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。     

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及受体CXCR4在卵巢上皮性癌中的表达及其临床意义

目的:探讨趋化因子CXCL12及其受体CXCR4在卵巢上皮性癌组织中的表达及与临床病理特征和预后的关系。方法:采用免疫组织化学SP法检测6例正常卵巢表面上皮、44例卵巢上皮性癌原发灶和30例相应大网膜转移灶组织中的CXCL12和CXCR4蛋白表达。结果:正常卵巢表面上皮无CXCL12和CXCR4蛋白表达;卵巢上皮性癌原发灶的CXCL12和CXCR4表达阳性率分别为91%和59%。CXCL12表达强度与术中腹水量有显著相关性(P=0.014)。难治复发组的CXCR4阳性率(81%)显著高于无复发组(28%,P<0.001)。单因素分析显示:CXCR4阳性表达的患者中位数肿瘤无进展生存时间和总生存时间(15个月、27个月)明显短于CXCR4阴性表达者(>21个月、>32个月,分别为P<0.001和P=0.017)。多因素分析显示:CXCR4表达和残余灶大小是影响卵巢上皮性癌患者的肿瘤无进展生存时间和总生存时间的独立预后因素。结论:CXCR4在卵巢上皮性癌中的表达阳性率较高,是影响其预后的独立指标之一。     

Expression of the CXCL12/SDF-1 Chemokine Receptor CXCR7 in Human Brain Tumours

Purpose: Receptor 7 (CXCR7) has recently been characterized as a novel receptor for CXCL12/SDF-1(stromal cell derived factor-1). Given the demonstrated importance of CXCL12/SDF-1 in angiogenesis and tumourmetastasis, we hypothesized that CXCR7 may also play a role in tumour pathogenesis. Located in the limitedspace of the intracranial cavity, any brain tumours can be inherently serious and life-threatening. However, theexpression of CXCR7 in pituitary adenoma, neurilemmoma or hemangioblastoma remains to be elucidated.Therefore, we aimed to determine the potential contribution of CXCR7 in the development of brain tumours.Methods: In this study we examined and quantified the mRNA expression of CXCR7 in four different humanbrain tumours - 27 patients with neurilemmoma (8 patients), pituitary adenoma (7 patients), hemangioblastoma(6 patients), or meningioma (6 patients) undergoing surgical resection in the West China Hospital of SichuanUniversity. There were 15 females and 12 males aged from 28 to 70 years old. Total RNA was isolated and mRNAwas measured by quantitative real-time RT-PCR. One-way analysis of variance (ANOVA) was performed usingSPSS 11.0 statistical software to compare the mRNA levels of CXCR7 among four groups. Results: We foundthat CXCR7 mRNA was detected in all tumour samples. Quantitative results showed that the levels of CXCR7mRNA in brain tissues from patients with neurilemmoma or meningioma were significantly higher than thosewith pituitary adenoma or hemangioblastoma. Conclusions: The results suggest that the CXCR7 may play arole in progression, metastasis and angiogenesis of brain tumours.     

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...     

CXCR7/CXCL12与乳腺癌淋巴结转移的关系

目的探讨CXCR7/CXCL12在乳腺癌淋巴结转移中的作用。方法应用Western blot法,检测乳腺癌组织中CXCR7/CXCL12的表达情况。结果乳腺癌组织中CXCR7/CXCL12表达水平明显高于正常乳腺组织(P<0.05);48例淋巴结转移癌组织中36例CXCR7/CXCL12蛋白表达水平高于原发癌组织;CXCR7/CXCL12表达水平与肿瘤淋巴结转移有关(P<0.05)。结论 CXCR7/CXCL12在乳腺癌及其淋巴结转移癌组织中均呈高表达,CXCR7/CXCL12可能在乳腺癌淋巴结转移过程中起重要作用。     

趋化因子CXCL12及其受体在人前列腺癌嗜神经过程中表达及相关机制

目的:阐述CXCL12-CXCR4在前列腺癌嗜神经过程中的作用及相关机制.方法:H＆E染色观察前列腺癌细胞对肿瘤组织及其周围神经的浸润.免疫组织化学方法检测CXCL12和CXCR4、MMP-2、MMP-9在22例人前列腺癌和20例前列腺增生组织中的表达差别,浸润神经的肿瘤细胞CXCR4和CXCL12的表达.结果:在人前列腺癌组织中,存在着较明显的肿瘤细胞侵犯神经现象,人前列腺癌组织中CXCL12、CXCR4、MMP-2和MMP-9表达阳性率均较前列腺增生组织明显升高(P<0.05),侵犯神经的肿瘤细胞表达CXCR4,神经组织内神经鞘膜细胞表达CXCL12.结论:在前列腺癌组织中存在肿瘤细胞嗜神经现象,肿瘤肿瘤细胞分泌CXCL12,CXCR4与MMP-2、MMP-9促进了癌细胞的嗜神经浸润.     

