趋化因子CXCL12及其受体CXCR4与乳腺癌

 趋化因子CXCL12及其受体CXCR4在乳腺癌发生发展的多个过程中受到多种因素调控并表达,并且多项研究证实CXCL12及CXCR4不但有助于判断乳腺癌患者的预后,而且针对CXCR4的治疗更为乳腺癌患者提供了新的联合治疗方案,给患者更为理想的治疗。     

乳腺癌趋化因子受体CXCR4的表达及其意义

目的研究趋化性细胞因子受体CXCR4在乳腺癌中的表达,探讨其与淋巴结转移、远处转移及预后的关系。方法84例正常乳腺组织及84例乳腺癌组织、43例区域淋巴结转移癌组织标本（依据组织类型及临床病理特性分组）,取自福建医科大学附属第二医院2000年1月至2002年12月手术切除的病理存档蜡块,应用免疫组化方法（二步法）分别检测3组标本CXCR4的表达情况。对计数资料采用χ^2检验,对生存率采用时序检验进行统计学分析。结果正常乳腺组织、乳腺癌组织、区域淋巴结转移癌组织CXCR4阳性率分别为11．9％、53．6％、74．4％;转移组织CXCR4阳性表达率明显高于原发肿瘤。乳腺癌组织CXCR4阳性表达率与淋巴结转移、HER-2表达、临床分期密切相关（P〈0．05）,而与患者年龄、肿瘤直径、ER表达、PR表达、组织学类型及肿瘤分化程度无关（P〉0．05）。发生远处转移组CXCR4表达水平（74．1％）高于未发生远处转移组（43．9％,P〈O．01）。CXCR4阳性表达组5年生存率66．7％（30／45）明显低于阴性表达组87．2％（84／89,P〈0．05）。结论CXCR4阳性表达与乳腺癌的淋巴结转移、远处转移有关,有助于预后判断。     

趋化因子受体CXCR4在乳腺癌中的表达及临床意义

目的：探讨乳腺癌中趋化因子受体CXCR4的表达及临床意义。方法：采用免疫组化S—P染色法检：测乳腺癌、乳腺增生组织、及乳腺纤维腺瘤中CXCR4表达,分析CXCR4在乳腺癌中表达与患者淋巴结转移状态、Her2、PCNA关系。结果：CXCR4在乳腺癌组织中高表达,与乳腺增生组织及乳腺纤维腺瘤组织中表达有显著性差异,与患者淋巴结转移状态、Her2、PCNA密切相关。结论：CXCR4在乳腺癌中高表达,可以作为乳腺癌患者预后的一个指标,为寻找新的乳腺癌治疗靶点提供了依据。     

趋化因子受体CXCR4在乳腺癌中的表达及临床意义

目的:探讨乳腺癌中趋化因子受体CXCR4的表达及临床意义.方法: 采用免疫组化S-P染色法检测乳腺癌、乳腺增生组织、及乳腺纤维腺瘤中CXCR4表达,分析CXCR4在乳腺癌中表达与患者淋巴结转移状态、Her2、PCNA关系.结果: CXCR4在乳腺癌组织中高表达,与乳腺增生组织及乳腺纤维腺瘤组织中表达有显著性差异,与患者淋巴结转移状态、Her2、PCNA密切相关.结论: CXCR4在乳腺癌中高表达,可以作为乳腺癌患者预后的一个指标,为寻找新的乳腺癌治疗靶点提供了依据.     

乳腺癌中趋化因子受体CXCR4表达及临床病理意义

目的探讨趋化因子受体CXCR4在乳腺癌中的表达及临床意义,为临床治疗乳腺癌寻求新的治疗靶点提供依据。方法采用免疫组化SP染色法检测乳腺癌、乳腺增生组织及乳腺纤维腺瘤中CXCR4表达差异,以及CXCR4在乳腺癌中表达与患者肿瘤分级、淋巴结转移状态、Her2等相互关系。结果CXCR4在乳腺癌组织中高表达,与乳腺增生组织及乳腺纤维腺瘤中表达差异有显著性,而且与患者淋巴结转移状态、Her2、PCNA密切相关。结论CXCR4在乳腺中癌高表达,与患者淋巴结转移状态、Her2、PCNA密切相关,可以作为乳腺癌患者预后的一个指标,为寻找新的乳腺癌治疗靶点提供重要的临床依据。     

