肠癌组织中高表达,并且与肿瘤生物学行为密切相关,提示其在肿瘤的发生发展浸润转移过程中发挥重要作用。     

基质细胞衍生因子-1及其受体CXCR4在肿瘤转移中的作用

基质细胞衍生因子-1(Stromal cell-derived factor-1,SDF-1)及其受体CXCR4与人类多种肿瘤转移密切相关,CXCR4在一些肿瘤细胞系、原发肿瘤组织均呈高表达。SDF-1在肿瘤细胞潜在转移靶器官的表达量比非常规转移靶器官高,肿瘤细胞利用CXCR4与其天然配体间的趋化效应实现远距离转移。SDF-1/CXCR4驱动癌细胞转移模式的提出及其相互作用机制的深入研究对于肿瘤治疗具有重要的指导意义。     

sdf-1及其受体在成体干细胞迁移中的作用

基质细胞衍生因子是一种干细胞趋化因子,它可以通过与其受体CXCR4结合,调控干细胞定向迁移,发挥特定的生物学效应.SDF-1/CXCR4轴在调控骨髓造血干细胞归巢、调节干/前体细胞定向迁移至靶器官促进受损组织器官再生的病理生理过程中发挥着重要的作用.本文就SDF-1/CXCR4轴在成体干细胞迁移中的作用作简要综述.     

肝星状细胞通过SDF-1/CXCR4轴诱导肝癌细胞上皮间质转分化并促进其侵袭

目的 探讨肝星状细胞是否通过SDF-1/CXCR4轴促进肝癌细胞侵袭的作用和可能机制.方法 通过Westernblot和real time RT-PCR,检测肝星状细胞LX02和肝癌细胞系SDF-1、CXCR4表达.Transwell实验检测星状细胞LX02或外源性SDF-1干预对肝癌细胞HepG2以及CXCR4基因沉默后的HepG2侵袭的影响,Westem blot检测上皮标志E-cadherin和间质标志vimentin的表达变化.结果 肝星状细胞LX02中趋化因子SDF-1高表达,4株人肝细胞癌细胞系均有CXCR4高表达,其中HepG2细胞表达最强.星状细胞或SDF-1均能诱导肝癌细胞上皮-间质分化并促进其侵袭.通过RNA干扰技术靶向沉默肝癌细胞CXCR4基因,星状细胞或SDF-1均不能增强其细胞侵袭能力,不能诱导肝癌细胞HepG2发生上皮-间质分化.结论 肝星状细胞通过趋化因子SDF-1/CXCR4轴促进肝癌细胞侵袭,其机制可能与诱导肝癌上皮-间质转化有关.     

胃癌中SDF-1、CXCR4、MMP-2和MMP-9的表达及意义

目的研究趋化因子SDF-1及其受体CXCR4以及MMP-2和MMP-9在胃癌中的表达,探讨SDF-1对MMP-2和MMP-9表达的影响。方法应用免疫组化EnVision两步法检测109例胃癌组织中SDF-1、CXCR4、MMP-2和MMP-9的表达。结果 (1)SDF-1、CXCR4、MMP-2、MMP-9在胃癌组的表达阳性率分别为88.1%、56.9%、80.7%和83.4%,高于切缘对照组的47.8%、30.4%、43.4%和47.8%,差异有显著性(P<0.05);(2)SDF-1和CXCR4的表达在淋巴结转移组高于无转移组(P<0.05),SDF-1、MMP-9表达程度与淋巴结转移、组织学分级、浆膜侵犯、临床分期指标呈正相关(P<0.05);MMP-2、CXCR4表达程度与淋巴结转移、浆膜侵犯、临床分期呈正相关(P<0.05);(3)SDF-1与其受体CXCR4的表达及与MMP-2、MMP-9均呈正相关(P<0.05)。结论 (1)SDF-1、CXCR4、MMP-2和MMP-9的表达水平与胃癌的发生、侵袭及淋巴结转移密切相关,可作为预测胃癌淋巴结转移及预后的指标;(2)SDF-1/CXCR4轴可通过加强肿瘤细胞MMP-2和MMP-9分泌的途径促进肿瘤的浸润和转移,提示SDF-1可能是药物靶向治疗的重要靶点。     