CXCL12，CXCR4及CXCR7表达检测对乳腺癌患者疾病预后意义探讨

目的：探讨乳腺癌患者肿瘤组织中CXCL12,CXCR4和CXCR7 mRNA表达情况在肿瘤转移和疾病预后中的价值。方法采用定量PCR方法检测115例乳腺癌,临近正常组织及乳腺癌肿瘤转移患者颈部淋巴结样本中CXCL12,CXCR4和CXCR7 mRNA表达情况。随访资料采用Kaplan-Meier生存分析,对影响生存质量的因素进行多重变量Cox回归分析。结果与正常组织相比,乳腺癌组织中CXCR4和CXCR7表达明显增加,差异均有统计学意义（P﹤0.001）,两种组织中CXCL12的表达差异无统计学意义（P﹥0.05）;CXCL12在肿瘤原发部位和淋巴结转移部位的表达差异有统计学意义（P﹤0.05）,转移瘤的CXCR4和CXCR7表达均增加（P﹤0.05）。Kaplan-Meier生存分析结果表明,与CXCR4和CXCR7低表达患者相比,高表达患者的总生存率较低（P﹤0.05）。Cox回归模型显示,CXCL12、CXCR4和CXCR7表达均为影响乳腺癌患者生存情况的独立因素。结论本研究结果表明CXCL12、CXCR4和CXCR7 mRNA表达在乳腺癌患者肿瘤发展和转移中发挥重要作用,可以作为乳腺癌患者疾病预后的生物标志物。     

Serum CXCL12, but not CXCR4, Is Associated with Head and Neck Squamous Cell Carcinomas

Background: Squamous cell carcinoma (SCC) is the most frequent malignancy of the head and neck (HN) region.We here evaluated associations of stromal cell derived factor-1 (SDF-1or CXCL12) and its receptor, CXCR4, withHNSCCs. Materials and Methods: Sixty newly diagnosed HNSCC patients were enrolled in the patient group, and 28healthy individuals in the control group. Plasma levels of CXCL12 and CXCR4 were measured using ELISA kits.Results: There was a significant difference in mean CXCL12, but not CXCR4, plasma levels between the patient andcontrol groups (P=0.0001). No significant associations were found between mean plasma levels of either CXCL12 orCXCR4 with age, gender, tumor site, tumor size, lymph-node involvement or tumor stage. Conclusion: For the firsttime, our findings demonstrate a significant association between serum CXCL12 but not CXCR4 levels and HNSCCs.     

CXCR4在原发性肝细胞癌中的表达及意义

目的:检测原发性肝细胞癌中CXCR4的表达及微血管密度情况,结合临床病理资料分析CXCR4表达对肝癌患者临床预后的影响,初步探讨CXCR4与肝癌微血管生成之间的关系.方法:收集2000年1月至2001年12月我院手术切除的符合实验条件的117例肝癌患者的临床病理资料,采用免疫组织化学方法检测肝癌组织中CX-CR4的表达状况,分析CXCR4的表达与临床病理因素之间的关系,进一步进行生存分析和Logistic回归研究,分析各因素对肝癌预后的预测价值;同时用免疫组织化学方法检测肿瘤微血管密度,结合CXCR4的表达情况初步分析CXCR4在肝癌微血管形成过程中的作用.结果:CXCR4在全部117例肝癌组织中呈不同程度表达,其表达情况在患者肝硬化程度、肿瘤Edmonson分级、肿瘤直径和术前Child-Pugh分级之间的差异无统计学意义(P>0.05),在肿瘤是否有血管侵犯之间的差异存在统计学意义(P<0.05).单因素分析显示:患者肝硬化程度、肿瘤直径、肿瘤Edmon-80n分级、肿瘤侵犯血管及CXCR4表达情况是影响患者无瘤生存时间的危险因素(P<0.05).COX回归显示患者肝硬化程度、肿瘤直径、肿瘤侵犯血管及CXCR4表达情况是影响患者无瘤生存时间的独立危险因素(P<0.05).结论:CXCR4在所有的原发性肝细胞癌中均呈不同程度的表达,其表达强度与肿瘤侵犯血管之间存在明显相关关系.同时是预测肝癌术后转移的独立危险因素.     

