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。     

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。     

Correlation between CXCR4/CXCR7/CXCL12 chemokine axis expression and prognosis in lymph‐node‐positive lung cancer patients

The CXCR4/CXCR7/CXCL12 chemokine axis plays important roles in the migration of tumor cells during cancer development by modulating site‐specific distant metastasis including to regional lymph nodes. We investigated the correlation of these chemokine expressions to prognosis in lymph‐node‐positive non‐small‐cell lung cancer (NSCLC) patients. A total of 140 surgically resected specimens of primary site (PS) and metastatic lymph nodes (MLN) of NSCLC involving hilar and/or mediastinal lymph nodes (N1‐2) were collected. CXCR4, CXCR7 and CXCL12 expressions were evaluated. Cox regression analysis was performed to determine whether these chemokines were independent prognostic factors in N1‐2 NSCLC. High expression of CXCR4 in PS and CXCL12 in MLN was associated with poor overall survival (OS) (P = .025 and .033, respectively). Significant correlations between CXCR4 expression in PS and CXCL12 expression in MLN were observed (P = .040). There was significant difference in OS between 2 groups according to expressions of CXCR4 in PS and CXCL12 in MLN (P = .0033). Expression of CXCL12 in MLN was identified as an independent prognostic factor (HR 1.79, 95% CI 1.08‐3.04, P = .023). CXCL12 in MLN was mainly expressed by tumor cells compared with stromal cells (56% vs 25%, respectively, P < .0001). CXCR4/CXCL12 may play roles in tumor progression in MLN and is associated with poor prognosis of lymph‐node‐positive NSCLC patients.     

Expression of CXCL12 and its receptor CXCR4 correlates with lymph node metastasis in submucosal esophageal cancer

BACKGROUND AND OBJECTIVES: The chemokine CXCL12 and its receptor CXCR4 are involved in cell migration, proliferation, and angiogenesis, and promote organ-specific localization of distant metastases in various carcinomas. We examined their expression and microvessel density (MVD) in submucosal esophageal squamous cell carcinoma (ESCC) and analyzed their connection to clinicopathological findings including lymph node micrometastasis (LMM). METHODS: Eighty-six patients with submucosal ESCC underwent curative resection from 1985 to 2002. Immunohistochemical staining of CXCL12, CXCR4, and CD34 was performed with primary tumors, and staining of cytokeratin was performed with dissected lymph nodes. MVD was calculated from CD34 expression, and LMM detected by cytokeratin staining. RESULTS: Expression of CXCL12, but not CXCR4, correlated with lymph node metastasis. There was no significant correlation between the expression of CXCL12 and/or CXCR4 and MVD. LMM was detected in 8 cases and 14 lymph nodes. CXCL12 expression and high MVD were found in tumors with lymph node metastasis including LMM. Furthermore, in the CXCR4-positive tumors, positive CXCL12 expression was more significantly correlated with lymph node metastasis and/or LMM than negative CXCL12 expression. CONCLUSIONS: Evaluation of CXCL12 and CXCR4 expression should assist detection of lymph node metastasis including LMM in submucosal ESCC.     

Human epidermal growth factor receptor-2 expression in primary and metastatic gastric cancer

Background

Amplification and overexpression of human epidermal growth factor receptor-2 (HER-2) has been shown in subgroups of gastric cancer, correlated to more aggressive disease and predictive for the treatment with HER-2 antibodies. In this study, we examined the prognostic value of HER-2 expression in primary gastric cancer and in associated lymph node metastases and confirmed the role of HER-2 in tumor angiogenesis by examining vascular endothelial growth factor (VEGF) expression.

Methods

Immunohistochemistry was used to detect HER-2 and VEGF expression in 110 gastric cancer specimens and associated lymph node metastases and in 96 specimens of normal gastric mucosa.

Results

The expression level of HER-2 in gastric tissues was significantly higher than in normal tissues (19.1 % vs. 8.3 %; P < 0.05). HER-2 overexpression was homogeneous in primary gastric cancer and metastatic lymph nodes (P = 0.607). There was a significant positive correlation of HER-2 expression and VEGF expression (P = 0.007). HER-2 overexpression in primary tumor correlated with lymph node metastasis, distant metastasis, and American Joint Committee on Cancer (AJCC) stage. Cox regression multivariate analyses confirmed that tumor size, histological grade, lymph node ratio, AJCC stage, chemotherapy, and HER-2 expression were all prognostic factors. Patients with HER-2 positivity in both primary and metastatic tissues (+/+) had the poorest survival (OS, 12.5 months; DFS, 11.0 months) (P < 0.01).

