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Western blot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。     

结直肠癌组织Fascin和CXCR4表达及其临床意义的探讨

目的:探讨骨架蛋白Fascin和趋化因子CXCR4在结直肠癌组织的表达及其与患者临床病理特征的关系。方法:采用免疫组织化学SP法,检测126例结直肠癌及20例正常黏膜组织Fascin和CXCR4的表达。结果:癌组织中,Fascin和CXCR4阳性率分别为47.62%和41.27%,正常黏膜阳性率均为15.00%,差异均有统计学意义,P值均<0.05。结直肠癌组织Fascin和CXCR4的表达与肿瘤组织学分级、临床Duke’s分期和淋巴结转移有关,P值均<0.05,CXCR4的表达还与肿瘤浸润深度有关,P<0.05。结直肠癌组织Fascin和CX-CR4表达水平呈正相关(r=0.411,P=0.002)。结论:结直肠癌组织Fascin和CXCR4的表达均高于正常黏膜组织,且呈正相关,Fascin和CXCR4可能在结直肠癌的浸润和转移中发挥一定作用,但其具体的分子机制尚待深入研究。     

结直肠癌组织趋化因子受体CXCR4表达及其与淋巴结和肝转移相关性的探讨

目的:研究趋化因子受体CXCR4在结直肠癌组织中的表达,探讨其与淋巴结、肝转移及预后的关系.方法:应用免疫组化方法(SP法)检测20例正常结直肠黏膜组织、64例结直肠癌组织、34例区域淋巴结转移癌组织以及18例肝转移组织CXCR4表达情况.同时应用逆转录聚合酶链反应(RT-PCR)检测其mRNA在4株大肠癌细胞株中的表达.结果:正常结直肠黏膜、结直肠癌、区域淋巴结转移癌以及肝转移组织中CXCR4阳性率分别为15.0%、51.6%、72.2%和73.5%;转移组织阳性表达率明显高于原发肿瘤.CX-CR4 mRNA高表达于2株人大肠癌细胞株.结直肠癌组织CXCR4阳性表达率与Duke临床分期、淋巴结转移和肝转移密切相关,P<0.05,而与患者年龄、性别、肿瘤所在部位及病理分化程度无关.CXCR4阳性表达组3年生存率明显低于阴性表达组,P<0.05.结论:CXCR4阳性表达与结肠直肠癌的淋巴结、肝转移有关,有助于预后判断.     

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。     

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。     

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.     

Galectin-3蛋白表达与结直肠腺癌临床病理特征的关系

目的:探讨结直肠腺癌组织中Galectin-3蛋白表达及其与临床病理参数的关系.方法:采用微波-EliVisionTM免疫组化染色方法检测60例结直肠腺癌组织中Galectin-3的表达情况并分析其与结直肠腺癌浸润转移等的关系.结果:Galectin-3阳性表达主要在细胞质.60例结直肠腺癌组织中Galectin-3蛋白阳性表达率为68.3%(41/60).在结直肠腺癌浆膜浸润、淋巴结转移和TNMⅢ+Ⅳ期中明显高于无浆膜浸润、无淋巴结转移及TNM Ⅰ+Ⅱ期(P<0.05),不同分化肿瘤之间也有显著差异(P<0.05).结论:Galectin-3蛋白的高表达与结直肠腺癌高侵袭能力、淋巴结转移等有一定相关性,可作为潜在预测大肠癌浸润转移的指标.     