CXCL12-CXCR4生物学轴在胰腺癌中的表达及其与血管生成的相关性

肿瘤转移是一个复杂的、非随机的多步骤过程,肿瘤细胞的运动迁移、黏附、生长、新血管生成、特异性转移器官的归巢和逃避免疫等关键步骤.近年来的研究显示,趋化因子CXCL12与其特异性受体CXCR4所构成的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.     

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。     

CXCL12-induced VLA-4 activation is impaired in trisomy 12 chronic lymphocytic leukemia cells: a role for CCL21

Homing to distinct lymphoid organs enables chronic lymphocytic leukemia (CLL) cells to receive pro-survival and proliferative signals. Cytogenetic aberrations can significantly affect CLL cell compartmentalization. Trisomy 12 (tri12) defines a CLL subgroup with specific clinical features and increased levels of the negative prognostic marker CD49d, the α4-subunit of the integrin VLA-4, which is a key regulator of CLL cell homing to bone marrow (BM). Chemokine-induced inside-out VLA-4 activation, particularly via the CXCL12-CXCR4 axis, increases the arrest of various cell types on VCAM-1 presenting endothelium. Here, we demonstrate that high CD49d expression in tri12 CLL is accompanied by decreased CXCR4 expression. Dissecting functional consequences of these alterations, we observed that tri12 CLL cell homing to murine BM is not affected by CXCR4-CXCL12 blockage using AMD3100 or olaptesed pegol/NOX-A12. In line, CCL21-CCR7 rather than CXCL12-CXCR4 interactions triggered VLA-4-mediated arrests of tri12 CLL cells to VCAM-1 under blood flow conditions. Concordantly, in real-time kinetic analyses we found CCL21 but not CXCL12 being capable to induce inside-out VLA-4 conformational changes in this CLL subgroup. Our results provide novel insights into the peculiar clinico-biological behaviour of tri12 CLL and emphasize its specific chemokine and integrin utilization during pathophysiologically and therapeutically relevant interactions with the microenvironment.     

膀胱癌增殖细胞核抗原及花生凝集素受体对比研究

（目的）寻求对膀眈癌的诊断和预后有意义的肿瘤标记物。（方法）应用免疫组化ABC法对63例膀股移行细胞癌（TCC）行花生凝集素（PNA）受体和增殖细胞核抗原（PCNA）染色检测。（结果）PNA受体在膀跳癌C1、C2和C3中的强阳性表达率分别为54．55％、85.7％和100％，而PCNA的强阳性表达率为18．2％、80．7％和92．3％；PNA受体和PCNA在Ta-T1期肿瘤中的强阳性表达率为65．6％和40．6％，在T2-T4期中为93．5％和80．6％；5年生存率比较，PNA和PCNA弱阳性表达组显著比强阳性表达组高；PNA受体与PCNA的表达呈显著相关（p＜0．005）。（结论）PNA受体和PCNA的强阳性表达随肿瘤组织病理学分级和临床分期增高而增强，PNA受体的增强表达与细胞增殖有关，PCNA和PNA受体是对TCC预后有重要意义的肿瘤标志物。     