脂联素调控SDF-1α/CXCR4信号轴在炎症微环境下牙周膜干细胞成骨分化中的作用

目的 研究脂联素通过调控基质细胞衍生因子-1α(SDF-1α)/CXC趋化因子受体4(CXCR4信号轴对炎症微环境下牙周膜干细胞（PDLSCs）成骨分化中的影响。方法 原代培养PDLSCs后取第三代细胞进行分组处理，进行成骨分化诱导并用10 ng/mL肿瘤坏死因子-α(TNF-α)模拟微炎症环境、用10μg/mL脂联素处理、转染阴性对照（NC）或SDF-1α的siRNA。成骨诱导第3、5、7 d时，检测碱性磷酸酶（ALP）活性，骨钙素（OCN）、骨保护素（OPN）、SDF-1α、CXCR4的m RNA表达，SDF-1α的含量；成骨诱导第21 d时，进行茜素红染色、观察钙盐沉积情况。结果 炎症微环境下PDSCSs的成骨分化及SDF-1α/CXCR4信号轴的激活均受到抑制；脂联素在炎症微环境下促进PDSCSs的成骨分化及SDF-1α/CXCR4信号轴的激活；转染SDF-1α的siRNA后，SDF-1α/CXCR4信号轴的激活受到抑制，脂联素在炎症微环境下促进PDSCSs成骨分化的作用也被抑制。结论 脂联素通过激活SDF-1α/CXCR4信号轴促进炎症微环境下PDSCSs的成骨分化。     

SDF-1/CXCR4轴活化诱导内皮祖细胞增殖、迁移及管型形成

目的观察趋化因子SDF-1促内皮祖细胞增殖、迁移和管型形成的作用。方法用免疫细胞化学检测内皮祖细胞SDF-1和CXCR4表达;用MTT法、Millicell趋化法及Matrigel体外三维成型法分别检测不同浓度的趋化因子SDF-1促内皮祖细胞增殖、迁移和管型形成。并应用CXCR4受体抑制剂AMD3100观察上述指标的变化。结果免疫细胞化学显示内皮祖细胞表达SDF-1和CXCR4蛋白。SDF-1可促进内皮祖细胞的增殖、迁移和体外小管样结构的形成。AMD3100可抑制SDF-1的诱导作用。结论SDF-1/CXCR4轴在内皮祖细胞参与血管新生中可能发挥重要作用。     

SDF-1/CXCR4在肿瘤相关成纤维细胞中的作用

肿瘤相关成纤维细胞(CAFs)是肿瘤微环境的重要组成成分,分泌多种因子在恶性肿瘤发生、发展过程中起重要作用。CAFs来源的基质细胞衍生因子-1(SDF-1)通过其特异性受体CXCR4以自分泌或旁分泌方式调控包括CAFs的激活和维持、肿瘤的增殖、侵袭和转移,血管生成、肿瘤耐药等在内的肿瘤生物学行为。因此,靶向SDF1/CXCR4能为抑制肿瘤进展、临床肿瘤治疗提供新策略。     

SDF-1α/CXCR4轴通过诱导胰腺癌上皮-间充质转化促进肿瘤迁移和侵袭

目的:探讨SDF-1α/CXCR4轴对胰腺癌细胞迁移和侵袭能力的影响及其作用机制。方法:应用RT-qPCR检测4种胰腺癌细胞株CXCR4 mRNA的表达。Transwell实验检测外源性SDF-1α及其受体CXCR4靶向抑制剂AMD3100对胰腺癌细胞迁移和侵袭能力的影响。MTS法检测外源性SDF-1α及AMD3100对胰腺癌细胞活力的影响。Western blot法检测外源性SDF-1α及AMD3100对胰腺癌细胞上皮-间充质转化(EMT)相关标志物表达的影响。结果:(1) 4种胰腺癌细胞株均不同程度地表达CXCR4 mRNA,其中PANC-1细胞株表达量最高。(2)外源性SDF-1α可增强PANC-1细胞的迁移和侵袭能力,该作用可被AMD3100所阻断。(3)外源性SDF-1α处理PANC-1细胞72 h可增强细胞活力,该作用可被AMD3100阻断。(4)外源性SDF-1α通过上调SNAIL和TWIST促使PANC-1细胞发生EMT,该作用可被AMD3100所阻断。结论:SDF-1/CXCR4轴通过促进胰腺癌细胞发生EMT而促进肿瘤迁移和侵袭。     