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。     

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。      

结直肠腺癌组织中MMP2、ADAM17及E-cadherin的表达及临床意义

目的探讨基质金属蛋白酶2(MMP2)、AD AM金属肽酶域17(AD AM17)及E-钙黏蛋白(E-cadherin)在结直肠腺癌组织中的表达及临床意义。方法采用免疫组化PV-9000法检测120例结直肠腺癌组织、56例结直肠腺瘤组织和30例正常结直肠黏膜组织中MMP2、ADAM17及E-cadherin的表达情况,并分析其与结直肠腺癌患者临床特征的关系。结果结直肠腺癌组织中MMP2、ADAM17阳性表达率均高于结直肠腺瘤组织和正常结直肠黏膜组织,E-cadherin阳性表达率低于结直肠腺瘤组织及正常结直肠黏膜组织,差异均有统计学意义(P<0.05)。不同肿瘤直径、分化程度、TNM分期及有无淋巴结转移、浆膜浸润结直肠腺癌患者的结直肠腺癌组织中MMP2、ADAM17、E-cadherin阳性表达率比较,差异均有统计学意义(P<0.05)。结论MMP2、ADAM17及E-cadherin与结直肠腺癌的侵袭和转移有关,对结直肠腺癌的临床诊断、预后判断及个体化治疗具有重要意义。     

CXCR1 and CXCR2 enhances human melanoma tumourigenesis, growth and invasion

The aggressiveness of malignant melanoma is associated with differential expression of CXCL-8 and its receptors, CXCR1 and CXCR2. However, the precise functional role of these receptors in melanoma progression remains unclear. In this study, we investigate the precise functional role of CXCR1 and CXCR2 in melanoma progression. CXCR1 or CXCR2 were stably overexpressed in human melanoma cell lines, SBC-2 (non-tumourigenic) and A375P (low-tumourigenic) exhibiting low endogenous expression of receptors. Functional assays were performed to study the resulting changes in cell proliferation, motility and invasion, and in vivo tumour growth using a mouse xenograft model. Our data demonstrated that CXCR1- or CXCR2-overexpressing SBC-2 and A375P melanoma cells had enhanced proliferation, chemotaxis and invasiveness in vitro. Interestingly, CXCR1 or CXCR2 overexpression in SBC-2 cells induced tumourigenicity, and A375P cells significantly enhanced tumour growth as examined in vivo. Immunohistochemical analyses showed significantly increased tumour cell proliferation and microvessel density and reduced apoptosis in tumours generated from CXCR1- or CXCR2-overexpressing melanoma cells. CXCR1- or CXCR2-induced modulation of melanoma cell proliferation and migration was observed to be mediated through the activation of ERK1/2 phosphorylation. Together, these studies demonstrate that CXCR1 and CXCR2 play essential role in growth, survival, motility and invasion of human melanoma.     

Functional activity of CXCL8 receptors, CXCR1 and CXCR2, on human malignant melanoma progression

We examined the autocrine/paracrine role of interleukin-8 (CXCL8) and the functional significance of CXCL8 receptors, CXCR1 and CXCR2, in human malignant melanoma proliferation, migration, invasion and angiogenesis. We found that a panel of seven cell lines, even though at different extent, secreted CXCL8 protein, and expressed CXCR1 and CXCR2 independently from the CXCL8 expression, but depending on the oxygen level. In fact, hypoxic exposure increases the expression of CXCR1 and CXCR2. The cell proliferation of both M20 and A375SM lines, expressing similar levels of both CXCR1 and CXCR2 but secreting low and high amounts of CXCL8, respectively, was significantly enhanced by CXCL8 exposure and reduced by CXCL8, CXCR1 and CXCR2 neutralising antibodies, indicating the autocrine/paracrine role of CXCL8 in melanoma cell proliferation. Moreover, an increased invasion and migration in response to CXCL8 was observed in several cell lines, and a further enhancement evidenced under hypoxic conditions. A CXCL8-dependent in vivo vessel formation, evaluated through a matrigel assay, was also demonstrated. Furthermore, when neutralising antibodies against CXCR1 or CXCR2 were used, only the involvement of CXCR2, but not CXCR1 was observed on cell migration and invasion, while both receptors played a role in angiogenesis.In summary, our data demonstrate that CXCL8 induces cell proliferation and angiogenesis through both receptors and that CXCR2 plays an important role in regulating the CXCL8-mediated invasive and migratory behaviour of human melanoma cells. Thus, blocking the CXCL8 signalling axis promises an improvement for the therapy of cancer and, in particular, of metastatic melanoma.     

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。     

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.     