CXCL12和CXCR4在食管鳞癌组织中的表达及其与预后的关系

背景与目的：新近研究显示CXCL12／CXCR4在多种肿瘤组织中有表达,并与肿瘤细胞的增殖、侵袭特性相关;本研究旨在检测CXCL12及其受体CXCR4在食管鳞癌中的表达,研究两者对食管癌预后的影响及其与临床及病理因素之间的关系。方法：收集食管癌术后标本186例及正常食管上皮组织20例（对照组）,应用免疫组化法检测食管癌组织中CXCR4与CXCL12的表达。结果：186例食管癌组织中CXCR4的表达率为67．2％,CXCL12的表达率为63．4％,20例正常食管上皮组织中无CXCR4及CXC112蛋白表达。多因素分析：PTNM分期及CXCR4的表达是影响食管癌根治术后患者预后的独立因素（P〈0．05）：CXCL12阳性组与阴性组5年生存率分别为18．8％和21．0％,差异无统计学意义（P〉0．05）。CXCR4阳性组与阴性组5年生存率分别为2．2％和28．5％。差异有统计学意义（P〈0．05）;有淋巴结转移组及病理分期T3期组CXCR4表达率较无淋巴结转移组及病理分期T1-2组高（P〈0．05）,食管癌组织中CXCR4的表达与CXCL12的表达之间无相关性。结论：CXCL12和CXCR4在食管癌组织中均有较高的表达,CXCR4的表达水平与食管肿瘤的发展及预后有一定的关系。     

Regional Expression of CXCL12/CXCR4 in Liver and Hepatocellular Carcinoma and Cell-cycle Variation during in vitro Differentiation

The CXCL12/CXCR4 system may be important in carcinoma. Expression of the a‐chemokine SDF‐lα (stromal cell derived factor‐lα)/CXCL12 mRNA is reduced in many carcinomas, yet its tissue protein expression may guide metastasis. Here we first compare the mRNA and protein expression of CXCL12 and its receptor CXCR4 in human liver, hepatocellular carcinoma, and malignant cell lines, and then assess cell cycle variation in CXCR4 expression. CXCR4 mRNA was present in most normal human tissues and malignant cell lines; it was only marginally reduced in hepatomas, while CXCL12 was markedly reduced, P<0.0001. Immuno‐histochemical staining of adjacent non‐malignant liver showed regional CXCR4 cytoplasmic and cell‐surface staining, limited to those hepatocytes around the central vein, a distribution resembling that of CXCL12. CXCL12 protein was not present in hepatocellular carcinoma cells in vivo, nor was cytoplasmic CXCR4 staining; nuclear CXCR4 protein expression in some malignant hepatocytes and CXCR4 staining of capillary endothelial cells around tumor cells were noted. In some malignant cell lines that had no CXCL12 on northern blots CXCL12 was weakly detectable by RT‐PCR or protein staining in the cytoplasm of a few cells. With a view to future manipulation of CXCL12/CXCR4 expression and growth we noted that in HT‐29 cells CXCR4 protein expression was less on confluent than on non‐confluent cells and varied during the cell cycle. Higher expression was associated most closely with the percentage of cells in the S‐phase and inversely with the percentage of cells in the G1‐phase. Treatment of HT‐29 cells with butyrate reduced CXCR4 cell surface expression and reduced the percentage of cells in S‐phase. In summary, CXCL12 protein expression parallels its mRNA, being markedly reduced in malignant cell lines and hepatomas; in liver, the regional distributions of CXCL12 and cytoplasmic CXCR4 are similar; finally, in HT‐29, CXCR4 expression correlates with the S‐phase of the cell cycle and is reduced during butyrate‐induced differentiation.     

趋化因子受体CXCR4和CCR7及其配体与食管癌转移相关性的研究进展

目的:总结国内外趋化因子受体CXCR4、CCR7及其配体与食管癌转移关系的研究进展.方法:应用PubMed及CNKI期刊全文数据库检索系统,以"CXCR4,CCR7,肿瘤,食管癌"等为关键词,检索2000-01-2010-01年的相关文献,共检到英文文献1 750篇,中文文献453篇.纳入标准:1)CXCR4、CCR7的结构和功能;2)CXCR4、CCR7在常见恶性肿瘤中的异常表达与预后;3)CXCR4、CCR7在食管癌中的表达情况.根据纳入标准,最后纳入分析65篇文献.结果:CXCR4、CCR7及其配体在多种恶性肿瘤中表达,与肿瘤的浸润、淋巴结转移、远处转移以及预后密切相关.CXCR4、CCR7及其配体在食管癌组织中异常表达,并与肿瘤的增殖分化、细胞凋亡、血管新生和侵袭转移等密切相关.结论:趋化因子受体CXCR4、CCR7及其配体在食管癌发生、发展中起重要作用,以CXCR4、CCR7为靶点有望为食管癌的治疗提供新的思路.