Conclusions

HER-2 was significantly overexpressed in gastric cancer versus normal tissue and correlated with VEGF expression. HER-2 in tumor or lymph nodes was an independent negative prognostic factor.     

结直肠癌中CXCR5、CXCL13、MMP-12和MMP-13的表达及意义

目的 观察结直肠癌组织中趋化因子CXCR5及其配体CXCL13以及MMP-12、MMP-13的表达,探讨其与临床病理特征、预后的关系。方法 应用免疫组织化学SP法检测236例结直肠癌及其切缘正常肠黏膜组织以及62例结直肠腺瘤组织中CXCR5、CXCL13、MMP-12和MMP-13蛋白表达。结果 （1）CXCR5、CXCL13、MMP-12、MMP-13在结直肠癌组织中的表达率为43.6%,41.5%、83.5%和80.5%均高于在切缘正常肠黏膜组织中的表达率（4.2% 、5.5%、11.9%和13.1%）及在结直肠腺瘤组织中的表达率（24.2%、17.7%、69.4%和64.5%）（P均<0.05）。（2）CXCR5、CXCL13、MMP-12、MMP-13蛋白表达与淋巴结转移、远处转移、肿瘤分期及复发呈正相关(P<0.05)。CXCL13蛋白表达与组织分化程度呈正相关(P<0.05)。（3）CXCR5与CXCL13蛋白表达呈正相关(P<0.05)。CXCR5、CXCL13蛋白表达分别与MMP-12和MMP-13呈正相关(P<0.05)。结论 CXCR5、CXCL13、MMP-12、MMP-13的表达促进结直肠癌的发生、发展以及转移、复发, 可作为预测结直肠癌转移和复发的有价值指标。     

宫颈腺癌细胞CXCR4/CXCL12过表达与淋巴结转移和慢性炎症的关系

背景与目的:CXCL12是一种炎症趋化因子,CXCR4是其特异性受体.有文献报道CXCR4参与多种恶性肿瘤的转移过程.但CXCR4/CXCL12在宫颈腺癌细胞中表达的意义鲜见报道.本研究探讨CXCR4/CXCL12在宫颈腺癌细胞中过表达与淋巴结转移及宫颈慢性炎症程度的相关性.方法:收集35例行子宫颈癌根治术的Ⅰ B1～ⅡB期宫颈腺癌标本,其中有淋巴结转移组8例,无淋巴结转移组27例.组织切片行CXCR4和CXCL12免疫组化染色及HE染色,90%以上肿瘤细胞强着色定义为过表达.采用Fisher's精确概率检验法、卡方检验及Pearson相关检验分析结果.结果:35例均有不同数量肿瘤细胞表达CXCR4.有淋巴结转移组CXCR4过表达率(62.50%,5/8)高于无淋巴结转移组(22.00%,6/27),P＜0.05.临床Ⅰ B期有淋巴结转移组CXCR4过表达率(33.33%,1/3)高于无淋巴结转移组(26.01%,6/23),但P＞0.05;临床ⅡB期,有淋巴结转移组CXCR4过表达率高于无淋巴结转移组(80.00%,4/5 vs.0.00%,0/4),P＜0.05.CXCR4过表达预测淋巴结转移的阳性预测值为45.45%,阴性预测值为87.50%.35例中33例有数量不等的肿瘤细胞表达CXCL12.无论有淋巴结转移组或无淋巴结转移组,临床Ⅱ期病例CXCL12过表达率均明显高于I B期(0.00% vs.80.00%,21.73% vs.75.00%),P＜O.05.23例临床Ⅰ B期无淋巴结转移组,CXCR4过表达率与CXCL12过表达率呈正相关(P＜0.05):但在Ⅰ B期有淋巴结转移组(3例)及ⅡB期(9例)病例组,两者间无相关性.35例病例均伴有不同程度慢性炎症,炎性浸润主要为淋巴细胞.CXCL12过表达率与宫颈慢性炎症浸润程度无相关性,P＞0.05.结论:宫颈腺癌细胞CXCR4过表达提示具有较高淋巴结转移潜能.随着肿瘤进展,CXCL12过表达率也随之升高.宫颈腺癌中慢性炎症细胞可能由其它趋化因子吸引所致,而非CXCL12.     

