CXCR4和CXCR7在肿瘤中的研究进展

以往的研究认为趋化因子受体4(chemokine receptor 4,CXCR4)是趋化因子CXCL12的唯一受体,CXCL12/CXCR4生物轴在肿瘤发展过程中起重要作用,然而最近研究发现CXCL12尚存在CXCR7这一新的受体,并且CXCL12/CXCR7生物轴同样对肿瘤的发生发展起重要作用.本文就有关趋化因子受体CXCR4和CXCR7在肿瘤中的表达、促进肿瘤增殖和转移、促进血管新生以及肿瘤治疗等方面的研究作一综述.     

CXCL12／CXCR4对肿瘤生物学行为的影响

恶性肿瘤细胞的侵袭转移是影响恶性肿瘤预后的根本原因。大量的研究发现趋化因子及其受体在肿瘤侵袭转移中发挥重要作用。其中关于趋化因子CXCL12及其受体CXCR4对肿瘤侵袭转移的影响的研究较多，本文通过国内外文献复习就CXCL12／CXCR4的生物学特性及其对肿瘤生物学行为的影响作一综述。     

胰腺癌CXCL12/CXCR4通路研究进展

目的:总结CXCL12/CXCR4生物学轴与胰腺癌侵袭和转移关系的研究现状.方法:应用PubMed及CNKI期刊全文数据库检索系统,以“CXCL12、CXCR4和胰腺癌”等为关键词,检索2005-2011年的相关文献,共检索到中文文献56条,英文文献152条.纳入标准:1)CXCL12-CXCR4生物学轴的生物学特性及功能;2)CXCL12/CXCR4生物学轴与肿瘤发生、发展的关系;3)CXCL12/CXCR4生物学轴信号转导通路的相关调控因子及其调节机制;4)CXCL12/CXCR4生物学轴在胰腺癌侵袭、转移中的作用及其机制;5)CXCL12/CXCR4生物学轴与胰腺癌的治疗及预后.根据纳入标准共采用中文文献3条,英文文献17条.结果:趋化因子受体CXCR4与其配体CXCL12结合组成的生物学轴具有高度特异性,在胰腺癌细胞的黏附、侵袭、转移、增殖和生存中发挥重要作用,与细胞外基质降解、胰腺癌血管、淋巴管生成及嗜神经侵袭密切相关,并受相关因子调控影响其信号转导通路.结论:CXCL12/CXCR4生物学轴在胰腺癌发生、发展中发挥着重要作用,有望成为胰腺癌靶向治疗的新靶点,但其具体作用的相关转导通路和调节机制还未完全明确,有待进一步研究.     

趋化因子受体CXCR7及其与肿瘤的关系

CXCR7是继CXCR4之后发现的趋化因子CXCL12的新受体.目前研究表明,CXCL12/CXCR7生物轴对多种肿瘤的发展有重要影响,与CXCL12/CXCR4生物轴的作用有一定相似性.CXCR7广泛表达于多种肿瘤组织及肿瘤细胞,在肿瘤细胞的生长增殖、黏附迁徙中起重要作用.抑制CXCR7表达或阻断其信号传导通路可能为肿瘤治疗提供新策略.     

CXCL12-CXCR4生物学轴在肿瘤侵袭与转移中的研究进展

研究发现多种肿瘤细胞表达趋化因子CXCL12及其受体CXCR4,并与肿瘤细胞的迁徙和转移密切相关;CXCL12-CXCR4生物学轴在多种肿瘤的播散和器官特异性转移中发挥重要作用.     

CXCL12-CXCR4生物学轴与肿瘤转移关系的研究

趋化因子CXCL12与其特异性受体CXCR4构成的CXCL12-CXCR4生物学轴在肿瘤细胞的选择性转移中起到重要的作用,并有可能参与了肿瘤的种植转移过程.对这一特殊生物学轴的研究可以为肿瘤的防治提供新的思路.     