SDF-1/CXCR4信号轴通过NF-κB通路诱导人退变髓核细胞凋亡

目的探讨趋化因子SDF-1/CXCR4信号轴对人退变椎间盘髓核细胞凋亡的调控作用及其分子机制。方法将术中摘取的椎间盘标本根据Pfirrmann退变程度分为正常组和退变组。用免疫组织化学法、定量PCR和Western blot等检测SDF-1和CXCR4的表达。用退变椎间盘髓核原代细胞培养,取第3~5代的细胞给予10 ng/mL SDF-1刺激、CXCR4-siRNA转染及NF-κB特异性抑制剂PDTC(20μmol/L)等不同处理,Western blot和q-PCR验证转染效率和信号通路上靶蛋白(基因)的表达;Annexin V/PI检测细胞凋亡率;细胞免疫荧光检测NF-κB的重要基团P65的核转移情况。结果 SDF-1和CXCR4在退变椎间盘组织中表达显著升高(P0.05);SDF-1可以诱导退变髓核细胞的凋亡,但在CXCR4的表达受到沉默后,SDF-1的促凋亡作用被抑制(P0.05);加入SDF-1的诱导后,磷酸化P65的表达水平明显增高(P0.05),P65向核内移位;用PDTC抑制NF-κB活性后,SDF-1促凋亡作用明显减弱(P0.05)。结论 SDF-1/CXCR4信号轴促进髓核细胞凋亡的机制可能与Akt/NF-κB信号通路相关。     

Expression patterns of SDF1/CXCR4 in human invasive breast carcinoma and adjacent normal stroma: Correlation with tumor clinicopathological parameters and patient survival

SDF-1/CXCR4 axis is involved in various steps of breast tumorigenesis such as tumor growth, angiogenesis and metastasis. The goal of the present study is to demonstrate in detail the immunohistochemical distribution of SDF-1 and CXCR4 in invasive breast carcinomas and identify possible correlation of their expression patterns with clinicopathological parameters and patients survival. We investigated the immunoexpression of CXCR4 and SDF1 in 76 invasive breast carcinomas. Both SDF-1 and CXCR4 had statistically significant higher expression in carcinomas compared with adjacent normal breast tissue. Furthermore the expression of CXCR4 in intratumoral fibroblasts had a positive correlation with overall and disease-free survival, while SDF1 membranous immunopositivity in normal breast epithelial cells was a risk factor for relapse. In addition, expression of SDF1 in fibroblasts of normal breast tissue was positively associated with tumor grade. Overall, our results suggest that the differential expression of CXCR4 in intratumoral stroma and SDF1 in adjacent normal mammary cells may predict clinical outcome in breast cancer patients.     

Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis

Stromal cell-derived factor-1 (SDF-1) participates in mobilizing bone marrow-derived stem cells, via its receptor CXCR4. We studied the role of the SDF-1/CXCR4 axis in a rodent model of bleomycin-induced lung injury in C57BL/6 wild-type and matrix metalloproteinase (MMP)-9 knockout mice. After intratracheal instillation of bleomycin, SDF-1 levels in serum and bronchial alveolar lavage fluid increased. These changes were accompanied by increased numbers of CXCR4(+) cells in the lung and a decrease in a population of CXCR4(+) cells in the bone marrow that did not occur in MMP-9(-)/(-) mice. Both SDF-1 and lung lysates from bleomycin-treated mice induced migration of bone marrow-derived stem cells in vitro that was blocked by a CXCR4 antagonist, TN14003. Treatment of mice with TN14003 with bleomycin-induced lung injury significantly attenuated lung fibrosis. Lung tissue from patients with idiopathic pulmonary fibrosis had higher numbers of cells expressing both SDF-1 and CXCR4 than did normal lungs. Our data suggest that the SDF-1/CXCR4 axis is important in the complex sequence of events triggered by bleomycin exposure that eventuates in lung repair. SDF-1 participates in mobilizing bone marrow-derived stem cells, via its receptor CXCR4.     

Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis

The alpha-chemokine stromal-derived factor (SDF)-1 and the G-protein-coupled seven-span transmembrane receptor CXCR4 axis regulates the trafficking of various cell types. In this review, we present the concept that the SDF-1-CXCR4 axis is a master regulator of trafficking of both normal and cancer stem cells. Supporting this is growing evidence that SDF-1 plays a pivotal role in the regulation of trafficking of normal hematopoietic stem cells (HSCs) and their homing/retention in bone marrow. Moreover, functional CXCR4 is also expressed on nonhematopoietic tissue-committed stem/progenitor cells (TCSCs); hence, the SDF-1-CXCR4 axis emerges as a pivotal regulator of trafficking of various types of stem cells in the body. Furthermore, because most if not all malignancies originate in the stem/progenitor cell compartment, cancer stem cells also express CXCR4 on their surface and, as a result, the SDF-1-CXCR4 axis is also involved in directing their trafficking/metastasis to organs that highly express SDF-1 (e.g., lymph nodes, lungs, liver, and bones). Hence, we postulate that the metastasis of cancer stem cells and trafficking of normal stem cells involve similar mechanisms, and we discuss here the common molecular mechanisms involved in these processes. Finally, the responsiveness of CXCR4+ normal and malignant stem cells to an SDF-1 gradient may be regulated positively/primed by several small molecules related to inflammation which enhance incorporation of CXCR4 into membrane lipid rafts, or may be inhibited/blocked by small CXCR4 antagonist peptides. Consequently, strategies aimed at modulating the SDF-1-CXCR4 axis could have important clinical applications both in regenerative medicine to deliver normal stem cells to the tissues/organs and in clinical hematology/oncology to inhibit metastasis of cancer stem cells.     

Effects of SDF-1/CXCR4 on Acute Lung Injury Induced by Cardiopulmonary Bypass

Acute lung injury (ALI) is one of the most important complications after cardiopulmonary bypass (CPB) and the complex pathophysiology remains to be resolved incomplete. SDF-1/CXCR4 chemokine axis can chemotactically accumulate inflammatory cell to local tissue and regulate the release of inflammatory factors, and SDF-1 has a strong chemotaxis effect on neutrophils with CXCR4. Since CPB animal model was difficult to establish, there was still no report about the effect of SDF-1/CXCR4 on neutrophil chemotaxis in ALI after CPB. Here, a stable CPB rat model was constructed to clarify the role of SDF-1/CXCR4 axis in the CPB-induced ALI. Real-time quantitative PCR (RT-qPCR), Western blot analysis, and enzyme-linked immunosorbent assay (ELISA) were used to detect the changes of SDF-1 and CXCR4 in lung tissues, blood, bronchoalveolar lavage (BALF), and/or isolated neutrophils. SDF-1/CXCR4 was increased after CPB, both of that were increased in blood; CXCR4 was increased in neutrophils; SDF-1/CXCR4 was also increased in BALF of CPB model. Results indicated that SDF-1/CXCR4 axis played a key role in the process of early ALI after CPB, also showed that lung injury was significantly reduce after blocking SDF-1/CXCR4 axis, suggest that CXCR4 might be a new target for ALI treatment.     

Stromal-derived factor-1alpha/CXCL12-CXCR 4 axis is involved in the dissemination of NSCLC cells into pleural space

Malignant pleural effusion (PE) is one of the poor prognostic factors in non-small cell lung cancer (NSCLC), and the detailed mechanism of the malignant PE formation is not fully elucidated. Recently, CXCR4, a receptor for chemokine stromal-derived factor-1alpha (SDF-1alpha) that can induce chemotaxis of cells, was reported to be expressed on NSCLC. In this study, we hypothesized that the SDF-1alpha/CXCR4 axis may be involved in the dissemination of malignant cells into pleural space, and investigated its expression, function, and signaling pathway using NSCLC cell lines and clinical samples from 43 patients with NSCLC with malignant PE. We found functional expression of CXCR4 on NSCLC cell lines, and also found that SDF-1alpha could induce migration via phosphatidylinositol 3 (PI-3) kinase- and p44/42 mitogen-activated protein kinase-dependent manner. The SDF-1alpha levels in malignant PE were significantly higher than those in transudate PE and showed a significant positive correlation with PE volumes. The sensitivity and specificity for prediction of recurrence of malignant PE was 61.5% and 83.3%, respectively (cutoff SDF-1alpha = 2,500 ng/ml), and better than those using pH of PE. Cancer cells in malignant PE expressed CXCR4, and mesothelial cells of the pleura stained positive for SDF-1alpha. The SDF-1alpha/CXCR4 axis is involved in the dissemination of NSCLC cells into pleural space.     