趋化因子受体CXCR4在乳腺癌中表达的研究

目的探讨趋化受体CXCR4在乳腺癌中的表达及其与肿瘤转移的关系,以及脂多糖(LPS)对其表达的影响.方法采用流式细胞仪和RT-PCR法检测23例乳腺癌患者的癌组织、癌旁组织、正常组织以及MDA-MB-231细胞中CXCR4在蛋白质和mRNA水平的表达情况,以及LPS对MDA-MB-231细胞 CXCR4表达的影响;用Transwell板检测经LPS作用前后MDA-MB-231对趋化因子SDF-1趋化活性的影响.结果乳腺癌组织MDA-MB-231细胞的趋化因子受体CXCR4在蛋白质和mRNA水平的表达均显著高于癌旁组织和正常组织(P<0.05),并且CXCR4的表达与乳腺癌的转移密切相关;脂多糖(LPS)能下调CXCR4的表达,经LPS作用后乳腺癌细胞趋化活性降低.结论趋化因子受体在乳腺癌的转移中起重要作用,下调乳腺癌细胞CXCR4的表达水平,可减少或抑制其转移.     

趋化因子CXCL12/CXCR4与肿瘤关系的研究进展

CXCL12及其受体CXCR4不仅在许多生命过程中发挥着重要的调控作用而且与肿瘤细胞的生长、增殖、侵袭、转移有密切的关系。本文将围绕CXCR4、CXCL12以及CXCL12/CXCR4轴在肿瘤增殖、侵袭、转移、肿瘤血管生成中的作用以及作用原理以及临床应用作一综述。     

趋化因子及其受体在乳腺癌中的研究进展

乳腺癌已成为妇女最常见的恶性肿瘤,其发病率占妇女恶性肿瘤第一位,且有逐年上升趋势。乳腺癌的远处转移缩短了无病生存期,增加了病死率,也是目前临床上的治疗难点。而肿瘤的侵袭与转移是一个主动过程,与白细胞迁移有许多相似之处,由趋化因子及其受体严密调控。     

CXCL12/CXCR4轴在肿瘤生长和转移中的作用及其机制

近年来,趋化因子在肿瘤生长和转移中的作用引起人们的强烈关注。在多种肿瘤中（包括乳腺癌、胰腺癌、前列腺癌、结直肠癌等）发现,CXCL12/CXCR4分子对能够促进肿瘤细胞的生长,抑制肿瘤细胞的凋亡,促进肿瘤血管生成,影响某些肿瘤的靶向转移,增强肿瘤细胞的黏附和迁移能力,影响肿瘤细胞的分泌行为,提示该轴可能成为抗肿瘤药物的新靶点,具有潜在的临床应用前景。     

Duffy抗原趋化因子受体参与人乳腺癌的淋巴结转移

目的探讨Duffy抗原趋化因子受体(DARC)与乳腺癌患者淋巴结转移的关系。方法乳腺癌原发灶组织标本75例,按淋巴结转移情况分为阳性组和阴性组,通过免疫组化技术检测DARC表达,并探讨其与乳腺癌淋巴结转移的关系。结果淋巴结转移阳性组中DARC强表达18例(48．6％),淋巴结转移阴性组中DARC强表达31例(81．6％),两组间差异有统计学意义(P< 0．01)。DARC强表达组与弱表达组的微血管密度(MVD)分别为(35．67±17．96)／HP和(53．38±20．29)／HP,差异有统计学意义(P<0．01)。此外,远处转移的13例患者中,有9例DARC弱表达(69．2％),4例DARC强表达(30．8％)。DARC表达与MVD、淋巴结转移状态及肿瘤远处转移呈负相关,而与患者的存活时间呈正相关。结论人原发乳腺癌组织中DARC表达降低和MVD增加可能易化肿瘤向淋巴结等远隔部位的转移。     

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.     

The Role of chemokine receptor CXCR4 in breast cancer metastasis

Breast cancer is one of the leading causes of cancer related deaths worldwide. Breast cancer-related mortality is associated with the development of metastatic potential of primary tumor lesions. The chemokine receptor CXCR4 has been found to be a prognostic marker in various types of cancer, including breast cancer. Recent advances in the field of cancer biology has pointed to the critical role that CXCR4 receptor and its ligand CXCL12 play in the metastasis of various types of cancer, including breast cancer. Breast tumors preferentially metastasize to the lung, bones and lymph nodes, all of which represent organs that secrete high levels of CXCL12. CXCL12 acts as a chemoattractant that drives CXCR4-positive primary tumor cells towards secondary metastatic sites leading to the onset of metastatic lesions. Since its discovery in 2001, the CXCR4 field has progressed at a very fast rate and further studies have pointed to the role of CXCR4 in dissemination of tumor cells from primary sites, transendothelial migration of tumor cells as well as the trafficking and homing of cancer stem cells. This review summarizes the information that has been obtained over the years regarding the role of CXCL12-CXCR4 signaling in breast cancer, discusses its potential application to the development of new therapeutic tools for breast cancer control, and elucidates the potential therapeutic challenges which lie ahead and the future directions that this field can take for the improvement of prognosis in breast cancer patients.     