趋化因子受体CXCR4及其配体CXCL12在胃癌组织中的表达及其意义

目的 探讨CXCR4/CXCL12在胃癌组织中表达及其在肝转移中的作用。方法 应用Western blot 检测40例胃癌患者标本中肿瘤组织、邻近正常黏膜以及肝转移组织中CXCR4/CXCL12通路成员的表达情况,免疫组织化学法检测CXCR4/CXCL12在细胞水平的分布。结果 胃癌组织中CXCR4/CXCL12表达水平明显增高（肿瘤组织vs正常黏膜,P<0.05）;10例肝转移组织中CXCR4/CXCL12表达增高（转移组织vs原发肿瘤,P<0.05）;CXCR4/CXCL12表达水平与TNM 分期晚（Ⅲ/Ⅳ）有关（P<0.05）。结论 CXCR4/CXCL12信号转导通路可能在胃癌肝转移过程中起一定作用,详细机制尚待进一步研究。     

CXCR4/CXCL12轴与白血病复发

趋化因子受体CXCR4与其特异性配体CXCL12结合,启动下游信号通路形成CXCR4/CXCL12生物轴,在造血干细胞的归巢、再植以及维持正常造血和造血微环境的稳定过程中发挥重要作用.CXCR4/CXCL12轴同时也可促进白血病细胞存活、增殖、转移及耐药,与白血病髓内外复发关系密切.CXCR4的表达水平可作为判断白血病...     

趋化因子CXCL12及其受体与肿瘤转移的关系

趋化因子CXCL12(C-X-C chemokine ligand 12)及其受体CXCR4(c-x-c chemokine receptor4)在胚胎发育、干细胞的迁移和各种免疫反应中发挥重要作用,是许多生理和病理过程中指导细胞运动的中心因素.最近发现肿瘤细胞的转移机制和白细胞的迁移相类似,趋化因子CXCL12及其受体与肿瘤的生长、侵袭、转移和分泌密切相关,动物实验表明CXCR4可能成为抑制肿瘤生长、转移的重要靶目标.本文将对趋化因子CXCL12及其受体CXCR4在肿瘤转移、进展中的作用以及与此相关的信号转导、调节因子进行综述.     

趋化因子受体CXCR4/CXCL12信号转导通路与胃癌淋巴结转移关系的研究

目的：检测趋化因子受体CXCR4/CXCL12信号转导通路在胃癌组织、远癌正常粘膜以及转移淋巴结中的表达情况,分析CXCR4/CXCL12在胃癌淋巴结转移中的作用。方法：应用Westernblot检测胃癌组织中CXCR4/CXCL12通路成员表达。结果：胃癌组织中CXCR4/CXCL12表达水平明显高于正常胃粘膜（P〈0.05）;32例淋巴结转移癌组织中22例CXCR4/CXCL12蛋白表达高于原发癌;CXCR4/CXCL12表达水平与淋巴结转移有关（P（0.05）。结论：趋化因子受体CXCR4/CXCL12在原发胃癌及其淋巴结转移癌组织中均呈高表达,CXCR4信号转导通路可能在胃癌淋巴结转移过程中起重要作用。     

CXCL12-CXCR4在胰腺癌侵袭转移中的作用

目前研究发现趋化因子及受体CXCL12-CXCR4生物轴在胰腺癌的侵袭转移中起重要作用.CXCL12-CXCR4可通过促进胰腺癌细胞增殖、增强癌细胞的迁移、促进细胞外基质蛋白降解和血管新生等机制而促进胰腺癌的侵袭转移.     

CXCL12-CXCR4在胰腺癌侵袭转移中的作用

目前研究发现趋化因子及受体CXCL12-CXCR4生物轴在胰腺癌的侵袭转移中起重要作用.CXCL12-CXCR4可通过促进胰腺癌细胞增殖、增强癌细胞的迁移、促进细胞外基质蛋白降解和血管新生等机制而促进胰腺癌的侵袭转移.     

CXCL12-CXCR4在胰腺癌侵袭转移中的作用

目前研究发现趋化因子及受体CXCL12-CXCR4生物轴在胰腺癌的侵袭转移中起重要作用.CXCL12-CXCR4可通过促进胰腺癌细胞增殖、增强癌细胞的迁移、促进细胞外基质蛋白降解和血管新生等机制而促进胰腺癌的侵袭转移.     

The dynamic yin-yang interaction of CXCR4 and CXCR7 in breast cancer metastasis

The contribution of CXCR7 to the tumor microenvironment has introduced a new level of complexity to CXCL12 signaling in breast cancer. In the previous issue of Breast Cancer Research, Hernandez and colleagues delineate the roles of CXCR4 and CXCR7 in tumor invasion and metastasis. The authors demonstrate that co-expression of CXCR7 and CXCR4 results in inhibition of CXCL12-mediated invasion, reduced intravasation of tumor cells into the vasculature, and fewer lung metastases compared with parental tumors. The results of this study suggest the combination of small molecule inhibitors of CXCR4 and CXCR7 could dramatically reduce invasion, intravasation, and metastasis and could be highly beneficial for the treatment of invasive breast cancer.     

Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer

CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activities. CXCL12 itself is a highly effective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neutrophils. CXCL12 regulates inflammation, neo-vascularization, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metastasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by different mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and proliferation. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a supportive chemokine for tumor neovascularization via attracting endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human bladder cancer (BC). Taken together, mounting evidence suggests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. However, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic.     

基质细胞衍生因子1及其受体与卵巢癌的关系研究进展北大核心

卵巢癌是常见的妇科恶性肿瘤,卵巢癌早期无特异性症状和体征,缺乏有效的诊断方法,超过70%的患者确诊时已属晚期,因此卵巢癌死亡率极高,预后差。基质细胞衍生因子1(stromal cell derived factor-1,SDF-1,CXCL12)及其受体CXCR4参与卵巢癌的增殖凋亡、侵袭转移以及血管新生,与卵巢癌的发生发展密切相关。本文综述了近年来卵巢癌中CXCL12/CXCR4的相关研究进展。     

Epigenetic silencing of CXCL12 increases the metastatic potential of mammary carcinoma cells

Expression of the chemokine receptor CXCR4 has been linked with increased metastasis and decreased clinical prognosis in breast cancer. The current paradigm dictates that CXCR4 fosters carcinoma cell metastasis along a chemotactic gradient to organs expressing the ligand CXCL12. The present study asked if alterations in autocrine CXCR4 signaling via dysregulation of CXCL12 in mammary carcinoma cells modulated their metastatic potential. While CXCR4 was consistently detected, expression of CXCL12 characteristic of human mammary epithelium was silenced by promoter hypermethylation in breast cancer cell lines and primary mammary tumors. Stable re-expression of functional CXCL12 in ligand null cells increased orthotopic primary tumor growth in the mammary fat-pad model of tumorigenesis. Those data parallel increased carcinoma cell proliferation measured in vitro with little-to-no-impact on apoptosis. Moreover, re-expression of autocrine CXCL12 markedly reduced metastatic lung invasion assessed using in vivo bioluminescence imaging following tail vein injection. Consistent with those data, decreased metastasis reflected diminished intracellular calcium signaling and chemotactic migration in response to exogenous CXCL12 independent of changes in CXCR4 expression. Together these data suggest that an elevated migratory signaling response to ectopic CXCL12 contributes to the metastatic potential of CXCR4-expressing mammary carcinoma cells, subsequent to epigenetic silencing of autocrine CXCL12.     

CXCL12-CXCR4 Promotes Proliferation and Invasion of Pancreatic Cancer Cells

Objective: CXCL12 exerts a wide variety of chemotactic effects on cells. Evidence indicates that CXCL12,in conjunction with its receptor, CXCR4, promotes invasion and metastasis of tumor cells. Our objective was toexplore whether the CXCL12-CXCR4 biological axis might influence biological behavior of pancreatic cancercells. Methods: Miapaca-2 human pancreatic cancer cells were cultured under three different conditions:normal medium (control), medium + recombinant CXCL12 (CXCL12 group), or medium + CXCR4-inhibitorAMD3100 (AMD3100 group). RT-PCR was applied to detect mRNA expression levels of CXCL12, CXCR4, matrixmetalloproteinase 2 (MMP-2), MMP-9, and human urokinase plasminogen activator (uPA). Additionally, cellproliferation and invasion were performed using CCK-8 colorimetry and transwell invasion assays, respectively.Results: CXCL12 was not expressed in Miapaca-2 cells, but CXCR4 was detected, indicating that these cells arecapable of receiving signals from CXCL12. Expression of extracellular matrix-degrading enzymes MMP-2, MMP-9, and uPA was upregulated in cells exposed to exogenous CXCL12 (P<0.05). Additionally, both proliferationand invasion of pancreatic cancer cells were enhanced in the presence of exogenous CXCL12, but AMD3100intervention effectively inhibited these processes (P<0.05). Conclusions: The CXCL12-CXCR4 biological axisplays an important role in promoting proliferation and invasion of pancreatic cancer cells.