The CXCR4-CXCL12 axis in Ewing sarcoma: promotion of tumor growth rather than metastatic disease

Background

Chemokine receptor CXCR4, together with its ligand CXCL12, plays critical roles in cancer progression, including growth, metastasis and angiogenesis. Ewing sarcoma is a sarcoma with poor prognosis despite current therapies, particularly for patients with advanced-stage disease. Lungs and bone (marrow), organs of predilection for (primary/metastatic) Ewing sarcoma, represent predominant CXCL12 sources.

Methods

To gain insight into the role of the CXCR4-CXCL12 axis in Ewing sarcoma, CXCR4, CXCL12 and hypoxia-inducible factor-1α protein expression was studied in therapy-naïve and metastatic tumors by immunohistochemistry. CXCR4 function was assessed in vitro, by flow cytometry and proliferation/ cell viability assays, in the presence of recombinant CXCL12 and/or CXCR4-antagonist AMD3100 or under hypoxic conditions.

Results

Whereas CXCR4 was predominantly expressed by tumor cells, CXCL12 was observed in both tumor and stromal areas. Survival analysis revealed an (expression level-dependent) negative impact of CXCR4 expression (p?<?0.04). A role for the CXCR4-CXCL12 axis in Ewing sarcoma growth was suggested by our observations that i) CXCR4 expression correlated positively with tumor volume at diagnosis (p?=?0.013), ii) CXCL12 was present within the microenvironment of virtually all cases, iii) CXCL12 induced proliferation of CXCR4-positive Ewing sarcoma cell lines, which could be abrogated by AMD3100. CXCR4 expression was not correlated with occurrence of metastatic disease. Also, therapy-naïve tumors demonstrated higher CXCR4 expression as compared to metastases (p?=?0.027). Evaluation of in vivo hypoxia-inducible factor-1α expression and culture of cells under hypoxic conditions revealed no role for hypoxia in CXCR4 expression.

Conclusions

Together, our results imply a crucial role for the CXCR4-CXCL12 axis in auto- and/or paracrine growth stimulation. Integration of CXCR4-targeting strategies into first- and/or second-line treatment regimens may represent a promising treatment option for Ewing sarcoma.

     

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。     

Investigation of CXCR4 in squamous cell carcinoma of the tongue

Cancer metastasis is not a random process and different cancer types have favorite metastatic sites. Recent studies on metastasis have focused on chemoattraction, particularly on the role of chemokines. Therefore, in this study we investigated whether CXCR4 (receptor for stromal cell-derived factor-1) is expressed in squamous cell carcinoma of the tongue. For this purpose, immunohistochemical staining was performed on 26 sections obtained from 23 patients (15 patients having tongue tumor without lymph node metastasis and eight patients having lymph node metastasis). All tumor cells expressed CXCR4, whereas normal mucosa of the tongue had no or faint expression CXCR4. Metastatic tumor cells in lymph nodes had stronger expression than primary tongue tumor cells. Our data raises the possibility that CXCR4 could be involved in lymph node metastasis of oral squamous cell carcinoma.     

Clinicopathological and prognostic significance of chemokine receptor CXCR4 overexpression in patients with esophageal cancer: a meta-analysis