CXCL12/CXCR4 and breast cancer

CXCL12 and its receptor CXCR4 can express in breast cancer, and are regulated by several factors in the genesis and development of breast cancer. Lots of researches have proved that CXCL12 and CXCR4 can be used as new independent prognostic makers of breast cancer. Treatment targeted for CXCR4 can be seen as a new kind of combination therapy, which may provides patients a more ideal treatment.     

CXCL12 / CXCR4 / CXCR7 chemokine axis and cancer progression

Chemokines, small pro-inflammatory chemoattractant cytokines that bind to specific G-protein-coupled seven-span transmembrane receptors, are major regulators of cell trafficking and adhesion. The chemokine CXCL12 (also called stromal-derived factor-1) is an important α-chemokine that binds primarily to its cognate receptor CXCR4 and thus regulates the trafficking of normal and malignant cells. For many years, it was believed that CXCR4 was the only receptor for CXCL12. Yet, recent work has demonstrated that CXCL12 also binds to another seven-transmembrane span receptor called CXCR7. Our group and others have established critical roles for CXCR4 and CXCR7 on mediating tumor metastasis in several types of cancers, in addition to their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Here, we review the current concepts regarding the role of CXCL12 / CXCR4 / CXCR7 axis activation, which regulates the pattern of tumor growth and metastatic spread to organs expressing high levels of CXCL12 to develop secondary tumors. We also summarize recent therapeutic approaches to target these receptors and/or their ligands.     

Functions of CXCL12 and CXCR4 in breast cancer

The chemokine CXCL12 (SDF-1) and its cognate receptor CXCR4 were first identified in the context of trafficking and homeostasis of immune cells, such as T lymphocytes. Subsequently, it has been determined that CXCR4 regulates several key processes in a wide variety of cancers. Functions of CXCL12 and CXCR4 in cancer first were described in metastatic breast cancer, and more recent studies also have identified roles for this signaling pathway in primary breast tumors. This review focuses on functions of CXCR4 and CXCL12 in primary and metastatic breast cancer, including molecular mechanisms of action and relationships of this pathway to other key regulators of breast cancer progression. We also describe pre-clinical studies indicating the potential to exploit CXCR4 as a new molecular target for diagnosis and treatment of breast cancer in patients.     

Differential functional activation of chemokine receptor CXCR4 is mediated by G proteins in breast cancer cells

CXCR4 is a G protein-coupled receptor of considerable biological significance, and among its numerous functions, it is suggested to play a critical role in cancer metastasis. We have investigated the expression and function of CXCR4 in a range of breast cancer cell lines covering a spectrum of invasive phenotypes and found that, while surface levels of CXCR4 were uniform across the entire panel, only highly invasive cells that are metastatic in immunocompromised mice expressed functional receptors. CXCL12/SDF-1 induced cellular responses such as calcium mobilization, actin polymerization, and chemotaxis in metastatic cells, whereas noninvasive cells were unresponsive. Moreover, CXCL12 activated multiple signaling pathways downstream of G proteins in highly invasive cells but failed to activate any of the examined kinase cascades in noninvasive cell lines. This blockade in nonmetastatic cell lines seems to be due to the inability of G protein alpha and beta subunits to form a heterotrimeric complex with CXCR4. Galpha and Gbeta were able to bind to CXCR4 independently in all cell lines, but the association of G protein alphabetagamma heterotrimers with the receptor, a prerequisite for signal transduction downstream from G protein-coupled receptors, was only observed in the highly invasive cell lines. Our findings show, for the first time, that CXCR4 function is subject to complex and potentially tightly controlled regulation in breast cancer cells via differential G protein-receptor complex formation, and this regulation may play a role in the transition from nonmetastatic to malignant tumors.     

胰腺癌中CXCL12-CXCR4生物学轴表达及临床意义的探讨

目的:探讨胰腺癌中CX-CL12、CXCR4表达与临床病理因素的关系。方法:采用免疫组织化学SP法和PCR技术检测胰腺癌、癌旁组织、正常胰腺和胰周淋巴结中CXCL12、CXCR4的表达。结果:CXCL12在正常胰腺、癌旁组织和淋巴结中等表达(阳性率56.7%、46.7%和50.0%),其表达与分化程度、TNM分期和淋巴结转移无关,P>0.05。CXCR4高表达于胰腺癌、癌旁组织和胰周淋巴结(阳性率80.0%、70.0%和73.3%);其表达与分化程度无关,与TNM分期显著相关,P<0.01。淋巴结转移者CXCR4均表达阳性。RT-PCR和实时荧光定量PCR均证实上述结果。结论:CXCR4表达与胰腺癌淋巴结转移及TNM分期密切相关,CXCL12-CXCR4轴在其进展中可能起重要作用。