The SDF-1-CXCR4 signaling pathway: a molecular hub modulating neo-angiogenesis

Pro-angiogenic bone marrow (BM) cells include subsets of hematopoietic cells that provide vascular support and endothelial progenitor cells (EPCs), which under certain permissive conditions could differentiate into functional vascular cells. Recent evidence demonstrates that the chemokine stromal-cell derived factor-1 (SDF-1, also known as CXCL12) has a major role in the recruitment and retention of CXCR4(+) BM cells to the neo-angiogenic niches supporting revascularization of ischemic tissue and tumor growth. However, the precise mechanism by which activation of CXCR4 modulates neo-angiogenesis is not clear. SDF-1 not only promotes revascularization by engaging with CXCR4 expressed on the vascular cells but also supports mobilization of pro-angiogenic CXCR4(+)VEGFR1(+) hematopoietic cells, thereby accelerating revascularization of ischemic organs. Here, we attempt to define the multiple functions of the SDF-1-CXCR4 signaling pathway in the regulation of neo-vascularization during acute ischemia and tumor growth. In particular, we introduce the concept that, by modulating plasma SDF-1 levels, the CXCR4 antagonist AMD3100 acutely promotes, while chronic AMD3100 treatment inhibits, mobilization of pro-angiogenic cells. We will also discuss strategies to modulate the mobilization of essential subsets of BM cells that participate in neo-angiogenesis, setting up the stage for enhancing revascularization or targeting tumor vessels by exploiting CXCR4 agonists and antagonists, respectively.     

Stromal cell-derived factor-1/CXCR4 signaling modifies the capillary-like organization of human embryonic stem cell-derived endothelium in vitro.

The molecular mechanisms that regulate human blood vessel formation during early development are largely unknown. Here we used human ESCs (hESCs) as an in vitro model to explore early human vasculogenesis. We demonstrated that stromal cell-derived factor-1 (SDF-1) and CXCR4 were expressed concurrently with hESC-derived embryonic endothelial differentiation. Human ESC-derived embryonic endothelial cells underwent dose-dependent chemotaxis to SDF-1, which enhanced vascular network formation in Matrigel. Blocking of CXCR4 signaling abolished capillary-like structures induced by SDF-1. Inhibition of the SDF-1/CXCR4 signaling pathway by AMD3100, a CXCR4 antagonist, disrupted the endothelial sprouting outgrowth from human embryoid bodies, suggesting that the SDF-1/CXCR4 axis plays a critical role in regulating initial vessel formation, and may function as a morphogen during human embryonic vascular development.     

The tumor microenvironment: CXCR4 is associated with distinct protein expression patterns in neuroblastoma cells

In previous studies, we demonstrated that human neuroblastoma cells are equipped with the machinery to direct their homing to bone marrow. These tumor cells express the CXCR4 receptor for the bone marrow stroma-derived chemokine CXCL12 (SDF-1) and secrete the CXCL12 ligand. The present study was undertaken to explore possible differences in gene-expression patterns between neuroblastoma variants that over-express CXCR4 (designated STH cells) and those which express very little of this receptor (STL cells). The results of the study clearly indicate that these variants show a differential gene-expression profile. They differ in expression of some integrins such as VLA2, VLA3 and VLA6, of neuroendocrine-markers such as CD56 and synaptophysin, in the expression of c-kit and in the secretion of certain cytokines and growth factors such as TNFalpha, SDF-1, VEGF, IL-8, GM-CSF and IP-10. We hypothesize that these differences are due to an autocrine SDF-1alpha-CXCR4 axis.