The prognostic significance of CXC chemokine receptor type 4 (CXCR4) for survival of patients with esophageal cancer remains controversial. To investigate its expression impact on clinicopathological features and survival outcome, a meta-analysis was performed. A comprehensive search in the PubMed, Embase, and Web of Science (up to October 8, 2013) was performed for relevant studies using multiple search strategies. Correlation between CXCR4 expression and clinicopathological features and overall survival (OS) was analyzed. A total of 1,055 patients with esophageal cancer from seven studies were included. The pooled odds ratios (ORs) which indicated CXCR4 expression was associated with tumor depth (OR?=?0.35, confidence interval (CI)?=?0.27–0.47, P?<?0.00001), status of lymph node (OR?=?0.36, CI?=?0.21–0.61, P?<?0.0002), TNM (tumor, node, metastasis) stage (OR?=?0.38, CI?=?0.25–0.56, P?<?0.00001), and histological type (OR?=?1.81, CI?=?1.07–3.05, P?=?0.03). Poor overall survival of esophageal cancer was found to be significantly related to CXCR4 overexpression (hazard ratio (HR) 1.49, 95 % CI?=?1.24–1.80, P?<?0.0001), whereas combined ORs exhibited that CXCR4 expression has no correlation with gender or tumor differentiation. Based on the published studies, CXCR4 overexpression in patients with esophageal cancer indicated worse survival outcome and was associated with common clinicopathological poor prognostic factors.     

CXCL12-CXCR4生物学轴与甲状腺乳头状癌淋巴结转移的相关性研究

探讨CXCL12-CXCR4生物学轴与甲状腺乳头状癌淋巴结转移的相关性。方法:采用半定量RT-PCR和免疫组织化学法分别检测72例新鲜甲状腺乳头状癌及淋巴结组织,52例甲状腺乳头状癌及淋巴结石蜡组织中CXCR4、CXCL12 mRNA及蛋白的表达。结果:甲状腺乳头状癌组织及转移灶组织中CXCR4 mRNA及蛋白高表达,淋巴结转移组的表达显著高于非转移组,差异有统计学意义（P<0.05）;颈部淋巴结组织中CXCL12 mRNA及蛋白均高表达,转移淋巴结及非转移淋巴结差异无统计学意义（P>0.05）。结论:CXCR4、CXCL12的表达与甲状腺乳头状癌淋巴结转移密切相关,推测CXCL12-CXCR4生物学轴在甲状腺乳头状癌转移的过程中发挥重要作用,CXCR4可作为抑制甲状腺乳头状癌转移的有效靶点。      

不同乳腺组织中肿瘤相关巨噬细胞与CXCL12表达的相关性

目的 探讨CXCL12表达和肿瘤相关巨噬细胞（TAMs）浸润在乳腺癌转移灶、乳腺癌原发灶及乳腺癌癌前病变中的相关性及其临床意义。方法 应用免疫组织化学法检测127例乳腺癌、71例乳腺癌转移灶、100例乳腺非典型导管增生、40例乳腺腺病组织中CXCL12的表达和TAMs的浸润情况。结果 CXCL12与TAMs在各组表达的阳性率分别为：乳腺腺病组为12.5%和7.5%,乳腺非典型导管增生组为39%和18%,乳腺癌原发灶组为63.8%和57.5%,乳腺癌转移灶组为78.9%和80.3%,CXCL12与TAMs在各组间表达水平的差异有统计学意义（P<0.001）,乳腺癌CXCL12与TAMs的表达分别与患者淋巴结转移、远处转移及临床TNM分期有关（P<0.05）,乳腺癌原发灶、乳腺癌转移灶TAMs浸润与CXCL12表达分别呈正相关（P<0.001）。结论 CXCL12与TAMs可能在乳腺癌的发生发展中发挥重要的协同作用,两者联合检测可作为乳腺癌患者淋巴结转移和远处转移的预测指标。     

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。     

胃癌组织中SNCG和CXCR4 mRNA的表达及临床意义

  目的  研究SNCG和CXCR4在胃癌和正常胃黏膜组织中的表达,探讨其在胃癌发生、发展、浸润转移中的作用。  方法  应用RT-PCR法检测不同组织中SNCG和CXCR4 mRNA的表达情况。  结果  SNCG和CXCR4 mRNA在胃癌组织中的表达量明显高于正常胃黏膜组织（P < 0.01）;胃癌组织中SNCG mRNA的表达量与癌组织的浸润深度和淋巴结转移有关（P < 0.05,P < 0.01）,CXCR4mRNA的表达量与淋巴结转移有关（P < 0.01）;胃癌组织中SNCG mRNA与CXCR4 mRNA的表达量呈正相关（r=0.346,P < 0.05）。  结论  SNCG和CXCR4在胃癌组织中高表达,可能与胃癌的发生、发展、浸润、转移密切相关。      

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.