The chemokine receptors CXCR4 and CXCR3 in cancer

Chemokines comprise a superfamily of at least 46 cytokines that were initially described based on their ability to bind to 18 to 22 G protein-coupled receptors to induce the directed migration of leukocytes to sites of inflammation or injury. In addition to mediating cellular migration, chemokine/chemokine receptor pairs have been shown to affect many cellular functions, including survival, adhesion, invasion, and proliferation, and to regulate circulating chemokine levels. Most malignancies also express one or more chemokine receptors. Early studies established a role for CXCR4 and CXCR7 in mediating breast cancer metastasis, but other chemokine receptors, including CXCR3, now are implicated in several malignancies as biomarkers of tumor behavior as well as potential therapeutic targets. This review summarizes our current understanding regarding the contribution of CXCR4 and CXCR3 to tumor behavior and how receptor expression is regulated, transduces intracellular signals, and contributes at the molecular level to tumor behavior. It also describes recent therapeutic approaches that target these receptors or their ligands.     

Clinical significance of CXCR3 and CXCR4 expression in primary melanoma

Tumor cell migration involved in metastases is a tightly regulated, nonrandom process. Chemokines have been identified as critical molecules guiding cell migration. We performed a prospective study to analyze a possible association between the expression of chemokine receptors CXCR3 and CXCR4 by primary melanoma and clinical outcome. Forty primary melanomas were available for analysis; 57% of the tumors expressed CXCR3 and 35% expressed CXCR4 by melanoma cells. At initial diagnosis, 5 patients had subclinical lymph node involvement and after a median follow-up time of 32 months, 2 additional patients developed regional lymph node metastases and 5 patients developed distant metastases. The expression of CXCR4, but not CXCR3, by melanoma cells in primary lesions was significantly associated with the presence of ulceration, increased tumor thickness, a greater risk of developing regional and distant metastases and a higher mortality rate. Our study underscores the value of CXCR4 expression as a useful marker for predicting outcome in patients with localized melanoma. In addition, our findings support that, among chemokine receptors, CXCR4 might be an appropriate therapeutic target for adjuvant therapy in patients at risk for metastatic disease.     

The role of CXCR3 and CXCR4 in colorectal cancer metastasis

Chemokines and their receptors play key roles in leukocyte trafficking and are also implicated in cancer metastasis. We previously demonstrated that forced expression of CXCR3 promotes colon cancer metastasis preferentially to the draining lymph nodes (LNs), with poor prognosis. Using clinical colorectal cancer (CRC) samples, here, we show that expressions of CXCR3 and CXCR4 are significantly higher in metastatic foci within LNs and liver compared to primary tumors, whereas ligands for CXCR3 and CXCR4 are not. We also have demonstrated that some human CRC cell lines constitutively express both CXCR3 and CXCR4, and that activation of CXCR3 strengthens the CXCR4‐mediated cell migration in vitro in a synergistic manner. By constructing SW620 cell lines with reduced expression of CXCR3 and/or CXCR4 using microRNA, we investigated in vivo metastatic activities in a mouse rectal transplantation model. Six weeks after inoculation, CXCR3‐, CXCR4‐, and CXCR3/CXCR4 double‐knockdowns significantly reduced metastasis to LNs, liver and lungs, compared to the control (p < 0.05). Importantly, its suppressive effect on LN metastasis was significantly stronger in CXCR3‐ and CXCR3/CXCR4 double‐knockdowns. In addition, CXCR3‐ and CXCR3/CXCR4 double‐knockdowns significantly decreased the dissemination of cancer cells to liver and lungs, even after 2 weeks. These results indicate that targeting CXCR3 and CXCR4 can be a promising therapy against CRC metastasis.     

Opposing roles of CXCR4 and CXCR7 in breast cancer metastasis

Introduction  

CXCL12-CXCR4 signaling has been shown to play a role in breast cancer progression by enhancing tumor growth, angiogenesis, triggering cancer cell invasion in vitro, and guiding cancer cells to their sites of metastasis. However, CXCR7 also binds to CXCL12 and has been recently found to enhance lung and breast primary tumor growth, as well as metastasis formation. Our goal was to dissect the contributions of CXCR4 and CXCR7 to the different steps of metastasis - in vivo invasion, intravasation and metastasis formation.